Documente Academic
Documente Profesional
Documente Cultură
AS DIETARY
INTERVENTIONS
FOR LIVER AND
GASTROINTESTINAL
DISEASE
ACKNOWLEDGMENTS FOR BIOACTIVE FOODS IN
CHRONIC DISEASE STATES
The work of editorial assistant, Bethany L. Stevens and the Oxford-based Elsevier
staff in communicatin with authors, workin with the manuscri!ts and the !ublisher
was critical to the successful com!letion of the book and is much a!!reciated. Their
daily res!onses to "ueries, and collection of manuscri!ts and documents were
extremely hel!ful. #artial su!!ort for $s Stevens% work, raciously !rovided by the
&ational 'ealth (esearch )nstitute as !art of its mission to communicate to scientists
about bioactive foods and dietary su!!lements, was vital
*htt!+,,www.naturalhealthresearch.or-. This was !art of their efforts to educate
scientists and the lay !ublic on the health and economic benefits of nutrients in the
diet as well as su!!lements. $ari Stoddard and .nnabelle &une/ of the .ri/ona
'ealth Sciences library were instrumental in findin the authors and their addresses in
the early staes of the book%s !re!aration.
BIOACTIVE FOOD
AS DIETARY
INTERVENTIONS
FOR LIVER AND
GASTROINTESTINAL
DISEASE
Edited by
RONALD ROSS WATSON AND
VICTOR R. PREEDY
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PREFACE) LIVER AND GASTROINTESTINAL
HEALTH+ L)IE( .&5 H.ST(O)&TEST)&.L 'E.LT'
O!timum functionin of the liver and astrointestinal systems is critical for health.
They are critical for the diestion and absor!tion of nutrients and foods to !roduce
rowth. &utrient and non-nutrients are im!ortant modulators of the liver function. The
sym!-toms related to liver dysfunction include both !hysical sins and sym!toms of
abnormal absor!tion of fat, chanes in blood suar, and altered metabolism. This
book !rovides evidence that foods and their com!ounds can modify some of these
diseases. Ex!ert reviews are !rovided on liver function as !eo!le mature and
mechanisms of fatty liver as modified wild and bioactive foods for he!ato-!rotection
and diestion. The data su!!ortin actions of bioactive, and es!ecially 6hinese foods,
to !revent and treat liver diseases are defined by ex!erts. S!ecific individual foods
and herbs have shown s!ecific liver disease benefits includin+ betal leaf, selected
)ndian herbs, ooseberries, and curcu -min.&on-botanical materials in reviews show
!romise, includin !robiotics. )n definin mechanisms includin antioxidant ca!acity
of antocyanins, extracts of !omeranate and medicinal !lants as well as s!ecifically
their carotenoids show benefits in modifyin liver function in reviews.
#hytochemicals% involvement in liver and astrointestinal health is concisely defined.
$ore diverse information is !rovided about bioactive foods in the thera!y of
astro-intestinal diseases and functions, which are many and im!ortant in health. )n
this book the astrointestinal focuses on the stomach and intestine. )t releases
hormones that hel! re-ulate the diestive !rocess and is subGect to many diseases and
!roblems. .n overview reviews functional assessment of astrointestinal tract
function and alkaline in diestive health. (eviews enerally define the !rotective
effects of bioactive botanical foods. The human microbiome diseases are defined in a
metaenomic a!!roach. S!ecific classes and ty!es of foods are reviewed for selected
astrointestinal diseases. ?or exam!le, a cha!-ter defines the role of milk bacteria in
astrointestinal alleries. Then selected reviews of !rebiotics and !robiotics
documented their value in irritable bowel syndrome, mucosal immunity, and viral
infections. Their lactic acid and its stimulation of folate !roduction are reviewed as
mechanisms of !robiotic astrointestinal health. The actions of non-bioactive fiber on
bowel health are reviewed. Several additional reviews focus on !oly-saccharides from
soy sauce and fiber from a!!les, sources readily available to the !ublic. 5ietary fibers
and cholelithiasis are shown to be im!ortant in li!id lowerin. S!ecific small
molecules and defined substances are im!ortant in astrointestinal health. Omea 9
fatty acids are shown to be an interestin story of biotechnoloy leadin to health.
One review describes fatty acids in inflammatory bowel diseases. Black !lum has a
lon research history, which is summari/ed on its !hytochemicals in health, as do
bioactive !oly!henols on other mucosal diseases of the lun. )ndian !lants have a
historical a!!li-cation to health such as s!ices in treatment of ulcerative colitis.
Hiner and basil are reviewed as an ancient remedy, while another ex!ert ives an
overview of medicinal !lants in astrointestinal diseases. ?inally not all bioactive
materials are safe. Therefore the daners of herbal weiht loss su!!lements and
alcohol on astrointestinal functions are reviewed. Bioactive foods however, as
reviewed, a!!ear to have a role in !reventin the e!idemic on non-communicable
diseases. 6learly bioactive herbs, foods and their extracts can !lay key roles in liver
function and astrointestinal health.
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CHAPTER >
Th( A,ai$( Way i$ Di"(sti+( H(ath
R. 5a''(
'ealth Studies 6olleium, .shburn, I., 8S.
The biochemical conse"uences of diet are the reatest influence on overall
metabolism for most !atients. ?ood choices clearly affect the course of common
!atho!hysioloical errors such as insulin resistance, metabolic syndrome, and their
se"uella. 'owever, these dynamics can also be considered a leverae !oint M an
o!!ortunity to reverse immune reactivity throuh !ractical interventions that !atients
can im!lement in their daily lives.
>. DIETARY FACTORS IN METABOLISM
The intestinal tract !lays a key !art in nutrient absor!tion, immune defense aainst
for-ein invaders, !hysioloic re!air from wear and tear, rowth, neurohormone
reulation and stress manaement. 5isorders anywhere in the astrointestinal system
can affect the function of the entire body and overall health. 5iestive com!etence
tends to !redict survival and the ca!acity to thrive years to decades later.
>.>. Pr!'i() M(tab!i& A&i/!sis as a Ma1!r Ca#s( !' Chr!$i&
Dis(as(
Toxin accumulation in the body can result from a diet that !romotes metabolic
acidosis *net acid excess after metabolism- as shown by low levels of bufferin
minerals such as !otassium and manesium. . number of lare research studies
involvin thousands of !artici!ants have re!orted about the association between
metabolic acidosis and insulin resistance *:affe and $ani, 144DE Souto et al., 1422-,
ty!e 1 diabetes *:affe and $ani, 144DE Schul/e et al., 1449-, cardiometabolic risk
*$urakami et al., 144C-, coronary heart disease *Liu et al., 1444-, and osteo!orosis
*:affe and Brown, 1444E :ehle et al., 144D-, as well as cancer *Tavani et al., 1444-. .
ty!ical .merican diet !rovides insufficient minerals and fiber to counter or buffer the
buildu! of metabolic acids and to hel! dis!lacement of toxic wastes. .s a result,
alkaline cellular reserves within the body reduce and de!lete as the intracellular
environment becomes !roressively acidic, mineral de!leted and !roton rich *Lim,
144<E Neidel and Seifter, 23CD-.
1.1.1. Associated signs and symptoms
The sym!toms associated with metabolic acidosis include malaise and fatiue,
metabolic syndrome and diabetes, osteo!enia and osteo!orosis, and de!ression.
$etabolic acidosis is associated with a broad rane of clinical conditions in the body
because of the biochemical reduction of the !roton radient, u!on which cell enery
de!ends. The ratio of .T#+ .5# is a measure of cell enery. . ratio of 244+2 is
healthy. . ratio less than C4 beins to shift cells from an elective !rotective,
!roactive, and !revention mode to a sur-vival mode.
2.2.2.2. ?atiue
Low enery is the maGor com!laint that !atients re!ort to their !rimary care
!hysician. Enery !roduction and the ability to remove toxins safely are com!romised
when even minor increases in acidity occur. $etabolic acidosis has also been linked
to chronic fa-tiue immune dysfunction syndrome *:affe and Brown, 1444-.
?ibromyalia and chronic muscle !ain that is unres!onsive to !ain medication have
been documented to !roduce acidic end !roducts that directly irritate and inflame
nerve muscle end !lates *5euster and :affe, 233C-. ;e observe restoration of vitality
and "uality of life when metabolic acidosis is corrected com!rehensively usin
!redictive tests com!ared to best outcome reference ranes thus incor!oratin
!ersonali/ed biochemical individuality into !rimary care.
2.2.2.1. Osteo!enia and osteo!orosis
Excess acid within the cells is also a key factor in osteo!orosis *$aurer et al.,
1449-. One of the best exam!les of this metabolic sensitivity is the influence of acidM
alkali balance on skeletal structure, health, and interity. Skeletal muscles are the
larest storehouse of available minerals in the body and are thus ex"uisitely sensitive
to small chanes in !'. Even a 24R reduction in !' increases osteoclastic activity
while inhibitin osteo-blastic function, inducin am!lified bone mineral loss *:ehle et
al., 144D-. ?or the !ast 14 years, we have consistently observed 1M24R new bone
rowth confirmed by 5EO. scores after Gust 1 years.
1.1.2. Relevant evaluations
One of the most useful assessments in the manaement of metabolic acidosis is
self-testin for !', which can be !erformed sim!ly by the !atient in their home. .fter
D h of rest, we find the urine !' is e"uilibrated with the urinary tract cells. 6ostin
!ennies !er day, this is a useful self-care test that motivates better com!liance with
healthier choices. .nother assessment involves laboratory testin for reactive food
antiens. )n tandem, these tests can be !ivotal in correctin metabolic acidosis and
re!air deficits often called inflamma-tion and their myriad se"uellae.
2.2.1.2. Self-evaluation+ Testin for !'
The ha/ard of metabolic acidosis is that it re"uires additional minerals to buffer
and remove excess acids from the body, stri!!in out needed minerals with !otential
harm to the kidneys and urinary tract. The role of metabolic acidosis in chronic
kidney disease has been extensively documented *Sahni et al., 1424-.
Fi"#r( >.> #icture of !' stri!s.
Fi"#r( >.? )nter!retation of first, mornin-urine measurements.
. !' assessment of the first mornin urine !rovides a clinically useful measure of
met-abolic acidosis risk. The urine !' is a !redictive indicator of the body%s mineral
reserves, as well as acid,alkaline status *;hitin and Bell, 1441-. Ty!ically !'
balance is restored durin slee! and rest when excess acids are excreted *Shafiee et
al., 1441-. This ca!acity varies widely based on the s!ecific toxic load and the
individual%s ability to make enery, deactivate toxins, and excrete those toxins as
re!orted by Ba/hin *144<- *see ?iure 2.2, !' stri!s and ?iure 2.1, reference rane
for urine measurement-.
. value of <.4 indicates a neutral state, a balance of acid, and alkaline elements.
The first mornin urine !' oal of D.0M<.0 shows healthy mineral balance. &eutral or
low-level acid excess reflected in lower !' values indicates that metabolic chemistry
is a!!ro!riately alkaline and that the small amounts of metabolic acids built u! from
daily metabolism have been easily concentrated and excreted. 6ell cyto!lasm or Scell
Guice% functions in an ex"uisitely narrow, slihtly alkaline o!timum functional !'
rane *5e =oun, 2337E Neidel and Seifter, 23CD-.
@N*BERINGALaboratory evaluation+ (educin immune reactivity
)mmune res!onses directly and indirectly enerate substantial amounts of acidic
!roducts. ?or the at-risk individual with im!aired dietary bufferin ca!acity, it is
es!ecially im-!ortant to avoid immune reactions due to antien reactivity or other
causes that can contribute to additional cell acidity in the system *:affe et al., 144D-. .
lym!hocyte re-s!onse assay *L(.- can identify delayed alleric reactivity.
Substitution of immune re-active substances lowers acid loads.
>.>.B Clinical interventions: the alkaline way @ALIGNMENTA
(eduction of hy!eracidity in the body can be achieved throuh a nutrient-rich alkaline
diet, tareted su!!lementation with alkaline nutrients, and the inclusion of buffered
fats.
2.2.9.2 .lkaline diet
The .lkaline ;ay diet is a health-!romotin, fiber-rich diet that consists !rimarily
of whole foods based on individual food tolerances and sensitivities. #reference is
iven to locally, vine-ri!ened, oranic, or biodynamic sources of foods. $ineral-rich
water is the !referred beverae. (educin the net excess cell acidity su!!orts a rane
of health benefits.
>.>.B.>.> E$ha$&i$" i..#$( /('($s(s .lkalini/in foods im!rove immune de-
fense and re!air functions *Lee and Shen, 144C- by reducin host hos!itality to
chronic infections. This reduced infectious challene results in lower levels of
inflammation, more resources for anticancer surveillance, and enhanced re!air
ca!acity. 6linical strat-eies that accom!any an alkaline diet include a rotation or a
substitution diet to reduce ex!osure to reactive foods cou!led with health-!romotin
food choices, fresh fruits and veetables, !ulses and rasses, whole rains, minimal
animal !rotein, and a !roram of individuali/ed nutritional su!!lements to fully meet
biochemical needs.
>.>.B.>.? B#''(ri$" &(#ar &h(.istry@FONT SICEA .
metabolically alkaline diet means that food has a bufferin or cell acid neutrali/in
effect on in vivo cellular chemistry, in vivo *Budde and 6renshaw, 1449-. The effects
of s!ecific food res!onses within the body can differ from that food%s test tube
chemistry *Honick et al., 23DC-. ?or exam!le, citrus fruits are alkalini/in in the body
because citrate, malate, succinate, and fumarate all !ro-mote the eneration of more
than twice as much bicarbonate as the acid contributed from the total amount of food
metaboli/ed *Brown and Trivieri, 144D-. This means that citrus fruits and similar
foods are acidic in a test tube environment, yet alkaline formin in the body.
?iure 2.9 reflects this real-time !ers!ective on metabolism M assessin nutrition for
in vivo efficacy rather than merely evaluatin the ash residue of the food as has been
historically !erformed in nutrient assays. The foods listed here are cateori/ed based
Fi"#r( >.B ?ood and chemical effects on acidic,alkaline body chemical balance
on an em!irical formula calculated from the actual com!osition of the foods% total
!ro-tein, fat, carbohydrates, minerals, cofactors, and fiber contents *:affe, 23C<-.
2.2.9.1 .lkaline nutrients
. diet hih in acidic foods tends to be less-nutrient-dense and fiber-rich than an
alkaline formin, whole foods, immune tolerant diet. Once mineral de!letion occurs,
cells be-come !roressively more acidic and less eneretic. The cell cyto!lasm !roton
radient is re"uired for the cellular !ower centers, mitochondria, to work effectively.
;hen the cell becomes acidic, the !roton radient is reduced and cells become
de!endent on anaerobic TsurvivalU metabolism. This is a less efficient form of enery
!roduction. Lower enery !roduction shifts cells into minimal function survival mode
until ade"uate mineral buffers are restored.
>.>.B.?.> B#''(ri$" .i$(ras $inerals are re"uired to activate en/yme catalysts
within cellsE lack of s!ecific minerals has been linked to numerous s!ecific ty!es of
en/yme deficits. Su!!lementation at maintenance levels includes a healthy balance of
cal-cium and manesium, as well as co!!er and /inc, and all of the divalent cations
that !er-form essential bufferin minerals needed for healthy function. These minerals
are re"uired su!!lements for individuals sufferin from metabolic acidosis *also
known as net acid excess- because buffered minerals neutrali/e metabolic acids to
maintain healthy !' homeostasis inside the cell.
>.>.B.?.? B#''(ri$" 'ats Short-chain and medium-chain fatty acids with less
than 2D carbons such as octanoate and decanoate are alkalini/in. ?ound in !alm
kernel oil, coconut oil, and hee *clarified butter-, these short and medium chain fatty
acids can acce!t acetate molecules.
1.1.4 Individual essential nutritional supplementation
.dditional functional strateies in clinical manaement include the reduction of
oxida-tive stress, su!!ort of detoxification !rocesses *throuh healthy methylation-,
and reduc-tion of risks such as homocysteine. ;e find a healthier, least risk oal
value for homocysteine to be VD mol,l. ;ith a combined 14-fold risk difference
between a ho-mocysteine of V1D versus VD mol,l, healthier homocysteine levels are
a maGor clinical o!!ortunity.
2.2.7.2 .ntioxidants+ .scorbate to /inc
.scorbates are the !rinci!al antioxidants in eukaryotic cells. .s one of but three
s!ecies that are unable to convert lucose to ascorbate, !eo!le are vulnerable to
chronic as well as acute scurvy. .scorbates uni"uely set the cell redox
electrochemical !otential. .scorbates recycle and reenerate vitamins E, taurine,
lutathione, al!ha li!oic acid and can even salvae mitochondrial cytochromes.
6umulative antioxidant deficits become re!air deficits observed clinically as
inflammation, in turn is associated with metabolic acidosis. .ntioxidant su!!lements
are !rovided to !rotect aainst oxidative damae, restore cell enery !roduction,
rehabilitate mitochondria, and reset homeostatic mechanisms *:affe and Brown,
1444-. ;e suest a functional !ersonali/ed assessment of ascorbate need
*www.#E(W8E.com-.
2.2.7.1 B-com!lex vitamins to su!!ort methylation
)m!aired methylation is commonly reflected in elevations in homocysteine above
the healthy value of VD Xmol l
-2
. #roblems with cell communication, detoxification,
and trans!ort result from such im!aired methylation. This reframes these common
states in !hysioloic rather than !atholoic terms, and offers interative a!!roaches to
care as evidence-based o!tions to be included as first-line com!rehensive care.
'ealthy alkaline cell balance is clinically assessed throuh first, mornin-urine !'
measurements. .n increase in alkali-formin foods and su!!lements is recommended
in !ro!ortion to individual need to reach the healthy oal rane of D.0M<.0 for first,
mornin-urine !'. 'ealthy methylation and detoxification is reflected in a !lasma
homocysteine of less than D m dl
-2
. Other measures of detoxification such as
lucarate, merca!turate, and hi!!urate urine excretion are discussed elsewhere *:affe,
144D-. . slow, steady u!take of lucose by manain lycemic load is another
im!ortant as!ect of this a!!roach.
?. GLYCEMIC LOAD AS A TOOL FOR BETTER DIGESTIVE
AND CARDIOVASC*LAR MANAGEMENT
Sim!le carbohydrates are easily taken u! and cause a ra!id rise of lucose in the
blood-stream, which re"uires the release of insulin to return blood suar levels to a
safer level. Onoin stress on the lucoseMinsulinMenery reulatory system
fre"uently leads to hih insulin levels of less functional insulin. 6hronically elevated
insulin is associated with a series of se"uella with adverse lon-term health effects. )t
is increasinly a!!arent that !roress in treatin chronic illness re"uires effective
manaement of food lucoseMinsulin interaction. ;e suest the .lkaline ;ay to
im!rove insulin sensitivity throuh cor-rected metabolic acidosis, antioxidant, and
mineral deficits and enhanced toxin removal.
?.>. Ass!&iat(/ Si"$s a$/ Sy.3t!.s
The consum!tion of a hih suar, low fiber diet invites the continuum of weiht
ain, obesity, metabolic syndrome and diabetes. .ssociated risks include !oor lucose
manae-ment, with effects such as li!oenesis, loss of insulin sensitivity,
develo!ment of insulin resistance, and a wide rane of cardiovascular and systemic
conse"uences.
Fi"#r( >.D 6om!arison of lycemic res!onse between 244R native whey meal and
standard 04 carbohydrate load from bread and Gam.
?.?. S('%(+a#ati!$
Two tools useful in lycemic manaement by !atients include the lycemic index
and calculation of lycemic load.
2.2.1. Glycemic inde: !lder and less use"ul
The lycemic index measures the effects of carbohydrates on blood suar levels
*.tkinson et al., 144C-. . measure of 244 on the index reflects the ty!ical metabolic
res!onse to white suar *based on research-determined norms-. ?oods rated 00 or
below on the index are identified as healthful because they re"uire lower levels of
insulin, defined as Sinsulin-s!arin% *?oster-#owell et al., 1441-. ?ructose, certain
!rocessed foods as well as the si/e, com!lexity and constituents of a meal, can
!rovide conflictin lycemic index results.
2.2.2. Glycemic load: #ewer and more use"ul
The lycemic load is a better measure of the im!act of carbohydrate consum!tion.
)t takes the lycemic index into account, but !rovides a fuller !icture than the index
alone *$urakami et al., 144<-. Hlycemic load indicates how ra!idly a s!ecific
carbohydrate food raises blood suar and factors in the actual amount of the !articular
carbohydrate bein consumed *see ?iure 2.7 for an ideal lycemic res!onse to a low
lycemic load meal that includes 244R whey-. This is evident since the ex!erimental
meal was 1.0 times the basic carbohydrate load and still showed a small chane in
blood lucose. The contrast with the blood lucose chane with 04 carbohydrate
*bread B Gam- was dramatic.
This cha!ter focuses on cellular metabolic acidosis and lycemic load as key
clinical as!ects of the .lkaline ;ay. )mmune tolerance and delayed alleries are also
discussed.
?.B. I$t(r+($ti!$) L!0 t! M!/(rat( Gy&(.i& Di(t
Hlycemic manaement involves the reduction of refined food !roducts in the diet
M foods that trier the release of hih levels of insulin, resultin in li!oenesis and
weiht ain. By definition, these foods are hih on the lycemic index and have a
hih lycemic load *:enkins 1447E (iccardi et al., 144C-. ?oods containin a lare
!ro!ortion of sim!le carbo-hydrates include white flour and other refined rains,
white rice, white !otatoes, and corn, as well as cane suar, corn syru!, fructose,
honey, ma!le syru!, and other sweet-eners. The o!timal diet is hih in fresh fruits and
veetables, whole rains, and !rotein *5e &atale et al., 1443E :enkins, 1447E (iccardi
et al., 144C-. &ote that this is essentially a more alkaline diet, so that the two systems
can be used in tandem by both clinicians and consumers. ?or other reasons, we
suest a minimum non-caloric sweeteners.
B NATIVE WHEY%BASED MEALS AND
GASTROINTESTINAL HEALTH
(esearch suests that hih amounts of animal !rotein can cause undesirable
astrointes-tinal issues. Excessive amounts of !rotein from meat and fish have the
!otential to in-crease disease risk as hih as threefold in the develo!ment of
inflammatory bowel disease and ulcerative colitis *:antchou et al., 1424-. . lare
)talian study of more than 24444 individuals demonstrated a sinificant association
between meat intake and the develo!ment of cancer *Tavani et al., 1444-.
)n selectin o!timal !rotein sources, a "uality whey !rotein !rovides essential
amino acids, such as lutamine and cysteine, and fatty acids, such as conGuated
linoleic acid *BelobraGdic et al., 1449-. The hih cysteine content of whey has been
found a su!erior means of su!!ortin lutathione levels and, therefore, antioxidant
function, a findin re!orted by Bounous *1444-.
?or healthy lycemic control, a balance of all food rou!s is essential with an
em!hasis on nutrients from fiber-rich whole foods that maintain stable blood lucose
levels.
4 FOOD ALLERGIES AND SENSITIVITIES
)mmune res!onses to s!ecific foods, chemicals, or contaminants can take the form
of classic alleries or of delayed sensitivities. ?or decades, the conventional a!!roach
to allery focused on histamine immunolobulin E or )E reactions, which can trier
a harmless case of hives or life-threatenin ana!hylactic shock. 'owever, it is now
widely reconi/ed that reactivity can be driven by ty!e 2 alleries *ty!ical skin tests
or radioallerosorbent *(.ST- )E reac-tions-, or by ty!e 1 antibody
reaction*).,TH,or )$ reactive antibodies-, ty!e 9immune com!lexes, and ty!e 7+
T-cell mediated res!onses. )n contrast, hel!ful neutrali/in anti-bodies are often
misunderstood when conventional EL)S. or E). )H tests are done.
D.>. Ass!&iat(/ Si"$s a$/ Sy.3t!.s
Eihty !ercent of food reactions are not )E-ty!e reactions M rather, they are
delayed ty!es of reactions. (eactive antibodies can cause sym!toms that become
a!!arent from hours to weeks later, so that they are fre"uently difficult to identify.
Hiven the rane of !otential antiens and the various ty!es of res!onses, a
com!rehensive food assessment is vital. )E tests do not measure delayed reactions.
4.1.1. $he link %etween allergies and digestive competence
?ood intolerance and alleries result from im!aired diestion. .ll of the followin
issues ty!ically develo! before food alleries or intolerances occur+
Maldigestion results in !artially diested diestive remnants that are
reconi/ed as for-ein antiens M thus evokin immune res!onses to neutrali/e
the forein invader.
Infectious and noninfectious foreign antigens (partially digested food) invade
the astrointes-tinal mucosa,are treated e"ually as invasive antiens. This
means that with increased !resence of diestive remnants, the individual has
fewer immune defense and re!air resources to defend aainst infection or
re!air from daily wear and tear. This results in a loss of immune tolerance and
emerence of delayed hy!ersensitivities with a shift from homeostasis to self-
attackin immune res!onses. The .lkaline ;ay restores homeostasis and
tolerance by !ersonali/ed dianostics and includin thera!eutic monitorin to
assess how much of the healthy oal states have been achieved.
Fi"#r( >.E ;heel of immune res!onse mechanisms.
4.1.2 &actose intolerance
;ith this ty!e of functional im!airment, the en/yme that diests milk suar M
lactase M is either not !roduced or available in such low levels that milk cannot be
com!letely diested. This intolerance is almost always ac"uired as a by!roduct of
maldiestion and entero!athy.
4.1.' Gluten or casein intolerance or sensitivity
6asein is one of the maGor !roteins in milk. Hluten is a !rotein from rains like
wheat. Both are amon the most difficult foods to diest. )ntolerance to casein or
luten can occur when diestive ability is im!aired. 8!!er abdominal discomfort and
alternatin consti!ation and diarrhea sometimes accom!any this condition. ?unc-
tional hy!ochlorhydria, maldiestion, dysbiosis, and entero!athy are ty!ically the
underlyin causes.
Hluten intolerance results from maldiestion, food intolerance, or delayed alleric
hy-!ersensitivity. .dvanced ex vivo L(.s can be em!loyed to measure all delayed
allery !athways.
D.B. E+a#ati!$) LRA by ELISAFACT T(sts
Testin for delayed, ac"uired sensitivities focuses on the ty!e of functional
antibody and the s!ecific reactive allerens. Sensitivities reflect the variety of immune
reactions !resent *see ?iure 2.0-. Older technoloies, such as )H antibody assays,
have !roven at best only tem!orarily hel!ful in the treatment of chronic autoimmune
conditions. The tests do not distinuish hel!ful from harmful antibodies. &ewer
functional tests such as L(.s are recommended because they detect only the reactive
antibodies. These antibodies are in-dications of a burdened immune system. L(. lab
tests can measures reactions Gust as they occur in the body *ex vivo-. This ty!e of
functional testin tarets antibodies that cannot be distinuished by standard antibody
detection systems.
.ssessin delayed allery or hy!ersensitivity to foods or other chemicals !rovides
an Simmunoloic finer!rint% of the foods, chemicals, and medications to which the
indi-vidual is tolerant and those which their lym!hocytes react aainst. Tests such as
the L(. by EL)S.,.6T
T$
can sensitively, s!ecifically, and !redictively identify
underlyin causes of immune burdens and increased hos!itality to infection, as well
as accelerate de-enerative, chronic, and autoimmune conditions with less than 9R
variance day to day *:affe and >ruesi, 2331-. These tests have been em!loyed to
identify the e!ienetic bur-dens on a iven individual%s immune system. The causes
of autoimmunity are ty!ically !rovoked by ex!osures to s!ecific foods or chemicals
to which the !erson has ac"uired hy!ersensitivity. Substitutin other food choices for
reactive items and minimi/in chemical ex!osure, while evokin human healin
res!onses is !art of the .lkaline ;ay. ;ith over 04,444 cases in our database, we
suest this technoloy hel!ful in
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealth
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
Vita.i$s
Iitamin ., from mixed
natural carotenoids
includin beta carotene
which re"uires retinol
bindin !rotein and /inc
for trans!ort into cellsE
available as a s!ecific
su!!lement and in cod
liver oil
$aGor factor in the rowth
and healin of the
astrointestinal *H)- tract,
intestinal linin, and other
mucous membranes in the
bodyE !roduction of
!rotective mucus and S).
*the !rimary antibody
!rotectin the H) tract-E
antioxidantE antibacterialE
and antimicrobialE 5&.
synthesis
Beta carotene conversion
is reduced by intestinal
disease, diabetes,
hy!othyroidism, ex!osure
to toxic metals or
chemicals. Sym!toms
include inflammation and
slower healin, rouh skin
on elbows or underside of
forearms, reflux-like
sym!toms
Thiamine *B
2
- Builds red cellsE
antioxidant !rotectionE
mental focus
6onsti!ation and bloatinE
conitive chanes
(iboflavin *B
1
- Enery !roductionE
antioxidant activity
throuh lutathione
!roduction
.ltered iron metabolismE
maenta tonue
&iacin *B
9
- Lowers L5L cholesterol
and trilyceridesE reulates
ene ex!ression
6hronic diarrhea, cracked
li!s, and mental confusion
#antothenic acid *B
0
- .nti-inflammatory,
antiviral !ro!erties, and
wound-healin actionE
iven after abdominal
surery to restart bowel
motility
Sluish motility and
bloatinE headache,
fatiue, insomnia,
com!romised immune
defenses and re!air
#yridoxine *B
D
- .mino acid metabolism
and neurotransmitter
synthesisE reduces
homocysteine
)rritable Bowel Syndrome
*)BS-, hih blood suar,
and !rediabetesE
deficiencies can result in
lactose intolerance,
alleries, or internal
bleedinE incom!lete
conversion of amino acids
to neurotransmitters such
as serotonin, causin
de!ression or confusionE
macrocytic anemiaE reflux-
like sym!tomsE !eri!heral
neuro!athyE !otential liver
damae
Biotin *B
<
- Biosynthesis of fatty acids
and luconeoenesisE
5&. re!licationE
.ccelerated ain, hair
loss, brittle nailsE
accelerated rayinE
im!roves lucose muscle !ain
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealthYcontZd
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
tolerance and decreases
insulin resistance
)nositol *B
C
-
*hexa!hos!hate-
Essential for fat trans!ortE
feeds brain cells
HastritisE alo!ecia
?olate *B
3
and B
22
- M low
folate can be caused by
low levels of activated
thyroid *T
9
-, selenium, and
trace minerals and by
irritation in the u!!er
duodenum due to wheat or
luten sensitivity, low
intake of fruits and
veetables, a enetic
disorder that interferes
with folate absor!tion,
malabsor!tion, or
microsco!ic !arasitesE
restored in !art by
su!!lementin selenium
and folic acidE available in
activated sublinual form
as folinic acid or as
inGectable folateE must be
su!!lemented at the same
time as B
21
E acts in concert
with riboflavin, niacin,
vitamin 6, /inc, and serine
)nstrumental in healin the
H) tractE minimi/es
!eriodontal infectionsE
su!!orts immune functionE
!rotective aainst yeast
and !arasitic infectionsE
strenthens connective
tissueE key in methylation
and moderation of
homocysteine levelsE 5&.
synthesisE su!!ort of T cell
!roduction healin
!rocesses
5eficiency can be caused
by im!aired absor!tion
and leaky ut syndrome.
6an !lay a role in chronic
H) inflammationE bleedin
umsE reflux-like
sym!toms, sinusitis, or
fre"uent colds. Low levels
can result in hih
homocysteine. .nemia
resultin in weakness or
fatiue, de!ression, loss of
a!!etite, and weiht lossE
foretfulness, irritabilityE
sore red tonue. #otential
liver damae.
Betaine, trimethyllycine
*B
24
and B
20
-
Es!ecially !rotective,
lowerin homocysteine by
recyclin it into
methionineE !revents fatty
liverE characteri/ed by
hih trilyceridesE acts as a
diestive aid
#rotein maldiestion and
hih homocysteineE
!otential liver damae
'ydroxocobalamin *B21-
M essential nutrient in
metabolism, absorbed in
the ileum and reduced by
ileitis, celiac disease,
bacterial and !arasitic
infections, chronic )BS,
6rohn%s disease, low
intrinsic factor *enetic
disorder-, or a strict vean
dietE available in meats or
)nstrumental in healin the
H) tract and a source
material for com!etent H)
defensesE key factor in
methylation, lowerin
homocysteine levelsE
essential for en/yme
!roduction and enery
!roduction, 5&.
synthesis, and health of the
nervous system
5eficiency can be caused
by im!aired absor!tion
and leaky ut syndrome.
Sym!toms include
im!aired !rotein diestion,
diestive disorders, hih or
low stomach acid, !e!tic
ulcers, fatiue, or
weakness, bloatin,
diarrhea, or anemia.
.dditional sym!toms+
throuh sublinual numbness, tinlin of
hands and feetE !ernicious
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealthYcontZd
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
su!!lements or inGectionsE
must be su!!lemented at
the same time as folateE
acts in concert with
riboflavin, niacin, vitamin
6, /inc, and serine
anemia linked to
autoimmune conditionsE
smooth tonue, beet redE
!otential liver damaeE
!remature ain and a
form of irreversible
dementia
#ara amino ben/oic acid
*Bx-
$etabolism and utili/ation
of amino acidsE su!!orts
folates !roduction
)rritability, de!ression,
skin !roblems, ec/ema,
headaches, diestive
disorders, and hair
!rematurely ray
6holine as citrate )m!ortant in moderatin
homocysteine levels
5eficiency linked to hih
homocysteineE insomnia,
fatiueE in the extreme,
heart disease, liver and
kidney dysfunction
6holine citrate ;orks with inositol to
balance communication
between cells
)m!aired diestion of fatE
low acetylcholineE reduced
mental clarity
.scorbate *vitamin 6- as
buffered ascorbate
*calcium, manesium,
!otassium, /inc ascorbate-
6ontrollin inflammation
and immune resistance.
6ollaen and structural
!rotein formationE
antioxidantE lutathione
enhancedE
antihy!ertensiveE
detoxifyin aent for
heavy metals
)mmune su!!ressionE
inflamed and bleedin
ums, chronic H) infection
or inflammation,
es!ecially in the ut wallE
leaky ut, includin
bloatin, soreness,
malabsor!tion, toxicity,
delayed astric em!tyin,
and resultin free radical
damae
6holecalciferol *vitamin
5- M hormone adhesion
molecule
.nti-inflammatoryE
reulates calcium
homeostasis and
absor!tion, com!romisin
function of lands,
im!airin diestionE
su!!orts conitive healthE
vital in !roduction of
diestive en/ymes
)ncreased vulnerability to
infectionE im!aired mineral
metabolism, !articularly
calciumE com!romised
diestionE !oor blood
suar reulationE altered
bone and Goint healthE
diabetic conditions
Toco!herols and
tocotrienols *vitamins E-
#rimary backu! when
cellular antioxidants are
com!romised due to
inflammationE !rotects cell
membrane from oxidative
?at malabsor!tionE vitamin
E deficiency anemia in
infantsE !eri!heral
neuro!athy
damaeE antiatheroenic
and neuro!rotective
Su!!orts a!!ro!riate blood
clottin
5eficiencies rare, exce!t in
the case of heavy antibiotic
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealthYcontZd
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
Iitamin >, fat-soluble
nutrients !roduced in the
lare intestine
usae, malabsor!tion, or
maGor damae to the
intestines
C!'a&t!rs
6oen/yme W
24
.ntioxidantE
cardio!rotectiveE
neuro!rotective
#eriodontal diseaseE
im!aired .T# enery
!roductionE statin
medication ty!ically
reduces 6oW
24
by 04R.
Fatty A&i/s
Omea 9 essential fatty
acids, E#.,5'. M
available in fish oil and in
those able to convert it, in
flax oil
(esistance to infectionE
anti-inflammation effectsE
su!!orts cell hydration and
functionality, !reventin
brittle cell wallsE reulates
calcium metabolismE turns
on inflammatory and anti-
inflammatory defenses at
the cellular level throuh
!rostalandinsE lower
trilycerides. E#. has
antithrombotic effectsE
5'. is vital for normal
brain develo!ment and
function
)ncreased susce!tibility to
infection and
inflammationE increased
alleriesE sym!toms from
dry skin, rashes, and hair
loss to incontinenceE
deficiencies can result in
either consti!ation or
diarrheaE a factor in
inflamed nerves and
neuroloical disorders
Omea Ds M a source of
linoleic acid, which is the
basis for amma linoleic
acid
(eulate metabolismE
!romote the rowth of skin
and hairE !lay a role in
brain function
5eficiency M increased
susce!tibility to infectionE
thinnin hair and dry skin,
dandruff or ec/emaE !oor
concentration, learnin
disabilities
Excess M contribute to
inflammatory conditions
due to the buildu! of
arachidonic acid
Short-chain fatty acids
such as butyrate M found in
butter and creamE also
made from starches and
!roteins by diestive flora
The !referred fuel for cells
in the colon linin and
maGor factor in diestive
health
)ncreased risk of chronic
colitis and eventually
cancer
H.B. 6alms and stabili/es
nervous system
Loss of mental clarityE
more aberrant thouht
Mi$(ras
6alcium M as the !rinci!le
mineral in the teeth,
essential
Essential to muscle rowth
and function, includin
heart
5eficiency M unformed
stools, increased risk of
colon cancerE
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealthYcontZd
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
to mastication in order to
!re!are food for diestion
beatE transmission of nerve
im!ulses
weakened teeth and bones
Excess M muscle and
abdominal !ainE kidney
stones
6o!!er M trace mineral (educes hy!eracidityE
re"uired in various en/yme
!rocessesE assists in the
absor!tion of ironE
intracellular antioxidant
6an become deficient with
diet hih in sweets,
resultin in hy!eracidity,
indiestion and dys!e!siaE
astritis or ulcers
)ron M mineral (e"uired for the
!roduction of red blood
cells and the trans!ort of
oxyen to cellE resistance
to infectionE enery
!roduction
5eficiency Manemia
Excess M consti!ation,
abdominal cram!s, black
stools
$anesium M mineral Essential to a!!ro!riate
motility and in some cases,
an effective, inex!ensive
solution to chronic
consti!ation
6onsti!ationE reuritation
due to constriction of
lower eso!haus
$ananese M trace mineral 8seful in the treatment of
diestive disordersE
antioxidantE cofactor in
en/yme, lucose, and li!id
metabolism
5eficiency M a factor in the
develo!ment of diabetesE
the develo!ment of
myasthenia ravis *muscle
weakness- Excess M
hy!ertensionE sym!toms
resemblin #arkinson%s
Selenium as
selenomethionine M trace
minerals found in whole
rain breads and cereals
(educes hy!eracidityE
im!roves immune
resistance and healin of
all kinds of H) !roblemsE
su!!orts !roduction of
both folate and T9E
antioxidant
'y!eracidityE chronic
indiestionE increased risk
of astric cancer
Ninc M trace mineral #aired with vitamin .,
essential to the !roduction
of secretory ). *S).-,
the most !revalent
antibody that !rotects the
utE antioxidant
5eficiency M )ncreased
infection due to low S).
levels
Excess M hy!eracidity,
with indiestion and
dys!e!sia
A.i$! A&i/s
.mino acids M derived
from !rotein breakdownE
!rovide the basis of
Essential for effective
immune defensesE
intracellular antioxidant
To !erform antioxidant
functions, re"uires trace
minerals includin
!rotective antibodies selenium, /inc, co!!er, and
mananese
6arnitine M s!eciali/ed
amino !roduct, one of the
most
&ourish the H) tract and
ut lininE !rovide enery
to trans!ort micronutrients
into
6hronic bowel
irreularityE bloatinE
fatiue
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealthYcontZd
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
!revalent aminos in
diestive tract
the bloodstreamE su!!orts
mitochondria in
conversion of fats into
enery within the cell
6ysteine M amino acid
derived from methionine,
from sulfurous veetables,
and animal !roteins
)ntracellular antioxidant To !erform antioxidant
functions, re"uires trace
minerals includin
selenium, /inc, co!!er, and
mananese
Hlutathione M !e!tide
manufactured from lycine
*a form of lutamine-,
lutamic acid, and cysteine
found in sulfurous
veetables and animal
!rotein
The !rimary antioxidant in
the bodyE a maGor cellular
defenseE essential to
enery !roductionE
detoxification of
carcinoensE buildin
5&. and !roteins
6hronic fatiueE hemolytic
anemiaE metabolic acidosis
Hlycine M metabolic
by!roduct of lutamine,
nucleic acid !recursor
One of the most im!ortant
factors in ut healthE
detoxificationE synthesis of
bile acids, and of
lutathioneE construction
of (&. and 5&.
5eficiency M !oor enery
!roduction Excess M
fatiue #eo!le with kidney
or liver disease should not
consume
L-lutamine M the amino
acid most !revalent in the
diestive tractE recycled by
#yridoxal .l!ha
>etolutarate *#.>-
&ourish the diestive tract
and ut linin, which
enhances nourishment
throuhout the body
6hronic bowel
irreularityE bloatinE
fatiue
$ethionine M amino acid
derived from sulfurous
veetables and animal
!roteins, which is
converted to cysteine, a
!recursor of lutathione
#rotein synthesisE
methylation *a !rimary
form of
detoxificationwhich occurs
in every cell of the body-E
essential in the !roduction
of adrenaline and creatine,
as well as choline and
carnitine
Excess M ;ith the intake
of animal !rotein,
methionine is converted
into excess homocysteine.
6hronic levels of
homocysteine increase the
risk for all maGor
deenerative diseases
Taurine .ntioxidant, role in
detoxificationE im!roves
insulin resistance by
increasin the excretion of
cholesterol
'ih homocysteineE
reduced bile acidsE
allstones, abdominal !ain,
intolerance of fat
Hlucosamine and other
suar aminos M !recursor
in the synthesis of
lycosylated !roteins and
li!ids
Enhances defenses by
bindin to and dis!osin
of undesirable microbes
5eficiency occurs with
ainE dietary sources
often inade"uate
#robiotics and related
factors ?iber M ideally C4R
soluble fiber and 14R
insoluble fiber
Lower carbohydrate
content to food, and
therefore, lower weiht
ainE cleansin
Slowed stool motility
Tab( >.> $aGor &utrients &oted for Beneficial Effects in 5iestive
'ealthYcontZd
N#tri($t M(tab!i& '#$&ti!$ Sy.3t!.s !' /('i&i($&y
functionE !revention of
!athoen adherence to the
ut wallE im!roved
cholesterol levelsE vitamin
activationE im!roved
eliminationE toxin
reduction
#rebiotics M fibers, soluble
and insoluble, ?OS
*fructooliosaccharides-,
non absorbable
carbohydrates
Su!!ort the rowth of
flora and lactic acidE
!romote beneficial
fermentation, reducin
ammonia by!roducts
Beneficial when sins of
ammonia intoxication are
!resent, such as headache
and fatiueE ?OS not well
tolerated by those with
sensitivities or are lactose
or carbohydrate
intolerance
#robiotics M beneficial
flora
#roduction of nutrients
such as butyrateE
!rotection aainst
!athoensE !roduction of
diestive en/ymesE
reduction of li!id levelsE
metabolism of nutrients
such as folate
Source+ Haby .. &utritional $edicine. 'endler, S.S., (orvik, 5.$., 1444. #5(
for &utritional Su!!lements, second ed. Thomson (euters, &ew =orkE :affe, (., 1424.
The .lkaline ;ay+ )nterative manaement of autoimmune conditions. Townsend
Letter for 5octors and #atients. &ovember, !!. 77M02E Shils, $.E., Shils, $., (oss,
..6., 6aballero, B., 6ousins, (.:., 1440. $odern &utrition in 'ealth and 5isease,
tenth ed. Li!!incott ;illiams and ;ilkins, #hiladel!hia, #..
all conditions where immune tolerance is lost. This includes all autoimmune and most
chronic, deenerative ills.
D.B. I$t(r+($ti!$) Hy3!a(r"($i& Di(t
By avoidin offendin food and chemical substances, followin an alkalini/in
diet, and utili/in tareted su!!lementation, the body can stimulate healin and
induce re!air. This conce!t has been successfully tested in controlled outcome studies
on diabetes *:affe et al., 1447, 144D-, as well as fibromyalia and chronic fatiue
syndrome *5euster and :affe, 233C-. 6linical data indicate that other autoimmune
conditions re-s!ond to this a!!roach as well. The .kaline ;ay includes the
identification of acute and delayed food and chemical alleries and intolerances. This
allows for a diet that can be diested, assimilated, and eliminated efficiently, while
enhancin the individual%s vitality and homeostatic com!etence. $ental and !hysical
exercises are as im!ortant for astrointestinal health as they are for any oran system.
. hih-nutrient, low-toxicity diet in the context of a lifestyle of mindfulness and
ratitude rounds out the .lkaline ;ay to sustainable health.
E. THE ROLE OF SPECIFIC N*TRIENTS IN DIGESTIVE
HEALTH
;hen chronic diestive disorders are !resent, the use of nutritional
su!!lementation can im!rove clinical outcome. Thousands of research studies
evaluatin nutritional su!!le-ments have shown the benefits of s!ecific nutrients in
treatin a wide rane of com!lex conditions. The followin table !rovides a brief
overview of maGor nutrients that have been found to !lay an im!ortant role in
diestive disorders. Su!!lementation with stan-dardi/ed inredients makes it !ossible
to !rovide nutrients at a level that will su!!ort ac-tive metabolic function, while
im!rovin com!romised diestion and assimilation based on individual re"uirements
revealed throuh their functional, interative a!!roach *Table 2.2-.
.G CONCL*SION
The combined effects of individuali/ed dietary !rorams, su!!lementation
tareted to the s!ecific needs of the !atient and reduction of allerenic stimulation
offer the !rovider viable tools for conservative and effective clinical manaement of
cardiovascular condi-tions. )n this context, treatment stratey includes a detailed
history of health, lifestyle, and diet. Laboratory assessment, develo!ment of a case-
s!ecific treatment !lan that includes diet and nutritional su!!lements, and a lon-term
!lan to su!!ort !atient motivation and com!liance, reinforced by onoin carin and
com!etence.
REFERENCES
.tkinson, ?.S., ?oster-#owell, >., Brand-$iller, :.6., 144C. )nternational tables of
lycemic index and lycemic load values. 5iabetes 6are 92 *21-, 11C2M11C9.
Ba/hin, &., 144<. #roton radient enery in the catalytic .T# synthesis. (eaction
>inetics and 6atalysis Letters 34, 742M747.
BelobraGdic, 5.#., $c)ntosh, H.'., Owens, :..., 1449. ;hey !roteins !rotect
more than red meat aainst a/oxymethane induced .6? in ;istar rats. 6ancer Letters
23C, 79M02.
Bounous, H., 1444. ;hey !rotein concentrate *;#6- and lutathione modulation
in cancer treatment. .nticancer (esearch 14, 7<C0M7<31.
Brown, S.E., Trivieri :r., L., 144D. The .cid .lkaline ?ood Huide+ . Wuick
(eference to ?oods and Their Effect on !' Levels. S"uare One #ublishers, Harden
6ity #ark, &=.
Budde, (..., 6renshaw, T.5., 1449. 6hronic metabolic acid load induced by
chanes in dietary electrolyte balance increased chloride retention but did not
com!romise bone in rowin swine. :ournal of .nimal Science C2, 23<M14C.
5e &atale, 6., .nnu//i, H., Bo//etto, L., et al., 1443. Effects of a !lant-based
hih-carbohydrate,hih-fiber diet versus hih-monounsaturated fat,low-carbohydrate
diet on !ost!randial li!ids in ty!e 1 diabetic !atients. 5iabetes 6are 91, 12DCM12<9.
5e =oun, L., 2337. $ayo 6linic 5iet $anual+ . 'andbook of &utrition
#ractices, seventh ed. $osby, St. Louis, $O.
5euster, #..., :affe, (., 233C. . novel treatment for fibromyalia im!roves
clinical outcomes in a commu-nity based study. :ournal of $usculoskeletal #ain D,
299M273.
?oster-#owell, >., 'olt, S.'..., Brand-$iller, :.6., 1441. )nternational table of
lycemic index and lycemic load values. .merican :ournal of 6linical &utrition <D,
00M0D.
Honick, '.6., Holdber, H., $ulcare, 5., 23DC. (eexamination of the acid-ash
content of several diets. .merican :ournal of 6linical &utrition 12, C3CM349.
:affe, (., 144D. $anain toxic minerals, biocides, hormone mimics, solvents and
chemical disru!tors. )n+ >ohlstadt, )., *Ed.-, &utrition for $usculoskeletal 'ealth.
$arcel 5ekker,6(6 #ress, &ew =ork *6ha!ter 94-.
:affe, (., Brown, S., 1444. .cidMalkaline balance and its effect on bone health.
)nternational :ournal of )nterative $edicine 1, <M2C.
:affe, (., >ruesi, O., 2331. The biochemical immunoloy window+ a molecular
view of !sychiatric case manaement. :ournal of .!!lied &utrition 77, 1DM79.
:affe, (., $ani, :., 5eIane, :., $ani, '., 144D. Tolerance loss in diabetics+
association with forein antien ex!osure. 5iabetic $edicine 19, 317M310.
:affe, (., $ani, :., Trocki, T., $ehl-$adrona, L., 1447. ?irst line com!rehensive
care+ the diabetes continuum of insulin, lucose, enery dysreulation+ better clinical
manaement of causes im!roves outcomes, reduces risks and vascular com!lications.
Oriinal )nternist 22, 22M1<.
:antchou, #., $orois, S., 6lavel-6ha!elon, ?., Boutron-(uault, $.6., 6arbonnel,
?., 1424. .nimal !rotein intake and risk of inflammatory bowel disease+ the E9&
!ros!ective study. .merican :ournal of Hastroenteroloy 240, 1230M1142.
:ehle, S., Nanetti, .., $user, :., 'ulter, '.&., >ra!f, (., 144D. #artial
neutrali/ation of the acidoenic western diet with !otassium citrate increases bone
mass in !ostmeno!ausal women with osteo!enia. :ournal of the .merican Society of
&e!hroloy 2<, 9129M9111.
:enkins, 5.:., >endall, 6., $archie, .., .uustin, L., 1447. Too much suar, too
much carbohydrate, or Gust too much[ .merican :ournal of 6linical &utrition <3,
<22M<21.
Lee, $.$., Shen, :.$., 144C. 5ietary !atterns usin Traditional 6hinese $edicine
!rinci!les in e!idemi-oloical studies. .sia #acific :ournal of 6linical &utrition 2<
*Su!!l. 2-, <3MC2.
Lim, S., 144<. $etabolic acidosis. .cta $edica )ndonesiana 93, 270M204.
Liu, S., ;illett, ;.6., Stamfer, $.:., et al., 1444. . !ros!ective study of dietary
lycemic load, carbohydrate intake, and risk of coronary heart disease in women.
.merican :ournal of 6linical &utrition <2, 2700M27D2.
$aurer, $., (iesen, ;., $user, :., 'ulter, '.&., >ra!f, (., 1449. &eutrali/ation
of ;estern diet inhibits bone resor!tion inde!endently of > intake and reduces
cortisol secretion in humans. .merican :ournal of #hysioloy. (enal #hysioloy 1C7,
?91M?74.
$urakami, >., Sasaki, S., Okubo, '., et al., 144<. 5ietary fiber intake, dietary
lycemic index and load, and body mass index+ a cross-sectional study of 9392
:a!anese women aed 2CM14 years. Euro!ean :ournal of 6linical &utrition D2, 3CDM
330.
$urakami, >., Sasaki, S., Takahashi, =., 8enishi, >., 144C. :a!an dietetic
students% study for nutrition and biomarkers rou!. .ssociation between dietary acidM
base load and cardiometabolic risk factors in youn :a!anese women. British :ournal
of &utrition 244, D71MD02.
(iccardi, H., (ivellese, ...., Hiacco, (., 144C. (ole of lycemic index and
lycemic load in the healthy state, in !rediabetes, and in diabetes. .merican :ournal
of 6linical &utrition C<, 1D3SM1<7S.
Sahni, I., (osa, (.$., Battle, 5., 1424. #otential benefits of alkali thera!y to
!revent H?( loss+ time for a !alatable Ssolution% for the manaement of 6>5. >idney
)nternational <C, 24D0M24D<.
Schul/e, $.B., $anson, :.E., ;illett, ;.6., 'u, ?.B., 1449. #rocessed meat
intake and incidence of ty!e 1 diabetes in youner and middle-aed women.
5iabetoloia 7D, 27D0M27<9.
Shafiee, $..., >amel, >.S., 'al!erin, $.L..., 1441. 6once!tual a!!roach to the
!atient with metabolic acidosis a!!lication to a !atient with diabetic ketoacidosis.
&e!hron 31 *Su!!l. 2-, 7DM00.
Souto, H., 5ona!etry, 6., 6alvi\o, :., .deva, $.$., 1422. $etabolic acidosis-
induced insulin resistance and cardiovascular risk. $etabolic Syndrome and (elated
5isorders 3 *7-, 17<M109.
Tavani, .., La Iecchia, 6., Halus, S., et al., 1444. (ed meat intake and cancer
risk+ a study in )taly. )nternational :ournal of 6ancer CD, 710M71C.
;hitin, S.:., Bell, :., 1441. ?irst mornin urine measured with !' !a!er stri!s
reflects acid excretion. #roceedins of the .merican Society for Bone and $ineral
(esearch. .merican Society for Bone and $ineral (esearch, ;ashinton, 56.
Neidel, $.L., Silva, #., Seifter, :.L., 23CD. )ntracellular !' reulation and !roton
trans!ort by rabbit renal medullary collectin duct cells. (ole of !lasma membrane
!roton adenosine tri!hos!hatase. :ournal of 6linical )nvestiation << *2-, 229M214.
RELEVANT WEBSITES
htt!+,,www.'ealthstudiescolleium.or
htt!+,,www.EL)S..6T.com
htt!+,,www.#E(W8E.com
htt!+,,www.#E(W8E;heyHuard.com
htt!+,,www.ncbi.nlm.nih.ov,!ubmed
CHAPTER ?
F#$&ti!$a Ass(ss.($t !'
Gastr!i$t(sti$a H(ath
R. 5a''(
'ealth Studies 6olleium, .shburn, I., 8S.
5iestive illness is fre"uently a cause of or dis!osition to maldiestion-induced
autoim-mune conditions, as well as a factor in chronic deenerative disorders such as
cancer and cardiovascular diseases. ;orldwide, more than 2.0 million children die
each year from diarrheal diseases *8&)6E?,;'O, 1443-.
)n the 8nited >indom 5e!artment of 'ealth, diestive disorders affect one of
every three !eo!le and are associated with one of every four sureries *5o',
1441,1449-. )n the 8nited States, diestive health issues affect D4M<4 million !eo!le
at a direct annual cost of ]3<.C billion *Everhart, 144C-. The association between
diestive disorders and health issues is reflected in conditions such as acute and
delayed alleries, insulin resis-tance, and metabolic syndrome, as well as diabetes, an
avoidable, costly, too common conse"uence. ?urthermore, ut malfunction and
!athoen overrowth are the common underlyin factors in numerous other chronic
conditions, as discussed below.
>. PHYSIOLOGY OF DIGESTION
5iestion is a series of so!histicated metabolic !rocesses that convert !lant
carbohydrates, !roteins, fats, and other nutrients into buildin blocks that the body
can utili/e for nour-ishment, rowth, and re!air when toxin load and stress hormones
!ermit. 'ealthy dies-tion !roduces molecular buildin blocks that su!!ort immune
system tolerance and enable !roactive re!air. $ulti!le mechanisms exclude tra! and
neutrali/e larer mole-cules that can be bioactive and sometimes immunoenic. ;ith
cumulative stress, toxin ex!osure and nutritional deficits, maldiestion re!laces
eudiestion. The erosion of di-estive defenses and the shift of immune res!onses
from tolerant to hy!er-reactive is a molecular ex!ression of what !eo!le feel when
they are chronically unwell althouh somewhat functional. )n the 23D4s, my
astroenteroloy !rofessors were alarmed at the ra!idly risin e!idemic of e!idemics
related to the many ex!ressions and comorbid-ities of maldiestion. 5iestive
metabolism involves chemical and mechanical functions that break down food so it
can be assimilated, utili/ed, and eliminated efficiently, safely, and effectively.
Essential nutrients released or manufactured by the body durin this !rocess must be
derived in sufficient amounts to meet individual enetic, e!ienetic, and sustainability
needs for the body to row, heal, and function well.
5iestion beins with the initial visual and ustatory contacts with food that tell
the brain and then the body which diestive Guices to secrete. The !rocess of seein
the food to be eaten, tastin it, and smellin the aromas stimulates the release of saliva
containin s!ecific en/ymes such as li!ase *which beins the !rocessin of fats- and
amylase *which o!ens u! and beins breakin down carbohydrates-. This favors the
locavore, Sslow food% a!!roach.
The stomach exerts remarkable com!etence in mechanically churnin diverse
food mixtures. This !rocess breaks u! and acidifies the stomach contents *to create a
mixture termed chyme-, while addin the diestive en/yme !e!sin to the stomach%s
contents. This ex!oses food molecules to en/ymes and hydrochloric acid that hydrate,
cleanse, and !rocess carbohydrates and !rotein-rich foods. The resultin !rediested
chyme, the consistency of oatmeal, is !assed from the stomach to the small intestine.
;hen suf-ficient hydrochloric acid is !resent, biosensors are triered to em!ty
contents into the duodenum. )f the chime is sufficiently acidified, bicarbonate and
!ancreatic diestive en-/ymes are then released. .de"uate stomach acid is essential
for healthy diestion. Block-in stomach acid !roduction dis!oses one to
maldiestion and its !ervasive conse"uences.
5iestion occu!ies D4R of the body%s enery !roduction and its consum!tion is
devoted to diestin food. )f the 14^24 ft of intestines were unfolded to create a flat
surface, the intestinal membrane surface covers an area the si/e of a tennis court, a re-
markable 1044 ft
1
or 1D4 m
1
of surface area.
?. CLINICAL ISS*ES IN DIGESTIVE HEALTH
The issues reviewed in this cha!ter im!act or are comorbidities for numerous
chronic health issues. .!!roximately a third of the astrointestinal *H)- com!laints
seen are truly disablin, whereas 1,9rds are a !art of an underlyin chronic issue. ;e
will also see how livin the .lkaline ;ay_ restores diestive health.
?.>. Pr!'i() Dysbi!sis
'ealthy flora are a maGor, increasinly a!!reciated as!ect of health. The contents
of the healthy human diestive tract ty!ically contain at least 2C44 different s!ecies of
flora that in total number in the trillions. The !resence of infection by a forein
!athoen or the overrowth of any resident s!ecies is termed dysbiosis, which can
result in !oor health and a rane of nondescri!t sym!toms *6ani and 5el/enne, 1424-.
Beneficial microflora minimi/e this ty!e of imbalance. 'ealthy bus in abundance
crowd out bad bus. #ath-oenic oranisms do not ive out their toxins until crowd
sinalin confirms that they are !resent in hih density.
2.1.1. Associated signs and symptoms
)n a healthy human body, there are ty!ically five to seven !ounds of bacteria, of
which more than 30R are anaerobes. .ntibiotic thera!y has been found to destroy
both harmful and beneficial bacteria in the body *6harteris et al., 233C-. ;hen healthy
flora is absent, food decom!osition is slowed or incom!lete, im!airin diestion and
reducin the level of nutrients available for absor!tion. Sym!toms and dianoses
associated with com!ro-mised flora and dysbiosis include diarrhea, consti!ation,
urinary tract infections, irritable bowel syndrome *)BS-, irritable bowel disease *)B5-,
6rohn%s disease, and even diabetes *Iaarala et al., 144C-. 5iestive health !rotects
and !romotes health. 5iestive ill health is a comorbidity in almost all autoimmune,
chronic, and deenerative illnesses.
2.1.2. (tiology
$ulti!le courses of antibiotics favor !athoenic bacterial overrowth *Es!osito et
al., 144<E $aGewski and $c6allum, 144<-, such as Clostridium difficile, and yeast
overrowth, such as the 6andida s!ecies. )n some cases, this !romotes antibiotic-
resistant strains of bac-teria or other !athoens to which the individual is ex!osed and
vulnerable. . diet hih in suars, milk, or meat !roducts can also result in the
overrowth of various bacterial s!ecies with adverse effects on health *:antchou et al.,
1424-. 'arder to diest foods like cow dairy and rains become sources of diestive
intolerance.
1.2.1.2. Sidebar+ initial !robiotic research
)n 234C, &obel !ri/e-winnin scientist Elie $etchnikoff of the #asteur )nstitute in
#aris !rovided the first evidence that microoranisms may be res!onsible for the
health-!romotin effects of fermented milks. .fter observin that Bularian !easants
live to ri!e old aes, $etchnikoff became convinced that their health and lonevity
were linked to the beneficial microbes in the cultured milk they drank co!iously. )n
his book, The Pro-longation of Life, $etchnikoff suests that disease-causin
bacteria were minimi/ed or elim-inated by inestin lare amounts of Bularian kefir
or yourt, which contained beneficial bacteria later identified as Lactobacillus
bulgaricus. These oranisms are members of the bacterial s!ecies Lactobacillus M
bacteria that !roduce lactic acid. ifidobacter and !treptococcus thermophilus are
other maGor beneficial !robiotic oranisms. ;e recommend 74M244 billion !robiotic
oranisms taken daily between fermented foods and bioactive su!!lements.
?.>.B. I$t(r+($ti!$) 3r!bi!ti& s#33(.($tati!$
(estoration of a healthy level of ut microflora hel!s !romote the balance toward
healthy and away from harmful microoranisms.
1.2.9.2 Benefits of microflora
Beneficial microflora !rovide a sur!risinly extensive rane of !rotective
functions in the body. #robiotic oranisms decom!ose food in both the small and
lare intestines to liberate nutrients to be assimilated and utili/ed for enery and
re!air.
?.>.B.>.>. @FONT SICEAPr!/#&ti!$ !' /i"(sti+( ($-y.(s by .i&r!'!ra
#robiotic bacteria normally found in a healthy ut su!!ort the !roduction of essential
en/ymes, which in-creases the availability of nutrients as food is more efficiently and
com!letely broken down *6ha!man et al., 1422-. ?or exam!le, the en/yme lactase,
!roduced by lactic acid bacteria, im!roves diestion, metabolism, and absor!tion of
milk suar *lactose-. 'eyman *1444- found that these bacteria also facilitate the action
of intestinal lactase, im!rovin overall diestion by reducin sym!toms such as
diarrhea.
?.>.B.>.?. R(/#&(/ i3i/ (+(s . variety of studies have shown that healthy !ro-
biotics at ade"uate levels can im!rove overall health, increasin metabolic breakdown
of certain li!id or li!o!hilic substances and reducin toxins, bindin toxins to
!rebiotic fiber that are contained in bile *Iaarala, 144C-. This is im!ortant, for
exam!le, in fat emulsification that occurs in the u!!er area of the small intestine
*duodenum-, where fats are mixed with bile durin diestion. )m!roved li!id
metabolism also reduces the reu!take of cholesterol and fatty acid !roducts, and this
has been associated with a 0M2<R reduction in serum cholesterol after Gust 2 month of
daily consum!tion of viable !robiotic oranisms in the 24M14 billion oranism,day
*colony-formin units, 6?8- rane *:ackson et al., 2333-.
?.>.B.>.B. I$hibiti!$ !' 3ath!"($s One of the maGor beneficial effects of
!robioticsis the su!!ression of harmful microoranisms *?uller and Hibson, 233<-.
;hen the mi-croflora are sinificantly de!leted, there is heihtened risk for intestinal
conditions such as viral astroenteritis *Biller et al., 2330-. (esearch by 6am!ieri and
Hionchetti *2333- suests that when there are sufficient numbers of healthy
!robiotics in the ut, the risk of inflammatory bowel disease,syndrome *)B5,)BS-, is
substantially reduced. 6onditions such as )B5 and )BS, ulcerative colitis, and reional
enteritis *6am!ieri and Hionchetti, 2333- have been reversed in individuals who have
develo!ed these sym!toms throuh the use of !robiotics as !art of com!rehensive
care. (ecent research also re!orts !robiotic mixtures beneficial in the treatment of
diarrhea, ut microbiota modulation, and "elico-bacter pylori infection, as well as
ato!ic disease and res!iratory tract infections *6ha!man et al., 1422-. )n our
ex!erience, an ounce of !rebiotic and !robiotic su!!lementation is worth a !ound of
diestive diseases cures.
1.2.9.1. #robiotic dosae
;hen flora are killed off by takin antibiotics, or from xenotoxins or distress,
beneficial bacteria levels can be restored with !robiotic su!!lements. 6urrent clinical
recommen-dations suest a maintenance intake of 24M04 billion bacteria daily from
a variety of mixed cultures. ;e !refer multi!le strains of human im!lantable
acido!hilus, bifidobac-ter, and healthy !# thermophilus.
?.>.B.?.>. Pr(+($ti+( a33i&ati!$s ;hen one is travelin, under stress, or recov-
erin from illness or disease, or !ost antibiotic consum!tion, the ideal dosae is a
!robiotic culture that contains 14M244 billion viable !robiotic oranisms consumed
daily for 1M9 months to restore diestive com!etence. #roducts are currently available
on the market that !rovide as many as 144 billion count in a sinle dose.
?.>.B.?.?. Th(ra3(#ti& i$t(r+($ti!$s #robiotics are recommended in cases of
bac-terial and yeast infection or overrowth *Hionchetta and 6am!ieri, 1444-. To
address these forms of dysbiosis, many researchers now advocate antibiotic,!robiotic
combina-tions of 14M144 billion 6?8 mixed flora for conditions such as consti!ation,
diarrhea, urinary tract infections, and infective endocarditis *6harteris et al., 233C-.
?.>.B.?.B. M(/i&a 3r!bi!ti&s #robiotics harvested in the lo !hase for o!timum
rowth and viability of 6?8 are recommended. $ulti!le strains, ty!ically containin
nine to ten different strains, are more effective in re!o!ulatin the ut. The level of
su!-!lementation is based on the severity of the !atient condition, their res!onse, and
other factors determined by the !hysician. Ty!ical re!lenishment needs are intakes of
14M244 billion oranisms,day for 1M9 monthsE 0M24 billion !er day for maintenance.
?.?. Pr!'i() Hy3(r3(r.iabiity @L(a,y G#t Sy$/r!.(A
. condition described as intestinal !ermeability or Sleaky ut% results whenever
the linin of the small intestine leaks its contents into the intestinal lym!hatics and
then the blood-stream *Solly et al., 1442-. ;hen the body is under stress or in shock
or nutritional deficit, !ores that line the H) tract o!en wide and release metabolic and
microbial toxins from the ut. These toxins are then !assed on to the liver *6ariello et
al., 1424-, the lym!hatic system, the bloodstream, and the immune system and
distributed throuhout the body and vasculatures. Leakae from the ut can also occur
in conditions such as 6rohn%s dis-ease, with the deterioration of tissue in the intestinal
wall. )ntestinal surfaces are also sus-ce!tible to erosion from mechanical action,
toxins, and the !roducts of !athoenic bacteria.
2.2.1. Associated signs and symptoms
Leaky ut is im!licated in chronic conditions with a broad rane of clinical
sym!toms *Liu et al., 1440-Emany include a direct inflammatory com!onent such as
)BS, or toxic reactions, such as certain ty!es of miraines. Leaky ut has also been
im!licated in both Ty!e 2 and Ty!e 1 diabetes *Secondulfo et al., 2333E Iisser et al.,
1443-.'y!er!ermeability is also im-!licated in skin conditions due to inflammation
*reconi/ed as re!air deficit- and may reflect the intake of foods that induce delayed
alleric reactions !resentin as ec/ema, !soriasis or any other autoimmune condition.
;hen diestion is incom!lete, diestive remnants accumulate in the H) tract and
increase inflammation *re!air deficit-. This cause atro!hy and subse-"uently
entero!athy.
Leaky ut also occurs whenever the body oes into shock in res!onse to inGury,
surery, or severe illness.
'y!er!ermeability can result from any number of insults to the body+
.lcohol abuse
?ood !oisonin, !arasitic infections, bacterial overrowth
?ull rane of H) conditions, includin astritis, colitis, and 6rohn%s disease
Eatin disorders *!articularly anorexia-
Shock, trauma, burns, or surery
6ancer and chemothera!y
6hronic he!atitis, !ancreatitis
&S.)5S and certain other medications
(heumatoid arthritis
Oenotoxins * toxic metals, !ersistent oranic !ollutants, solvents, endocrine
disru!tors-
5istress
;hen the immune system detects oversi/ed food molecules in the bloodstream,
these molecules are tareted as forein Sinvaders%. This results in one or more delayed
immune reaction that release !owerful and !otentially damain cytokines and other
am!lifiers.
2.2.2 Intervention: recycled glutamine supplementation
Leaky ut syndrome and damaed mucosa are usually associated with lutamine
defi-ciency. These conditions have been reversed throuh lutamine su!!lementation
*Byrne et al., 2330-. Hlutamine and butyrate are the !rinci!al fuels that eneri/e the
in-testinal linin cells. Henerally s!eakin, diestion and normal metabolic function
of the intestines are de!endent on ade"uate amounts of lutamine, abundant in health
and conditionally essential with res!ect to stress. The effects of lutamine have also
shown to maintain the interity of the ut barrier structure and decrease intestinal cell
wall dam-ae *;u et al., 144D-.
Throuh the action of lutamine on the kidneys, the body controls !' balance and
eliminates acids. (esearch indicates that lutamine can effectively enhance bowel
func-tion in !eo!le with short bowel syndrome and other H) conditions involvin
extensive intestinal surery, includin trans!lantation *Byrne et al., 2330-. #rovidin
L-lutamine and !yridoxal-al!ha-ketolutarate in combination !rovides clinically an
enhancement of lutamine u!take !resumably throuh recyclin. This a!!roach
allows full lutamine dosin without the risk of lutamate buildu!.
?.B. Pr!'i() A(r"i& R(a&ti!$s as a Ca#s( a$/ E''(&t !'
L(a,y G#t
(esearch and clinical ex!erience indicate that alleries and intestinal
hy!er!ermeability are linked *=amauchi et al., 144D-. )n an ae of increasinly
!ersonali/ed medicine, L(. by EL)S.,.6T tests !rovide insiht into individual
ac"uired delayed or late !hase alleries. 6om!rehensive !rorams have been tested
and found to sinificantly im!rove outcomes *:affe, 233C, 144D-. Either of these
conditions can serve as a cause or an effect. ;hile it may be useful to identify the
initial cause, such as luten sensitivity, in !ractical clinical terms, it is not always
!ossible to determine which factor is the cause and which is
Fi"#r( ?.> Lym!hocyte res!onse assays.
the effect. 6onse"uently, it is enerally advisable to treat both conditions at the same
time.
2.'.1. )yperpermea%ility as a cause o" reactivity
The likelihood of develo!in antien reactivity and food sensitivities is
exce!tionally hih in anyone already ex!eriencin leaky ut from any cause. )n the
case of food reac-tions, C4R of food reactions are not )E-ty!e reactions. (ather, they
are delayed reactions caused by )., )H, or )$. 6onse"uently, a com!rehensive
food assessment is vital, iven the fre"uency of delayed reaction. .n )E screen alone
will not usually !ick u! delayed reactions *?iure 1.2-.
2.'.2. Allergies as a cause o" hyperpermea%ility
6onsum!tion of antienically reactive foods can trier hy!er!ermeability, often
within a matter of minutes. )n addition, it is common for !atients to consume more
than one reactive foods in their daily diet. This causes a constant state of antienic
stimulation and burdens immune res!onses. 6hronic inflammation and immune
reactivity occurs when immune tolerance is lost. Leaky ut has been associated with a
wide rane of chronic disorders, e.., arthritis * Goint and connective tissue disorders-,
asthma, ec/ema, !soriasis, vascular diseases and diabetes, as well as anxiety,
de!ression, learnin disabilities, and some dementias. To manae these conditions
effectively, it is essential to address the relationshi! between delayed food alleries,
nutritional distress, and leaky ut.
?.D. Pr!'i() Ma/i"(sti!$ a$/ E$t(r!3athy
$aldiestion is one of the undera!!reciated causes of illness that is increasinly
common in industrial society. The causes are elusive because of the lon la from
antien ex!osure to sym!tomatic ex!ression.
2.4.1. Comor%idities
#revalent sym!toms of im!aired or incom!lete diestion include weiht
manaement issues, adult failure to thrive, lack of restorative slee!, skin disorders,
and alleries. )m-!aired diestive function can result from any number of functional
disorders, includin low levels of essential stomach acid *hy!ochlorhydria-,
insufficient !ancreatic diestive en/ymes, and bile salt deficiency. 5isorders of the
liver, kidneys, and !ancreas can all result from, or contribute to, maldiestion.
2.4.2. Cause and Conse*uences
1.7.1.2. Low en/yme levels
;hen !ancreatic en/yme levels decrease, the cause is usually functional
hy!ochlorhydria. Sym!toms such as bloatin, heartburn, consti!ation, diarrhea,
insomnia, muscle aches, !ain, and skin conditions that occur when the skin is used as
an accessory ouster of ex-cretes. 6ausal factors include an abundance of !rocessed
food in the diet and overuse of medications such as antibiotics and !ainkillers.
En/yme insufficiencies can be caused by enetic conditions or low levels of
!robio-tics, which result in a lack of the en/ymes needed for diestion. Two !otential
solutions include the su!!lementation of !robiotics *described in the section S#rofile+
$aldiestion and Entero!athy%- and en/ymes *5omPnue/-$u\o/ et al., 1440-. ;e
find im!lantable !robiotics, un!rocessed dietary fiber a whole food-based
immunocom!atible diet to re-store diestive and detox com!etence that in turn
restores neuro-hormonal balance of the immune system.
1.7.1.1. #oorly timed astric em!tyin
Early or delayed astric em!tyin are additional sins of incom!lete diestion.
These dis-turbances in the naturally orchestrated !rocesses of diestion com!romise
the nutrition available to the body *see the Section S#rofile+ $aldiestion and
Entero!athy% for a dis-cussion of interventions-.
1.7.1.9. Surical restructurin of the H) tract
Surery can induce maldiestion if !ortions of the lare or small bowel are
removed or if the stomach is reconstructed. )n some cases, these structural chanes
are deliberate, for exam!le, in cases of bariatric weiht loss in which surery is
intended to limit diestion. .ll metabolic manaement a!!roaches should be
!erformed before surery is evaluated.
1.7.1.7. $alabsor!tion
6hronically !oor diestion can lead to malabsor!tion. The individual does not
obtain sufficient nutrients from the diet and therefore ex!eriences health !roblems as
a result. )ncrease in intake of !rebiotics *74M244 ,day- and re!lenishment of
!robiotics *74M 244 billion,day- and essential nutrients for healthy diestion, such as
recycled lutamine, is recommended.
1.7.1.0. Entero!athy
Loss of diestive com!etence can occur as a result of atro!hy, a lack of essential
nutrients, or excess toxins such as heavy metals, biocides, and hormone disru!ters.
(e!air nutrients described above are recommended for a year or two it ty!ically takes
to restore and re-build diestive com!etence after entero!athy.
?.E. Tra$sit Ti.(
The s!eed at which diested food moves throuh the H) tract is described as the
transit time. This time is the interval between food consum!tion and the elimination
of diested waste.
2.+.1. Associated signs and symptoms
. number of factors affect transit time, includin diarrhea, consti!ation, and
metabolic toxicity. Even with different sections of the H) tract, the time re"uired for
food to move throuh the diestive !rocess is sinificantly affected by the
com!osition of the meal !ass-in throuh. ?ats, for exam!le, s!eed u! muscle
contraction and !eristalsis. Transit time is also influenced by factors such as
!sycholoical stress, ender, and re!roductive status *(iccardi and (ivellese, 2332-.
1.0.2.2. 5elayed transit time
The loner the transit time, the reater the !otential for !utrefaction and the
develo!-ment of dysbiosis. ;hen this occurs, unhealthy waste !roducts are fre"uently
reabsorbed and interfere with !ro!er metabolism or with the overrowth of s!ecific
ty!es of bacteria such as "elicobacter pylori$ Clostridium or s!ecies of %scherichia
coli *associated with hih concentrations of meat !roducts in the bowel-. The result is
!redis!osition toward intes-tinal or systemic illnesses or their exacerbation.
Tab( ?.> Transit Time Evaluation+ 6harcoal 5osaes
D!sa"( a&&!r/i$" t! 0(i"ht
V204 lbs D ca!sules
204M144 lbs C ca!sules
144M104 lbs 24 ca!sules
`104 lbs 21 ca!sules
1.0.2.1. (a!id transit time
Iery short transit times may not !rovide ade"uate o!!ortunity to diest and
assimilate the food consumed. Sym!toms and res!onse are always individual and
a!!ro!riate for dis-cussion with a health !rofessional. )t is recommended that transit
time be rechecked twice a month until healthy bowel movements and normali/ed
transit time are achieved.
2.+.2. (valuation: sel",test "or transit time
.lthouh various methods have been suested to track transit time, a sim!le
!rotocol can be used usin charcoal ca!sules. *6harcoal is also sometimes utili/ed for
sym!tomatic relief of intestinal as.- This !rotocol involves takin 2.0MD of
charcoal with C o/. of water on a s!ecific occasion and recordin the time of
consum!tion. 6hoose a hih-"uality brand of activated charcoal ca!sules. ?or the
most accurate results, the ca!sules are inested Gust after a bowel movement. The
ideal dosae is based on body weiht *see Table 1.2-.
1.0.1.2. Observations
The first ste! is to note and record the time at which the charcoal is taken. This
marks the beinnin of the transit-time test. #atients are encouraed to observe the
consistency of their stool and note anythin unusual or different about the "uality,
texture, color, or com!osition of bowel movements.
Transit time test inter!retation
Twelve to eihteen hours is considered a healthy transit time. 8nfortunately,
many .mericans have a 9DM277 h transit time or loner. Slow transit time allows the
!roduc-tion and absor!tion of various toxins !roduced within the body M xenotoxins
that are absorbed from the chyme and stool directly into the bloodstream.
The loner the transit time, the reater the !ossibility that !utrefaction can occur
*with the overrowth of either commensal bacteria or !athoenic s!ecies-, leadin to
unhealthy waste !roducts that are too often reabsorbed and interfere with !ro!er
metab-olism. The result is !redis!osition toward chronic intestinal or systemic illness,
or the am!lification of existin conditions.
On the other hand, very short transit times may not !rovide ade"uate time to
diest and assimilate the food consumed. )t is recommended that the transit time be
rechecked twice a month until a healthy transit time is achieved.
2.+.'. Interventions
)nitial interventions for malada!ted transit time are relatively basic and can be
im!lement-ted by !atients throuh sim!le chanes in lifestyle.
1.0.9.2. 5ietary fiber
The Standard .merican 5iet is fiber deficient, ty!ically includin less than <
day
-2
. Low dietary fiber intake re"uires the body to work harder to !ush waste alon.
One of the best ways to su!!ort an o!timal transit time of 21M2C h is to increase fiber
content in the diet. Hood fiber intake also !rovides considerable benefit to ut health
and con-tributes to a healthy microflora !o!ulation. .dditional benefits of fiber
include
!revention of the develo!ment of !athoens in the intestine and their
adherence to the ut wallE
im!roved blood cholesterol levelsE
im!roved vitamin activationE
better absor!tion and elimination of toxins such as heavy metalsE
enhanced mental clarity and reduced brain foE
lower carbohydrate content and therefore healthier induction of lucose into
the bloodstreamE
reduced body weiht and lower body mass index *$urakami et al., 144<-.
?iber !rovides a cleansin function to swee! !athoens away from the intestinal tract
M fewer !athoens means that fewer immune defenses are re"uired, resultin in lower
levels of inflammation in the body.
On the most basic level, fiber !romotes ood elimination. The ideal oal is intake
of 74M244 of total soluble and insoluble fiber throuhout the day, with a balance of
C4R soluble fiber and 14R insoluble fiber to su!!ort healthy diestion. ?or exam!le,
on a diet that !rovides about 94 fiber daily, <M27 of additional fiber is indicated.
Su!!lemen-tation with 20M94 from multi!le forms of un!rocessed fiber is
recommended, selectin a source that contains no stimulants, artificial sweeteners, or
flavors.
1.0.9.1. Exercise and !hysical activity
6ore body strenth is a function of breath and stretch. ;ith the !ractice of
abdominal breath-in, stress is reduced and core body strenth is enhanced. Twenty
minutes a day of entle stretchin com!lements the breath in maintainin visceral,
core connective tissue, and mus-culoskeletal health. ;alkin as a source of
s!ontaneous, !leasant irreular movement can be enhanced by the !ractice of Traer
movement education, ?eldenkrais techni"ue, .lexander work, or such classic
a!!roaches as hatha yoa. )n the system !referred by the individual, a entle
a!!reciation for im!roved flexibility, resilience, comfort, and tolerance is suested
B. SYSTEMIC INFL*ENCES ON GI HEALTH
Seventy !ercent of the body%s immune system lies alon the diestive tract *the
#eyers !atches housed here are also known as Hut .ssociated Lym!hoid Tissue
*H.LT--. )n a healthy !erson, the food is broken down com!letely and is never
immunoenic. 'owever, malabsor!tion, takes a toll on the immune system. . !oorly
functionin diestive system has lost ability to turn food that is consumed into a form
the body can use. #oor diestion creates the same !redicament as !oor nutrition M a
lack of nutrients to su!!ort immune res!onse and !hysioloic function.
Today, loss of tolerance and homeostasis accounts for an estimated one third of all
chronic disease. =et, research and clinical ex!erience have shown that healin can be
stim-ulated and re!air induced with the !rotocol described here+ identifyin and then
avoidin offendin substances, followin an alkalini/in diet, and individuali/in
su!!lementation. This conce!t has been extensively tested in controlled outcome
studies on insulin resistance and diabetes, in cases of )BS and chronic fatiue
syndrome. 6linical outcome studies su-est that autoimmune conditions res!ond to
this com!rehensive clinical a!!roach over C4R of the time throuh a!!lication of
lower risk, lower cost, safer, and yet more effective !ersonali/ed interative thera!ies
known as The .lkaline ;ay.
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;u, O.W., Shu, L.'., Sun, $., ;an, '., Hao, '., 144D. Effect of lutamine on
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=amauchi, &., Suita, (., $iki, .., et al., 144D. Hastrointestinal candida
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RELEVANT WEBSITES
htt!+,,www.'ealthstudiescolleium.or
htt!+,,www.EL)S..6T.com
htt!+,,www.#E(W8E.com
htt!+,,www.#E(W8E;heyHuard.com
htt!+,,www.ncbi.nlm.nih.ov,!ubmed
CHAPTER B
A$ti!Hi/a$ts i$ I$'a..at!ry B!0(
Dis(as(I *&(rati+( C!itisI a$/ Cr!h$
Dis(as(
H. Asa,#ra
*
I T. Kitah!ra
*
>oukann 6linics, >awasaki, >anaawa, :a!an
l
Takanashi $ilk #roducts 6o., Ltd., =okohama, >anaawa, :a!an
I R.K. Ta$/!$
*
,
#ush!awati Sinhania )nstitute of Liver, and Biliary 5iseases, &ew 5elhi, )ndia
I M.V. V($,atara$"a$$a
I P.
V($,at(sh
W
I R. Faya/
l
?ather $uller $edical 6ollee, $analore, >arnataka, )ndia
I R.
Faya/
*
?ather $uller $edical 6ollee, $analore, >arnataka, )ndia
I S. Sa.i$($
*
)nstitute of .rochemistry and ?ood Science *).T.-6S)6-, Ialencia, S!ain
I A. Mira
I M.P. Fra$&i$!
*
)nstitute of .rochemistry and ?ood Technoloy, S!anish &ational (esearch
6ouncil *).T.-6S)6-, Ialencia, S!ain
:oint 8nit of (esearch in Henomics and 'ealth 6entre for #ublic 'ealth
(esearch *6S)S#-, Ialencia, S!ain
I A. /( M!r($!
/( L(Ba$&
*
I G. P(r/i":$
*,
*
6entro de (eferencia !ara Lactobacilos *6E(EL.-6O&)6ET-, TucumKn,
.rentina
I P. Mah!tra
I S. S#$/riya
I H.S. Yasha+a$th
I R.5. Pai
I M.S.
Bai"a
*
6hief 6ontroller (esearch and 5evelo!ment *Life Sciences and )nternational
6oo!eration-, &ew 5elhi, )ndia
#ush!awati Sinhania )nstititute of Liver, and Biliary 5iseases, &ew 5elhi, )ndia
>. INTROD*CTION
Hallstone disease is a manifestation of cholelithiasis and !oses a health ha/ard.
&ew treat-ment o!tions are available as bile salts and bile acids, fibrates, cholesterol
lowerin, and cholesterol metabolic reulators as drus, but none of them is
satisfactory because of dif-ficulty in com!liance and hih rate of recurrence. Thus,
dietary thera!y may be !referable. Emerence of bioactive foods has shown some
!romise in cholesterol lowerin for lon !eriods with no side effects. )n the !resent
article, current state of art is !resented on !ossible thera!eutic effect of dietary
interventions. Benefits of a!!le !ul! or skin are hihlihted in !revention of
cholelithiasis. )n the end, emerin concerns reardin !re-vention and treatment of
cholelithiasis, includin chane of sedentary affluent lifestyle to veetarian and active
lifestyle, are addressed.
>.>. R!( !' Di(t Th(ra3y a$/ Cha($"(s i$ Ch!(ithiasis
Tr(at.($t
&aturally occurrin bile acids *ursodeoxycholic acid or chenodeoxycholic acid-
have been widely used to achieve dissolution of minimally sym!tomatic all stones.
'owever, recurrences are seen in u! to 04R of !atients after the treatment is
discontinued. (ecent re!orts indicate that there are hih risks of !arenteral nutrition,
!ure bile salts, and cho-lecystectomy *5ella 6orte et al., 144CE 5ray et al., 144<E 'artl
et al., 1443E >elly, 1424E Stroohle et al., 144DE Teitelbaum et al., 1440E Nhurikhin et
al., 1424-. 'owever, #& *!ar-enteral nutrition- is not associated with increased
mortality, overall fre"uency of com!li-cations, or loner lenth of hos!ital stay
*LOS-. )n fact, risk of com!lications of #& *e.., refeedin syndrome, hy!erlycemia,
bone deminerali/ation, catheter infections- can be minimi/ed by carefully monitorin
!atients and the use of nutrition su!!ort teams !ar-ticularly durin lon-term #&.
6om!lications may be !atients sufferin from severe mal-nutrition with the initiation
of refeedin or metabolic, hy!ertrilyceridemia, hy!erlycemia, osteomalacia, or
osteo!orosis, and he!atic com!lications such as fatty liver, nonalcoholic fatty liver
disease, cholestasis, cholecystitis, and cholelithiasis. &ew findins suest that water
and electrolyte balance, blood suar, and cardiovascular func-tion should reularly be
monitored durin #&. (eular checks of serum electrolytes and trilycerides as well
as additional monitorin measures are necessary in !atients with al-tered renal
function, electrolyte-free substrate intake, li!id infusions, and in intensive care
!atients in ho!e of better outcome. The metabolic monitorin of !atients under lon-
term #& should be carried out accordin to standardi/ed !rocedures. $onitorin met-
abolic determinants of bone metabolism is !articularly im!ortant in !atients receivin
lon-term #&. $arkers of intermediary metabolism, electrolyte, and trace element
me-tabolism re"uire reular checks. Early re!orts leave us in dismay to search other
ways of reduce cholelithiasis such as nutrition su!!lements and dietary thera!y or
other factors in allstone !atients *'eshka et al., 233DE 'oy et al., 2337E :ayanthi et
al., 233CE >amrath et al., 2331E >lawansky and 6halmers, 2331E $ennde/-Sannche/ et
al., 1442E $orann et al., 233<E (oslyn et al., 23C9E Serrano #a/ et al., 2330-. The next
section focuses on the dietary manaement as an initial thera!y of allstones and that
dru thera!y may not be needed in all cases.
5i-etary advice+
5urin an acute cholecystitis attack, si! water occasionally, but do not eat.
&o "uestion of treatin acute cholecystitis with any diet or dru thera!y. .t
other times, eat low-fat diet. 6aution+ ?atty meals may brin on mild attacks
of bile duct conestion.
)f !erson is overweiht, bein a weiht reduction !roram as !reventive
measure alon with nutrient su!!lementation.
The followin factors may also increase the chances of havin cholelithiasis+
Bein overweihtE
6ertain medicines, such as estroen, antibiotics, and cholesterol-lowerin
medicinesE
5iabetes or !revious surery of the small intestinesE
?astin *oin without food- or ra!id weiht lossE
'avin another family member with cholelithiasisE
#renancy.
>.?. Di(tary Fa&t!rs a$/ Ch!(ithiasis
1.2.1. !%esity and weight loss
Obesity is associated with an increased risk of allstones *$ust et al., 2333-.
;eiht loss may reduce the risk of allstone formation in overweiht individuals, but
excessively ra!id weiht loss *i.e., more than three !ounds !er week- may !romote
the develo!ment of allstones or increase the risk that silent allstones will become
sym!tomatic. The in-creased risk associated with ra!id weiht loss may be due to an
increase in the ratio of cholesterol to bile salts in the allbladder and to bile stasis
resultin from a decrease in allbladder contractions *Lee et al., 23C0E Lei et al.,
144C-.
>.?.? Di(tary &h!(st(r! a$/ 'at
)n a 9-week randomi/ed trial, increasin intake of cholesterol *over a rane of
044M2444 m day
2
- resulted in increasin biliary cholesterol saturation in both healthy
volunteers and !atients with asym!tomatic allstones *$isciana et al., 2333-.
.uthors inferred that the rise in biliary cholesterol saturation !resumably would
increase the risk of allstone for-mation. )n observational studies, hiher intake of
saturated fat or trans fatty acids was as-sociated with an increased incidence of
allstones *Tsai et al., 1447a, b, c, 1440a, b, 144C-. )n contrast, hiher intake of
!olyunsaturated or monounsaturated fatty acids was associated with decreased risk
*(obins and ?asulo, 23<9-. The a!!arent !rotective effect of !olyunsaturated fatty
acids is consistent with ex!erimental observations, in which ham-sters fed an essential
fatty acid-deficient diet had a hih incidence of cholesterol allstones and lithoenic
bile *diets low in essential fatty acids are, in eneral, low in !olyunsaturated fatty
acids- *Berr et al., 2331E 6airella et al., 23C3E #ixley and$ann, 23CC-. )n addition, in
!atients with allstones, su!!lementation with 22.9 day
2
of fish oil *which is hih in
!olyunsaturated fatty acids- decreased the cholesterol saturation of bile by 10R.;hile
both omea-9 and omea-D !olyunsaturated fatty acids may be !rotective, further
research is needed to determine the o!timal amounts and ratios of these fatty acids to
be administered.
>.?.B R('i$(/ s#"ar i$ta,(
Observational studies in humans have shown that hiher intake of refined suars
such as sucrose and fructose is associated with a hiher fre"uency of allstones
*Loefler, 23CCE $oerman et al., 2337E Tamimi et al., 2334E Tsai et al., 1440a, b-.
;hile the association between refined suar intake and allstones could be due in !art
to the fact that consum-in lare amounts of suar can lead to obesity, there is early
evidence that refined suars are themselves lithoenic. )n rabbits fed a lithoenic diet
*containin 97R sucrose, re!la-cin sucrose with starch- !rotected aainst the
develo!ment of allstones *Berman et al., 23DD-. )n another study in rabbits,
re!lacin dietary sucrose with starch decreased the total weiht of allstones by 7CR
in females and 14R in males, althouh these differences were not statistically
sinificant *$oersen and Borman, 23C7-. )n !atients with allstones ran-domly
assined to consume a diet hih or low in refined carbohydrates *!rovidin a mean of
24D day
2
vs. D day
2
of refined suar-, the cholesterol saturation of bile was si-
nificantly reater on the diet hih in refined carbohydrates *! V .440- *Thornton et al.,
23C9a, b-. 'owever, another study was unable to confirm those findins *;erner et
al., 23C7-. .lthouh it has not been !roven that consumin refined suar !romotes
allstone formation, it would be !rudent for !eo!le at risk of develo!in allstones to
avoid ex-cessive intake of refined suar.
1.2.4 1egetarian diet li"estyle
)n a cross-sectional study, the !revalence of allbladder disease *asym!tomatic
allstones or history of cholecystectomy- was sinificantly lower in female
veetarians than female omnivores *21R vs. 10RE ! V .42- *#ixley et al., 23C0-. )n
addition, a 14-year !ros!ective study of C4 C3C women found that increased
consum!tion of veetable !rotein was associated with a decreased risk of ac"uirin a
cholecystectomy. . se!arate evaluation of the same cohort of women found that
increasin consum!tion of fruits and veetableswas associated with a decreased
incidence of allstones. Similar results were seen for bothtotal fruits and total
veetables examined se!arately *Tsai et al., 1447a, b, c, 144D-. )n very early studies,
hamsters fed on lithoenic diet, incidence of allstones was decreased in adose-
de!endent manner by !roressively re!lacin casein *a milk !rotein- with soy!rotein
in the diet *>ritchevsky and >lurfeld, 23<3, 23C9-. These observations suest that
consum!tion of a veetarian diet, and !articularly veetable !roteins, may decrease
the risk of develo!in allstones.
1.2.+ 8ietary "i%er and %ran
5ietary fibers, bran, and !ectins as bioactive foods have been !roven effective in
serum cholesterol lowerin or hy!ocholesterolemic effect. .!!le dietary fiber and
rice bran, a!redominantly insoluble fiber source, were re!orted to show
hy!ocholesterolemic effect in hamsters *.ka/ome, 1447-. .!!le fiber is amon the
to! five hih-fiber diets rich in cellulose, hemicellulose, linin, and !ectin contents
with a hih !otentials of hy!ocho-lesterolemiceffect *Oino et al., 144<E Osada et al.,
144D-. The mechanism of this effectof these dietary fibers still does not clearly define
how cholesterol concentration in bileand liver are reulated by en/ymes as outlined in
?iure 19.2. 6holesterol breakdown is done by cholesterol <a hydroxylase en/yme
*BGoorkhem et al. 2332-. The hydroxyl rou! on seventh carbon in cholesterol !lays a
maGor metabolic reulatory role in the action of
Fi"#r( ?B.> Scheme of en/ymatic role in cholelithiasis
cholesterol <c hydroxylase en/yme activity. 5ietary cholesterol controls the
biosynthesis of cholesterol by inactivatin the existin 9-hydroxymethyllutaryl-6o.
reductase *'$H-6o. reductase- and su!!ressin the synthesis of additional
reductase as shown in ?iure 19.2 *&don-.koume et al., 1441E Tanaka et al., 1447-.
;e showed that the dietary fiber binds and removes the extra bile acids from the
system and !romotes more conversion of cholesterol into bile acids * ?iure 19.2-.
)n ex!erimental models, hih intake of fiber was re!orted to be associated with a
lower than ex!ected !revalence of allstones *5onowski, 2333E Scaion et al.,
23CC-. 'owever, all ex!erimental studies showed a reduced cholesterol saturation.
The biliary li!id contents chaned after nonfermentable ty!e of fiber, linin, or
ferment-able fiber analoue, lactulose *(otstein et al., 23C2-, were iven to !revent
cholesterol allstones in cholelithiasis ex!eriencin !atients receivin 24M04 day
2
or more of wheat bran for 7MD weeks. The !atients with cholelithiasis showed
decreased cholesterol saturation of bile in healthy volunteers, individuals with
consti!ation, and !atients with allstones *$arcus and 'eaton, 23CDE $c5ouall et
al., 23<CE #omare et al., 23<D-. Bran is another dietary o!tion thouht to work
!rimarily in the colon, decreasin the forma-tion of deoxycholic acid by intestinal
bacteria and increasin the synthesis of chenodeoxycholic acid *'eaton and ;icks,
23<<-. 5eoxycholic acid a!!ears to increase the lithoenicity of bile, whereas
chenodeoxycholic acid decreases lithoenicity and has been used thera!eutically to
!romote dissolution of allstones. The followin section describes the scientific basis
and our ex!erimental hamster model to com!are cholesterol lowerin and
desaturation in animals fed different fiber diets.
?. PRESENT STAT*S OF CHOLESTEROL SAT*RATION
AND DIETARY FIBERS
6holesterol !lays a maGor role in the body as a !recursor of several vitamins,
steroids, bile salts, and synthesis of esters. )ncreased amounts of cholesterol in the
blood and tissues, however, !ose a serious health ha/ards, for exam!le, strokes,
cardiovascular accidents and renal vessels occlusion, as cholesterol de!osits in the
vessels *.!rikian et al., 1441E BGqrkhem et al., 2332E Einarsson et al., 23C3E 'onda et
al., 2330E &don-.koume et al., 1441E Sembries et al., 1447, 144DE Shimi/u et al.,
233D-. 'owever, cholesterol sat-uration initiates in liver durin bile salt synthesis in
bile formation. 5urin initiation !ro-cess in liver cells, balance between *mevalonate
conversion in to '$H 6o. vs cholesterol conversion to hydroxycholesterol- driven
by ratio of two en/ymes+ hydroxyl-methyllutaryl 6o. reductase en/yme+cholesterol
<V hydroxylase en/yme, is the deter-minin factor of cholesterol saturation or
cholesterol desaturation in the bile* Boll et al. 2333E &don-.koume et al., 1441E
Tanaka et al., 1447-. 'owever, the reulation of *'$H 6o.-reductase + 6holesterol <
hydroxylase ratio 9- is not known at molecular level how it is driven and what
factor*s- kee! '$H-6o. reductase in forward direction[ The initial increased
cholesterol saturation leads to initiate bile saturation and slowly later it occludes
vascular walls in renal, cardiovascular, and cerebrovascular system *'onda et al.,
2330E $atheson et al., 2330E Sembries et al., 1447, 144D-. Lithoenic diets are ad-
vocated to reduce cholesterol saturation due to their slow action on esterified
cholesterol to make more free cholesterol *reduced free cholesterol- as one of the
maGor lithoenic effect. These lithoenic diets are considered to have neative effect
on omea-9 and omea-D fatty acids in the body and remain a maGor focus of their
characteristic in !la"ue formation or atherosclerosis. The cholesterol-lowerin diets
rich in omea-9 and omea- D fatty acids have been re!orted to show maGor benefit in
li!id lowerin includin cho-lesterol lowerin *#ella et al., 1449-. (ecently, a!!le
skin has attracted the attention as an aent for in reducin cholesterol saturation in
bile. 6holesterol lowerin by a!!le fiber in is described in the followin section in
detail.
.n a!!le a day !rovides reat !hytonutrients *!hytoe!lant- and a ood dose of
fiber. Onemediuma!!le contains about 19 of carbohydrates and 7 of fiber..!!le
!ul! !rocess-sin and Guicemanufacturin are now a boomin industry, and recently,
a!!le !roducts are identified with cholesterol-lowerin !ro!erty for cholelithiasis
*.ka/ome, 1447E .!rikian et al.,1441E5onowski, 2333EOinoet al., 144<E Sembries
et al.,1447, 144DE Shimi/uet al., 233D-. The dietary fiber content in a!!le further adds
u! the double benefit of cholesterol lowerin with renal dysfunction and enhanced
fecal steroid excretion *Table 19.2-.
?iber-rich diets have attracted attention durin the last decade due to their double
benefit, i.e., li!id lowerin by cholesterol desaturation and maintained intestinal
function free from any microvillus membrane damae *see ?iure 19.1- *5onowski,
2333E
Tab( ?B.> .!!le 5ietary 6om!osition is Shown in ;hole .!!le and
.!!le #ul! ?iber 6ontent with Enery
S!#r&( S(r+i$" C!$t($t P E$(r"y
.!!le !ul! fiber
(aw 2 small 00MD4
a
9.4
(aw 2 med <4 7.4
(aw 2 lare C4M244
a
7.0
Baked 2 lare 244 0.4
.!!le sauce 1,9 cu! 2C1 9.D
;hole a!!le
(aw 2 whole 2< 4.C
5ried 1 halves 9D 2.<
6anned in syru! 9 halves CD 1.0
!ource+ Bowel function and dietary fiber+ ;arren Enker.
htt!+,,www.wehealny.or,healthinfo,dietaryfiber,index.html-.
a
)m!ortant as dietary fiber, laboratory technicians have not yet been able to
ascertain the exact total content in many foods, es!ecially veetables and fruits,
because of its com!lexity. 6onse"uently, estimates vary from one source to another.
;here differin estimates have been found, an a!!roximation is iven in the chart, as
indicated by an asterisk. The same symbol followin calorie content means the
number of calories has been estimated, varyin accordin to other added inredients,
es!ecially fats and suars, and to the si/e of the Saverae% fruit or veetable unit.
!ource+ Bowel function and dietary fiber+ ;arren Enker.
htt!+,,www.wehealny.or,healthinfo,dietaryfiber,index.html-.
Fi"#r( ?B.? Biochemical basis of cholelithiasis and biliary li!ids
Oakenfull and ?enwick, 23<CE Sembries et al., 1447, 144D-. The fiber is maGor content
in the bulk of a!!le. The a!!le fiber is rich in cellulose, hemicellulose, linin, and
!ectin contents and very com!atible to kee! the human diestive system, $oreover,
recently some investiators advocated that reular a!!le use in diet kee!s free from
any tro!ical s!rue, !ain, or consti!ation *.!rikian et al., 1441E Sembries et al., 1447,
144DE Shimi/u et al., 233D-. The a!!le fiber has sinificant activity to lower down the
cholesterol in the liver. The cause of cholesterol desaturation or cholesterol lowerin
could be either ra!id cholesterol conversion to its hydroxylated !roduct or it could be
slowin down of cho-lesterol !recursor '$H 6o. formation to make less available
cholesterol in bile or to de!rive the cholesterol formation. Several issues,however
remain unanswered+ ?irst, the !ro!osed cholesterol <c hydroxylase activity is not
solely cholesterol s!ecific but includes other cholesterol derivatives or its analoues.
Second, de!endence of cytochrome #704 and &.5# reduction does not solely
re!resent the hydroxylation reaction but other re-dox reactions active in the medium
at o!timal !' <.7 and tem!erature 9< 6. Third, liver microsomes are very s!ecific to
intracellular conditions such as state of substrate, reaction medium com!osition,
!hysioloical variables, etc. 5urin liver cell fractionation and mi-crosomal isolation,
there is every !ossibility of deactivation of en/yme and loss of en/yme !rotein.
?ourth, the dietary effect on cholesterol lowerin is not sinle biochemical or
metabolic disorder, but diet may also affect the other li!ids and bile salts made from
cho-lesterol. So, the dietary effect is a com!ound effect on rou! of li!ids in both
allbladder and blood !artici!atin in li!id disorder. ?ifth, cholesterol is not sinle
li!id com!ound to re!resent the li!id disorder or bile disorder in the body as other
li!id com!ounds also com!ete with cholesterol durin bile formation or li!id
lowerin. Sixth, hy!ocholester-olemic effect is really increased by activation of fiber
or !ul! bindin with alkaline earth metals, hydroxides, carbonates, and !hos!hates.
(ecently, bioactive foods were hihlihted to !lay maGor role in cholesterol
desaturation and li!id lowerin such as uuli!id, arlic, fish fatty acids. Still, fiber-
rich foods remain less known, and there is !aucity of information on the role of fibers
in li!id lowerin and cholesterol manaement. The cha!ter throws a !ossibility of the
hy!ocholesterolemic action of naturally available a!!le fibers and casein in the body
a!!licable to human. 6asein is known to !lay a maGor role in cholesterol lowerin and
increasin '5L cholesterol in the body *Ialhouny et al., 23C0-. Still, it remains to be
investiated if the biochemical action of both casein and a!!le diet is similar or
analoous. Other available fiber-rich foods do have !otential of lowerin li!ids in the
body such as soy, !ectins, brans of cellulose, rice, oat *)keami et al., 2334E Shimi/u
et al., 233DE Ialhouny et al., 23C0-. Still, the main !roblem of isolated !rinci!le or
fraction from com!lex fibers, diets, and bran remains to be solved while evaluation of
cholesterol lowerin based on en/yme activity is s!ecific to cholesterol.
?.>. H!0 t! E$ha$&( th( Hy3!&h!(st(r!(.i& E''(&t by
A33( Di(tsU
The method includes the ste!s of a!!le !ul! !rocessin by *2- disru!tin
*ru!turin- the cell structure of the !ul! material, *1- reactin the disru!ted !ul!
material with a first reactant*s- ca!able of chemically modifyin at least a !ortion of
the !endant hydroxyl rou!s on the fiber material contained in the !ul! to !endant
rou!s ca!able of chem.-ically cou!lin with alkaline earth metal ions, and then *9-
reactin the modified fiber material with a second reactant*s- ca!able of chemically
cou!lin an alkaline earth metal ion to the modified !endant rou!s. .n exem!lary
!rocess includes the ste!s of *a- !re-conditionin the !ul! by reactin the !ul! with an
a"ueous solution of &aO', *b- react-in the !reconditioned !ul! with an a"ueous
solution of 6'
1
6lM6OO' to carboxylate the !endant hydroxyl rou!s on the fiber
material contained in the !reconditioned !ul!, and then *c- reactin the carboxylated
fiber material with 6a*O'-
1
so as to bond 6a su!!lementation to the !endant carboxyl
rou!s *.!rikian et al., 1441E >uver and Lee, 1447E #ella et al., 1449E Sembries et al.,
1447, 144DE Shimi/u et al., 233D-.
#resent evidence of a!!le fiber is a !reliminary re!ort indicatin an evidence of
a!!le dietary benefit in cholesterol lowerin and a !ossible en/yme mechanism
res!onsible of cholesterol lowerin while cytochrome #704 !rotein may act as
biomarker in serum to evaluate the cholesterol lowerin.
6urrent state of the art on a!!le !ul! is in many directions of more intensive
invest-tiations on dietary modification and effect on active or inactive forms of
cholesterol <c hydroxylase en/yme, better tracer techni"ues of en/yme estimation,
better understandin of en/yme heteroeneity and !hysioloical effects amon
s!ecies, a!!le !rocessin ad-vanced methods, and effective cholesterol lowerin by
dietary servins. The a!!le !ul! has limitation in establishin the effect of a!!le
dietary fiber on cholesterol desaturation or li!id lowerin because ex!eriment
su!!orts the !ossibility of cholesterol lowerin by a!-!le fiber su!!lementation to
animals. )t needs more investiations at different amounts of a!!le !ul!
su!!lementation in diet and estimation of cholesterol <c hydroxylase in o!-timi/ed
reaction mixture in human subGects. Other issue is cytochrome #704 !rotein may not
re!resent as true cholesterol <a hydroxylase en/yme in liver. )t needs additional ex-
!eriments for isolation of a!!le dietary fiber !rinci!le*s- res!onsible of cholesterol
low-erin in blood or liver and additional benefits in renal dysfunction, fecal
excretion, etc. .t !resent, a!!le !unch is ?5. a!!roved as a safe table drink with the
ho!e of havin a cholesterol-lowerin effect, but the effect is unconfirmed. .!!le diet
is rich in !ul!, and a!!le fiber may have the cholesterol-lowerin effect on the li!id
metabolism in body. 6holesterol <c hydroxylase is rate-limitin en/yme of
cholesterol deradation. .!!le !ul! fiber may have stimulatory effect on cholesterol
<c hydroxylase en/yme while cholesterol also showed enhanced en/yme activities.
Based on !reviously re!orted ob-servational and biochemical studies, it would be
reasonable to recommend a hih-fiber diet with bran as !art of a com!rehensive
nutritional !roram to !revent allstones *'eaton and ;icks, 23<<E $c5ouall et al.,
23<CE #omare et al., 23<D-.
2.1.1 Ca""eine
6affeine is considered to decrease cholesterol due to its '$H-6o. reductase
inhibitory !ro!erties and enhanced bile flow yet unconfirmed but su!!orted with the
followin studies *Leit/mann et al., 2333, 1441E (uhl and Everhart, 1444-. )n dos,
administration of caffeine in drinkin water at a concentration of 2 m ml
-2
!revented
the develo!ment of allstones induced by feedin a hih-cholesterol diet. The
!rotective effect of caffeine a!!eared to be due in !art to stimulation of bile flow
*(uhl et al., 1444-. Two lare, !ros!ective cohort studies found that consum!tion of
caffeinated coffee may !rotect aainst the develo!ment of sym!tomatic allstones.
6om!ared with non-coffee drinkers, the reduction in risk associated with
consum!tion of two or more cu!s of coffee !er day was 74M70R in men and 11M1CR
in women in a cross-sectional study *Leit/mann et al., 2333, 1441-. 6onsum!tion of
decaffeinated coffee was not associated with lower allbladder disease risk,
suestin the beneficial effect of coffee is due to caffeine. . lare cross-sectional
study found little or no !rotective effect of coffee consum!tion *(uhl and Everhart,
1444-. 'owever, cross-sectional studies tend to be less reliable than !ros!ective
cohort studies.
2.1.2 0ild "ood as other dietary supplements
. !ros!ective study of C4<2C women !artici!atin in the &urses% 'ealth Study
showed that increased consum!tion of !eanuts and other nuts is associated with lower
risk of cholecystectomy *Tsai et al., 1447a, b, c-. ;omen who consumed five or more
ounces of nuts !er week had a 10R lower risk of havin a cholecystectomy, com!ared
with women who rarely or never ate nuts. )n contrast, circumstantial evidence
suested that consum!-tion of lare amounts of leumes may increase the incidence
of allbladder disease. )n a study of healthy youn men, consum!tion of a diet
containin 214 day
-2
of leumes for 94M90 days increased biliary cholesterol
saturation, com!ared with a control diet. This effect was due to a combination of an
increase in the concentration of cholesterol and a decrease in the concentration of
!hos!holi!ids in the bile *&ervi et al., 23C3-. )n addition, 6hileans and .merican
)ndians, who have some of the hihest !revalence rates of choles-terol allstones in
the world, both consume leumes as dietary sta!les *&ervi et al., 23C3-. 'owever, a
case-control study conducted in the ðerlands found an inverse association between
leume intake and allstone risk. This association did not a!!ear to be due to a
decrease in leume consum!tion as a result of astrointestinal intolerance to this food
rou! *ThiGs and >ni!schild, 2334-. Thus, the relationshi! between leume
consum!tion and allstone risk remains uncertain. The !ossibility that leume
consum!tion !romotes the develo!ment of allstones should be weihed aainst the
known beneficial effects of leumes, which include im!rovements in blood lucose
reulation and a reduction in se-rum cholesterol levels. )n healthy volunteers who
rarely consumed alcohol, consum!tion of 93 day
-2
of alcohol *e"uivalent to 9M7
drinks daily- for D weeks decreased cholesterol of bile *Thornton et al., 23C9a, b-. )f
the same effect could be achieved with smaller amounts of alcohol, then moderate
alcohol consum!tion miht also decrease the risk of develo!in allstones. )n mice
fed a lithoenic diet containin 4.0R cholesterol, feedin of arlic or onion reduced
the incidence of allstones and decreased the lithoenicity of the bile *Iidyashankar
et al., 1443, 1424-. )t remains to be confirmed if these findins are rel-evant to
allstones in humans *>aur and >aur, 1424-.
2.1.' <ood allergy and cholecystitis
?ood allery is a common cause of allbladder disease, and bioactive foods are
not free from allery. 5elay or failure to reconi/e food allery may result in many
unnecessary cholecystectomies *Black, 2372-. Hallbladder can be a taret oran for
alleric reactions as demonstrated in ex!erimental animals. )n one study, an alleric
reaction was induced in the allbladder of a (hesus monkey by administerin an
intravenous inGection of cotton-seed !rotein after !assively sensiti/in the allbladder.
.lleric reaction Talleric chole-cystitisU showed u! in the form of edema,
hy!eremia, increased mucus secretion, and eosino!hilic infiltration. Other study
showed allery reaction Talleric cholecystitisU in the rabbit allbladder after
sensiti/ed and inoculated to shee! serum into the allbladder cavity *5e $uro and
?icari, 237D-. )n addition to !otentially evokin an inflammatory res!onse, food
allery or intolerance miht also cause delayed allbladder em!tyin, an abnormality
known to !lay a role in the !athoenesis of cholelithiasis in !atients with celiac
disease. Six healthy volunteers, six !atients with untreated celiac disease, and six
!atients with treated celiac disease controlled on a luten-free diet drank a li"uid fatty
meal after an overniht fast. 'ealthy individuals and !atients with diet-controlled
celiac disease showed mean times of a!!roximately 14 min, as com!ared with 207
min in the !atients with untreated celiac disease *! V .41- until the allbladder
em!tied by 04R *$aton et al., 23C0-. These results indicated that !atients with celiac
disease have a all-bladder em!tyin defect that can be reversed by consum!tion of a
luten-free diet.
)n an uncontrolled trial, elimination of allerenic foods minimi/ed allbladder
sym!-toms in 244R of D3 !atients bearin allstones or !ostcholecystectomy
syndrome. Sixty-nine !atients *aes 92M3< years- with allstones or
!ostcholecystectomy syndrome were iven an elimination diet made of beef, rye, soy,
rice, cherry, !each, a!ricot, beet, and s!inachE fat intake was not restricted *Breneman,
23DC-. .fter 2 week on the diet, the !atients were iven individual foods. )f a food
evoked ty!ical Tallbladder sym!toms,U then that food was discontinued and not
iven for several weeks. .ll com!onents of each !erson%s diet were tested, and each
sym!tom-evokin food was retested several times. .ll D3 !atients were sym!tom free
within 2 week of elimination diet iven, with im!rove-ments seen within 9M0 days.
E, !ork, and onion were re!orted as the most alleric foods, with reactions
occurrin in 39R, D7R, and 01R of !atients, res!ectively, with av-erae of 7.7
*Hoodman and Hilman, 23<4-. .lthouh lon-term follow-u! information was not
available in these !atients, the study suested that food allery is an im!ortant factor
in the develo!ment of allbladder-related sym!toms. .t !resent, it is considered that
different food alleries of fatty, reasy, and rich foods may not always !roduce
ex!ected results in !atients with allbladder disease. )n most cases, food alleries can
be identified by an elimination diet followed by individual food challenes.
B. N*TRITION TREATMENT OF CHOLELITHIASIS
B.>. Hy3!&h!rhy/ria
'y!ochlorhydria is common in !atients with allbladder disease occurrin in 01R
of 04 !atients with allstones in one study *Bell, 23<3-. ;hile there is no evidence
that hy!o-chlorhydria contributes to the !athoenesis of allstones, it may be
res!onsible in !art for some of the nons!ecific sym!toms associated with chronic
cholecystitis, such as belchin, bloatin, abdominal !ain, and nausea. )n
hy!ochlorhydric !atients, hydrochloric acid-re!lacement thera!y with meals may
relieve these sym!toms. 'ydrochloric acid is usually administered as betaine
hydrochloride. The dosae of betaine hydrochloride recom-mended for
hy!ochlorhydric !atients varies amon different !ractitioners from D44 m !er meal
to 9444 m or more !er meal *von Bermann et al., 23C<-.
B.?. R!0a&h!
a
(owachol
h
is a !ro!rietary !re!aration that contains six !lant monoter!enes
*Table 19.1-. Each ca!sule contains 244 m of the mixture. (owachol has choleretic
Tab( ?B.? 6onstituents of monoter!enes in (owachol
h
C!$stit#($ts P(r&($t !' t!ta &!$t($t @PA
$enthol 91
$enthone D
#inene 2<
Borneol 0
6am!hene 0
6ineol 1
Base of olive oil 99
!ource+ (owachol+ a !ro!rietary !re!aration.
htt!+,,www.smallflower.com,rowa,rowachol-ca!sules-244-ca!sules- 2D2D7
!ro!erties *i.e., it stimulates bile !roduction by the liver- and inhibits the
formation of cholesterol crystals in bile *Bell and 5oran, 23<3E Ellis et al., 23C7-. )n
clinical trials, treat-ment with (owachol for D months resulted in com!lete or !artial
allstone dissolution in 13R of 1< !atients with radiolucent allstones. )n addition,
(owachol enhanced the efficacy of chenodeoxycholic acid in dissolvin allstones,
allowin for the use of lower *and better tolerated- doses of chenodeoxycholic acid.
(owachol could !resumably also be used to enhance the efficacy of ursodeoxycholic
acid.
Twenty-four !atients with radiolucent allstones received one ca!sule of
(owachol !er 24 k bodyweiht !er day, in most cases for D months. Seven !atients
*13R- showed radioloical and,or surical evidence of !artial *n e 7- or com!lete *n
e 9- allstone dis-solution. &o side effects were seen, and there was no laboratory
evidence of he!atoto-xicity or hematoloical abnormalities *Ellis et al., 23C2-.
Thirty !atients with radiolucent allstones and a functionin allbladder were
treated for u! to 1 years with a combination of (owachol *2 ca!sule twice daily- and
chenodeoxycholic acid *<M24.0 m k
-2
body weiht !er day-. The dosae of cheno-
deoxycholic acid was slihtly lower than the usual, <04 m day
-2
in order to minimi/e
side effects and cost. The treatment was well toleratedE only one !atient re!orted
diarrhea. Stones disa!!eared in 22 !atients *9<R- within 2 year and in 20 !atients
*04R- within 1 years. )n com!arison, in the &ational 6oo!erative Hallstone Study, in
which cheno-deoxycholic acid was iven alone at a dose of <04 m day
-2
, com!lete
dissolution was seen in only 29.0R of !atients after 1 years. The authors of this re!ort
concluded that a combination of medium-dose chenodeoxycholic acid and (owachol
is economical, ef-fective, and likely to have fewer adverse effects than hiher doses of
chenodeoxycholic acid alone *Ellis et al., 23C2-.
!atient discontinued treatment Twenty-two !atients with radiolucent allstones
and a functionin allbladder re-ceived two or three ca!sules !er day of (owachol
!lus chenodeoxycholic acid *9<0 m at bedtime, e"uivalent to a mean of 9CR of the
recommended dose- for 21 months. The combination was well toleratedE only one
because of astrointestinal side effects. Thirteen !atients *03R- had com!lete *n e D-
or !artial *n e <- dissolution of stones *Somerville et al., 23C0-. (owachol at a dosae
of three ca!sules !er day, alone or in combination with chenodeoxycholic acid or
urso-deoxycholic acid, was also used with some success by one rou! of investiators
to dissolve radiolucent stones in the common bile duct. 'owever, durin the
treatment, C of 92 !atients re"uired emerency hos!itali/ation for biliary colic,
obstructive Gaundice, !ancreatitis, or cholanitis. These com!lications were
successfully manaed, and all but one !atient continued with the treatment. The
investiators concluded that dissolu-tion thera!y may be considered in !atients with
radiolucent common bile duct stones when endosco!ic s!hincterotomy or surery is
not feasible. 'owever, careful attention to !otential com!lications is re"uired while
stones !ersist *Ellis and Bell, 23<3E >otkas, 23C0-.
(owachol has been on the market for more than 04 years and has not been
re!orted to cause any serious side effects. The usual dosae is 1M9 ca!sules daily.
Larer doses are not recommended as they may increase biliary cholesterol saturation
*Bell and 5oran, 23<3E 5ekkers, 2333-.
B.B. Gaba//(r F#sh
. allbladder flush *also called a liver flush- is a folk remedy that is said to
!romote the !assae of allstones *Sies and Brooker, 1440-. One method is to take a
fast for 21 ' and then, beinnin at < !.m., inest four tables!oons of olive oil
followed by one tables!oon of lemon Guice every 20 min for a total of eiht treatment
cycles. .nother method is to consume only a!!le Guice and veetable Guice *no food-
durin the day until 0MD !.m. and then inest 2C ml of olive oil followed by 3 ml of
fresh lemon Guice every 20 min until C o/ of oil have been consumed. Some
!ractitioners use Cascara sagrada and arlic,castile enemas in combination with the
olive oil and lemon Guice treatment. 'owever, !atients often ex!erience diarrhea and
abdominal !ain from this treatment, but the ood news is the next mornin !atients
!ass multi!le soft reen or brown s!heroids !resumably allstones without
confirmation. )nvestiators re!orted !assed TallstonesU made of <0R fatty acids and
contained no cholesterol, bilirubin, or calcium. ?urther ex!erimentation suested the
s!heroids were Tsoa! stones,U created by the interaction of diestive en/ymes with
certain com!onents of olive oil and lemon Guice *Bhalotra, 2334-. .nalysis of another
s!heroid !assed after a allbladder flush revealed it was not a allstone *Savae et al.,
2331-. Other ultraso-nora!hic evidence showed a reduced number of allstones
followin the inestion of olive oil and lemon Guice on follow-u! ultrasound
evaluation after a allbladder flush *)ssacs and Hon/ale/, 144CE Tandon et al., 233D-.
8ltrasonic treatment can clear the !assae of allstones otherwise causes stones to
become tra!!ed in the common bile duct, leadin to a medical emerency.
.uthors suest an a!!roach of reduced risk of develo!in allstones by ideal
body weiht manaement and consumin a low-fat-, low-salt-, wild-food-, hih-
fiber-, or bran-su!!lemented diet with exercise and lifestyle chane. Some nutritional
su!!lements may hel! !revention of allstones, but evidences are inconclusive. )t is
reasonable to rec-ommend 044M1444 m day
-2
of su!!lemental vitamin 6 for !atients
at risk of develo!-in allstones with no use of alleric foods, in order to reduce the
lithoenicity of their bile. ?urther, it is recommended that iron status should also be
assessed. . mixture of !lant ter!enes may also be useful for dissolvin radiolucent
allstones !articularly when used in combination with a bile acid.
D. PREVALENCE OF CHOLELITHIASIS AND GALL
STONES IN INDIA) A PERSPECTIVE
Tandon et al. *233D- analy/ed and com!ared dietary intake and !lasma li!ids in
144 all-stone !atients with 3C matched control subGects for ae, sex, and social class
to show hiher intake of total calories from carbohydrates and hiher !lasma
trilyceride in !a-tients as com!ared with controls *! V.40 and ! V .42, res!ectively-.
The dietary intake of refined carbohydrates was hiher in females with allstones
*90.D ^ 91.3 day
-2
com-!ared with controls 17.0 ^ 22.C day
-2
E ! V .442-. $ale
!atients with allstones had increased intake of fat *!atients <3.4 r 9C.2 day
-2
vs.
controls D4.1 ^ 17.9 day
-2
E ! V .40- and had increased !lasma cholesterol values
*!atients 2DD.7 ^ 07.1 m dl
-2
vs. controls 274.9 91.C m dl
-2
E ! V .42- *Tandon et
al., 233D-.
E. F*T*RE PROSPECTIVES ON CHOLELITHIASIS AND
N*TRITION
6holelithiasis and its com!lications are seen a maGor challene to health. $ain
bottle-necks in our understandin are lack of data available on reconition of biliary
li!id cutoff values as risk levels in children, adolescents, !renant,lactatin women in
different social rou!s, elderly in different sexes, ae rou!s amon different
ethnicities or countriesE challenes of !arenteral nutrition and com!lications after
cholecystectomyE less-documented benefits of nutrition and dietary su!!lementationE
unconfirmed benefits of new synthetic diets from industriesE lack of social, enetic,
environmental, alleric, anthro!ometric, metabolic, and ethnic risk factors
contributin cholelithiasisE and lack of overnment !olicy and monitorin on
un!rescribed nondru su!!lements available at o!en counters. )t is !ossible that new
diet reimens includin wild foods, veetarian lifestyle may be a new a!!roach to
reduce cholesterol and biliary li!ids in bile and blood as !ro!osed decades ao
*Halloro et al., 23C9E #ixley et al., 23C0-. )t is ex!ected that nu-trition industries will
make available new ready-made foods after ?5. or 8S5. a!-!roval to reduce
cholelithiasis and lithoenic effects includin !roteins, !ectins *Ellis et al. 23<3E von
Bermann et al., 23C<E ThiGs et al. 2334-. (ecent review on nutritional thera!y of
cholelithiasis suested immediate attention on reconition and identification of
cholelithiasis as risk in different taret rou!s with active role of traditional dietary
manaement to manae cholelithiasis and dysli!idemia in s!ecial rou!s includin
chil-dren, !renant women, and !atients after cholecystectomy *#aul et al., 2333-.
$anae-ment of cholelithiasis in children still remains to be established and needs
uidelines on cholelithiasis, identification of allstone com!lications, and monitorin
of !ostcholecys-tectomy *5ella 6orte et al., 144CE 'artl et al., 1443-, new enetic risk
factors, factors of affluence, environmental, and metabolic factors *Boue et al.,
1424-.
(ole of nonsterols, cholesterol, and bile salts will be extensively investiated to
rule out the main mechanism of cholelitiasis, new risk factors, com!lications, and
outcome of allstones in children *>oivusalo et al., 1424-. &utrition deficiencies
develo!ed after all-stone removal !ose a challene if not !revented or treated in
time. Still, there is a need to !revent or treat !ossible nutrition deficiencies develo!ed
after bariatric surery, !ostcho-lecystectomy *Nieler et al., 1443-. )t is ex!ected that
two maGor achievements will chane the scenario of cholelithiasis and its !revention+
a!!roved clinical and laboratory evaluation of li!id !rofile established to evaluate
efficacy of !arenteral nutrition in cholecystitis *Haby, 1443, ;alcher et al., 1424-E
new knowlede of dietary surveys, benefits of diet reimens includin wild foods,
veetarian lifestyle in different social ethnic rou!s *Nhurikhin et al., 1424-. ;e
s!eculate that our mother S&ature% has iven us natural benefits of active and healthy
lifestyle *low fat, low salt, no smokin,alcoholic, no !ills, vean habits, and exercise-
to kee! cholesterol low and avoid cholelithiasis or allstone formation *Sharma and
$offatt, 1422-.
G. CONCL*SION
6holesterol, !hos!holi!ids, and bile salts remain in balance as emulsion in bile
stored in allbladder. #hysicochemical studies suest that cholelithiasis is due to
cholesterol saturation with com!lications of allstone formation due to nucleation and
de!osition of calcium, bilirubin, and !iments. 6holelithiasis is reconi/ed first by
ultrasound fol-lowed by biliary li!id !rofile in clinical lab su!!orted with clinical
evaluation and dia-nostic !rocedures. )nitially, cholelithiasis is !revented by dietary
and nutrition su!!lementation to kee! li!ids low, but success rates or benefits are less
understood or unconfirmed in different taret rou!s or social ethnicities because of
lack of data on !hysical, environmental, enetic, and affluent lifestyles. )n advanced
staes of cholelithi-asis, allstones et develo!ed and bile salt thera!y with modified
diet reimens is !re-scribed to !revent nutrition deficiencies, and com!lications. Still,
today, !arenteral nutrition com!lications after cholecystitis, cholecystectomy, and
cholelithiasis risk factors in children bearin allstones !ose a challene.
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cholesterol sterols and bile acids
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>otkas, L., 23C0. S!ontaneous !assae of allstones. : ( Soc$ed <C, 3<2.
>ritchevsky, 5., >lurfeld, 5.$., 23<3. )nfluence of veetable !rotein on allstone
formation in hamsters. .merican :ournal of 6linical &utrition 91, 12<7M12<D.
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>uver, (., Lee, S.#., 1447. 6alcium bindin to biliary mucins is de!endent on
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)nternational < *2-, D0MD3.
Leit/mann, $.?., ;illett, ;.6., (imm, E.B., et al., 2333. . !ros!ective study of
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20CM2D2.
Sembries, S., 5onowski, H., $ehrlLnder, >., ;ill, ?., 5ietrich, '., 1447. 5ietary
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and nutrition thera!y in dysli!idemia manaement. )n+ (oya, >. *Ed.-, 5ysli!idemia.
)ntech #ublishin 6om!any, 6roatia )SB& 3<C-309-94<-<1D-4.
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Strqhle, .., ;aldmann, .., ;olters, $., 'ahn, .., 144D. Ieetarian nutrition+
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Hastroenteroloy 11 *2-, 19M1<.
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case-control study. )nter-national :ournal of E!idemioloy 23, DD4MDD9.
Thornton, :., Symes, 6., 'eaton, >., 23C9. $oderate alcohol intake reduces bile
cholesterol saturation and raises '5L cholesterol. The Lancet 1, C23MC11.
Thornton, :.(., Emmett, #.$., 'eaton, >.;., 23C9. 5iet and allstones+ effects of
refined and unrefined carbohydrate diets on bile cholesterol saturation and bile acid
metabolism. Hut 17, 1MD.
Tsai, 6.:., Leit/mann, $.?., 'u, ?.B., et al., 1447a. ?re"uent nut consum!tion and
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.therosclerosis 0D *1-, 21<M29<.
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Iidyashankar, S., Sambaiah, >., Srinivasan, >., 1424. (eression of
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Nhurikhin, ..I., >itiashvili, ).N., >utukov, I.I., 1424. 6linical and laboratory
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Nieler, O., Sirveaux, $..., Brunaud, L., (eibel, &., Wuilliot, 5., 1443. $edical
follow u! after bariatric surery+ nutritional and dru issues. Heneral
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5iabetes and $etabolism 90 *D #t 1-, 077M00<.
CHAPTER ?D
Gastr!i$t(sti$a Pr!t(&ti+( E''(&ts !'
E#"($ia =am%olana &am. @Ba&, P#.A
a$/ Its Phyt!&h(.i&as
R.5. PaiI B. Va/(rI P.L. PaattyI A.R. Shi+asha$,araI M.S. Bai"a
?ather $uller $edical 6ollee, $analore, >arnataka, )ndia
ABBREVIATIONS
ALP .lkaline !hos!hatase
ALT .lanine aminotransferase
AST .s!artate aminotransferase
BAP Ben/o*a-!yrene
CAT 6atalase
CC
D
6arbon tetrachloride
DMBA <,21-5imethyl ben/*a-anthracene
GPH Hlutathione !eroxidase
GST Hlutathione S-transferase
LDH Lactate dehydroenase
SOD Su!eroxide dismutases
>. INTROD*CTION
%ugenia Cambolana Lam. *Syn. !yBygium cumini Skeels or !yBygium Cambolana
56 or %uge-nia cuminii 5ruce- *?iure 17.2- belonin to the family $yrtaceae is a
lare everreen tree indienous to the )ndian subcontinent. 'owever, today these trees
are found row-in throuhout the .sian subcontinent, Eastern .frica, South
.merica, and $adaascar and have also naturali/ed to the warmer reions of the
8nited States of .merica *in ?lorida and 'awaii- *Li et al., 1443E ;arrier et al.,
233D-. The trees are famous for their fruits and their collo"uial names, which include
:ava !lum, #ortuuese !lum, $alabar !lum, black !lum, )ndian blackberry, Gaman,
Gambu, Gambul, and Gambool *;arrier et al., 233D-. The other collo"uial names are
enlisted in Table 17.2.
Botanical studies have shown that in the )ndian subcontinent, there are two main
mor!hoty!es of Gamun, and this is based on the mor!holoical and oranole!tic
features, the &aatha Camun which is small and acidic to taste and the ras Gaman, which
is oblon, dark
Fi"#r( ?D.> #hotora!h of Gamun fruit, seed, and leaf.
!ur!le or bluish, and with !ink, sweet fleshy !ul! and small seeds *:abbar et al., 2337E
$orton, 23C<-. The trees row u! to a heiht of 04 ft and have lare cano!y. The
youn bark is !ale brown in color, while the mature are darkish-brown and scaly. The
leaves are elli!tic to broadly oblon, smooth, lossy, leathery, and fibrous in nature.
The trees flower once in a year, and in the )ndian subcontinent, it is mostly durin the
month of :uneM:uly. The flowers are sessile, small *<M21 mm-, white in color, and
with thin membranous !etals. They are arraned mostly in threes and a!!ear usually
from the scars of the fallen leaves *;arrier et al., 233D-.
'istorically, the Gamun tree was exclusive to the )ndian subcontinent but is today
found rowin throuhout the .sian subcontinent, Eastern .frica, South .frica,
$adaascar, and in the warmer reions of 8S. in states like ?lorida. The fruit of E.
Cambolana is called by different names such as Gamun, black !lum, )ndian blackberry,
Gambu, and Gambool *;arrier et al., 233D-. The youn barks are !ale brown in color,
while the mature are slihtly dark brown, scaly, and at times !eel off. The leaves are
el-li!tic to broadly oblon, smooth, lossy, leathery, and fibrous in nature *;arrier et
al., 233D-.
The trees flower and fruit once a year, which in the )ndian subcontinent is durin
the month of :uneM:uly. The flowers are sessile, small *<M21 mm-, white in color,
frarant, and with thin membranous !etals. They are arraned mostly in threes and
a!!ear usually from the scars of the fallen leaves *;arrier et al., 233D-. The fruits are
found in clusters of 7M14 and the !rocess of fruitin from the flowerin stae takes
around 1 months to com!lete. The Gamun fruits !resent in a bunch do not ri!en all at
once and dro! off when fully ri!e. Each fruit is round or oblon or elli!soid, 2,1M1 in.
lon with a centrally !laced lare seed. The raw fruits are reen in color and as they
mature, turn to liht maenta and then to dark !ur!le or black when fully ri!e. The
fully ri!e fruit has a combination of sweet, mildly sour, and astrinent flavor and
im!arts !ur!le color to the tonue of the consumer *;arrier et al., 233D-. :amun
contains various classes of !hytochemicals and are re!resented in Table 17.1, and
some im!ortant !hytochemicals are re!resented in ?iure 17.1.
Tab( ?D.> The 5ifferent Iernacular &ames of Euenia Gambolana in
)ndia and Other Southeast .sian 6ountries *6'E$EO6)L, 2331-
La$"#a"( Na.(s
Scientific !yBygium Cambolanum$ %ugenia cumini$
!yBygium cumini$ %ugenia Cambolana
name
Enlish :aman, black !lum, damson !lum, duhat
!lum, )ndian blackberry, Gambolan,
Gambolan !lum, :ava !lum, $alabar
!lum, #ortuuese !lum, black !lum,
black !lum tree
)ndian lanuaes
.ssamese :amu, kala Gamu
Benali >ala Gam
HiGrati :ambu, Gaambu
'indi :amun, duhat, Gam, Gaman
>annada &erale hannu
>onkani :ambul
$alayalam >aattucaam!a, nGaaval, nGaara, !erinGaara
$ani!uri Hulamchat, Gam
$arathi :ambool
$i/o 'mui!ui
&e!alese :amunu, !hanrir
Oriya :amkoli
#ali :ambu
#rakrit :ambulo, Gammulo
#unGabi :aman
Sanskrit :ambu, Gambulah, mehamodini
Tamil >ottai-nakam, naval
Teluu &eredu
8rdu :aman
Other lanuaes
Burmese Thabyay-hy!yoo
?ili!ino 5uhat, lomboi
?rench :amenlonue
:avanese 5uwet, Gamblan
>hmer #rin bai
$alay :ambolan, Gambulana, Giwat, obah
&e!ali :amun
Sinhala :ambu, Gambul, madan, naval
Swahili $sambarau, m/ambarau
Thai 'akhi!hae, wa
Tibetan 5/am-bu
Iietnamese Trm mc, vi run
Tab( ?D.? )m!ortant #hytochemicals #resent in 5ifferent #arts of
Euenia Gambolana *6'E$EO6)L, 2331-
Pa$t 3art Phyt!&h(.i&as
Leaves a-Sitosterol, betulinic acid, mycaminose,
crateolic *maslinic- acid, n-he!tacosane,
n-nonacosane, n-hentriacontane,
noctacosanol, n-triacontanol, n-
dotricontanol, "uercetin, myricetin,
myricitrin, and the flavonol lycosides
myricetin 9-1-*7NN-acetyl--c-L-
rhamno!yranosides. The essential oil
!inocarveol, c-ter!eneol, myrtenol,
eucarvone, muurolol, a-myrtenal, 2,C-
cineole, eranyl acetone, c-cadinol, and
!inocarvone
Stem bark ?riedelin, friedelan-9-c-ol, betulinic acid,
a-sitosterol, kaem!ferol, a-sitosterol-5-
lucoside, allic acid, ellaic acid,
allotannin and ellaitannin, and
myricetine
?lowers Oleanolic acid, ellaic acids, iso"uercetin,
"uercetin, kam!ferol, and myricetin
?ruit !ul! .nthocyanins, del!hinidin, !etunidin,
malvidin-dilucosides
The seeds :ambosine, allic acid, ellaic acid,
corilain, 9,D-hexahydroxy
di!henoyllucose, 7,D-
hexahydroxydi!henoyllucose, 2-
alloyllucose, 9-alloyllucose,
"uercetin, a-sitoterol
Fi"#r( ?D.? )m!ortant !hytochemicals !resent in :amun.
Fi"#r( ?D.? 6ontZd
?. TRADITIONAL *SES
.ll !arts of the :amun and the seeds in !articular have a lon history of medicinal
use in the various traditional and folk systems of medicines in countries where it
rows. The fruits are considered to be tonic, astrinent, carminative, and useful in
s!leen diseases. The fruits and seeds are also used to treat !harynitis and rinworm
infection. The fruits are acrid and sweet, coolin, dry, and astrinent to bowels
*;arrier et al., 233D-. Seeds are astrinent and diuretic and sto!s urinary dischare
*;arrier et al., 233D-. The bark of the !lant is astrinent, sweet, refrierant, carmi-
native, antihelmintic, febrifue, consti!atin, stomachic, antibacterial, diuretic, and
diestive *;arrier et al., 233D-. The leaves have been extensively used to treat
diabetes, consti!ation, leukorrhea, stomachalia, fever, astro!athy, stranury, and
dermo!athy and to inhibit blood dischares in the feces *;arrier et al., 233D-. The
leaves are considered to !ossess antibacterial effects and are used to strenthen the
teeth and ums *;arrier et al., 233D-.
)n the .yurvedic system of medicine, Gamun is considered ood for treatin sore
throat, bronchitis, asthma, dysentery, and diabetes mellitus. )n )ndia, decoction of
kernels of Camun is used as household remedy for diabetes. )n the Siddha system of
medicine, Gamun is reconi/ed to be a hematinic and semen-!romotin and to reduce
the excessive heat of the body *;arrier et al., 233D-. .ccordin to the 8nani system
of medicine, it acts as liver tonic, enriches blood, strenthens teeth and ums, and
forms ood lotion for removin rinworm infection of the head. The ashes of the
leaves are used as a dentrificant to strenthen the teeth and the ums *;arrier et al.,
233D-. The seeds are astrinent and diuretic, sto!s urinary dischare, and are remedy
for diabetes. The barks also !ossess wound healin !ro!erties. The homeo!athic
system of medicine, oriinally native to Euro!e, also uses Gamun to treat various
ailments, includin diabetes.
.ccordin to the .yurvedic system of medicine, Gamun is also considered to be a
liver tonic and a astrointestinal !rotective aent. The astrointestinal system
com!risin of the astrointestinal tract that extends from mouth to the anus, with
accessory orans like salivary lands, !ancreas, and he!atobiliary system, !erforms
im!ortant functions of the body. 'owever, various ailments and diseases of the
astrointestinal system are known that affect the "uality of life and health of the
individual. The conventional medications, althouh effective, !ossess inherent toxic
effects and neate the thera!eutic benefit. )n lieu of these observations, the use of
com!lementary and alternative medicines that are nontoxic and have been used by
humans since anti"uity is Gustified. The !resent cha!-ter collates the various scientific
observations !ertainin to the astrointestinal !rotective effects of Gamun and its
!rinci!al com!ounds.
B. ANTICARIOGENIC EFFECTS
5ental caries is one of the most common infections found in humans across all
eora!hy, races, sex, and ae and can cause severe masticatory disability. Studies
have shown that the a"ueous, methanolic, and hydromethanolic extracts are also
effective aainst the cario-enic bacteria Stre!tococcus mutans and to inhibit,su!!ress
the !la"ue formation in vitro *&amba et al., 23C0-.
D. GASTROPROTECTIVE EFFECTS
#e!tic ulcer is one of the most common astrointestinal ailments and affects
considerable amount of the world%s !o!ulation. #reclinical studies have shown that
Gamun fruits !os-sess astro!rotective effect in both normal *6haturvedi et al., 144<-
as well as in the stre!to/otocin-induced diabetic rats *6haturvedi et al., 1443- and
aainst various ulcero-ens like cold-restraint stress, as!irin, 30R ethanol, and
!ylorus liation *6haturvedi et al., 144<-. The effective dose was observed to be 144
m,k body weiht when ad-ministered orally for 24 days. $echanistic studies
showed that administerin Gamun be-fore treatment with the ulceroens decreased the
acidM!e!sin secretion and the levels of li!id !eroxides *L#O- and concomitantly
increased the levels of HS' in astric mucosa. The extract also enhanced the levels of
mucin and mucosal lyco!rotein and decreased the cell sheddin *6haturvedi et al.,
144<, 1443-.
.dministerin the "uantified tannins isolated from the Gamun seed !rotected rats
aainst the '6l,ethanol-induced astric ulceration *(amire/ and (oa, 1449-. The au-
thors observed that macrosco!ically there was no sinificant difference in the number,
si/e, and surface area of macrosco!ic lesions between the tannin and ome!ra/ole
*!ositive control- rou!. 'owever, when microsco!ically evaluated *usin Best%s
8lcer Stain )ndex-, the tannin treatment offered better !rotection and sinificantly
decreased the as-tric mucosal damae. ;hen com!ared to the cohorts receivin only
the ulceroen, ad-ministerin tannins reduced the levels of free radicals in the
stomach suestin that the observed astro!rotection may be !artly due to this
!ro!erty *(amire/ and (oa, 1449-. Toether, all these observations clearly indicate
that Gamun fruits and seed !ossess astro-!rotective effects and that this effect was
brouht about by increasin the mucosal defen-sive factors and the astric
antioxidants and by concomitantly decreasin li!id !eroxidation *6haturvedi et al.,
144<, 1443E (amire/ and (oa, 1449-.
;ith reard to the Gamun !hytochemicals, studies have shown that cyanidin 9-
lucoside, ellaic acid, and "uercetin !rotected aainst the chemical-induced astric
ulcerations. The anthocyanin cyanidin 9-lucoside was effective in !reventin rats
aainst the ethanol-induced astric ulcerations. #retreatment with various doses *7
and C m,k of body weiht- of cyanidin 9-lucoside before administerin C4R
ethanol was effective in reducin the ethanol-induced astric lesions. 6yanidin 9-
lucoside reduced the levels of li!id !eroxide and concomitantly increased the level
of lutathione and the activities of su!eroxide dismutases *SO5-, 6.T, and
lutathione !eroxidase *H#x- in astric tissues *Li et al., 144C-. The !oly!henol
ellaic acid is also shown to inhibit astric ' , >*+--.T#ase, and acid secretion in
stress-induced ulceration in rats *$urakami et al., 2332- and to !revent the astric
lesions induced by ammonia !lus ischemia or ischemia,re!erfusion ex vivo in rats.
The flavanoid "uercetin is shown to be effective in !reventin ethanol-induced ul-
cerations in rats *.larconn de la Lastra et al., 2337E >ahraman et al., 1449E $artznn et
al., 233C-. $echanistic studies have shown that "uercetin was effective in reducin
the !ro-duction of reactive oxyen s!ecies, decreasin the myelo!eroxidase activity,
and increase-in mucosal non!rotein S' com!ounds and H#x *$artznn et al., 233C-
and SO5 *>ahraman et al., 1449- activities. 'isto!atholoical studies have shown
that "uercetin treatment decreased the number of mast cells and reduced the area of
astric erosions *>ahraman et al., 1449-. .dditionally, Su/uki et al. *233C- have also
observed that "uer-cetin was effective in reducin the '6l !lus ethanol-induced
astric mucosal inGury and in reducin the thiobarbituric acid-reactive substances in
the inGured mucosa in rats. #reclinical studies have also shown that "uercetin was
effective in reducin the indomethacin- *.larconn de la Lastra et al., 2337- and
diclofenac sodium *Nahorodny, 1449--induced ulcerations in rats.
E. 5AM*N PREVENTS GASTRIC CARCINOGENESIS
(ecently, Hoyal et al. *1424- have also observed that the hydroalcoholic extract of
Gamun seed was effective in !reventin the ben/o*a-!yrene *B.#--induced astric
carcinoen-esis in mice. The oral administration of the extract *10 m,k body
weiht,day- before, durin, and after the treatment with B.# showed the o!timal
chemo!reventive activity when com!ared to that of before and after B.#
administration schedules. :amun reduced the tumor incidence, multi!licity, tumor
burden, and cumulative number of astric car-cinomas. $echanistic studies showed
that Gamun caused a sinificant increase in the levels of !hase )) detoxifyin en/ymes
and inhibited the li!id !eroxidation in the stomach *Hoyal et al., 1424-.
$echanistic studies have also shown that administration of the a"ueous extract of
Gamun was effective in reducin the enotoxic effects of the carcinoens urethane and
<,21-dimethyl ben/*a-anthracene *5$B.- in mice. The antienotoxic effects
o!eratin may have been res!onsible for the observed chemo!reventive effects of the
Gamun seeds, at least in !art *.run et al., 1422-. .dditionally, studies have also shown
that Gamun seed !ossesses free radical-scavenin effects *BanerGee et al., 1440E
Benherlal and .rumuhan, 144<E >shirsaar and 8!adhyay, 1443E &ahar et al., 1443E
(a"uibul-'asan et al., 1443E (uan et al., 144CE Ieias et al., 144<E Nhan and Lin,
1443-, inhibits li!id !eroxi-dation, increases antioxidant biomolecule HS', and
increases !hase )) detoxification *lutathione S-transferase *HST-- and antioxidant
en/ymes *SO5 and 6.T-, and they may have also contributed toward the observed
chemo!revention *.run et al., 1422E Hoyal et al., 1424-.
;ith reard to the Gamun, !hytochemical studies have shown that the !oly!henol
ellaic acid, the other im!ortant constituent, is re!orted to !revent the 5$B.-
induced astric carcinoenesis in the rainbow trout *Oncorhynchus mykiss- *'artti et
al., 233D-. Wuercetin, the other im!ortant constituent, is shown to inhibit the rowth
and to induce a!o!tosis of human astric carcinoma cells $H6-C49 *;an et al.,
144D- and to inhibit the cell cycle !roression and rowth of human astric cancer
cells in vitro *=oshida et al., 2334-. ?eedin rats with "uercetin *2, 0, 14, and 04 ,k-
is also shown to inhibit intes-tinal cry!t cell !roliferation and to inhibit 2,1-
dimethylhydra/ine induction of aberrant cry!ts *Hee et al., 1441-. E!idemioloical
studies have also shown that hih dietary intake of "uercetin was inversely related to
the risk of noncardia astric adenocarcinoma and !rotects women ex!osed to tobacco
smokin-induced oxidative stress *Ekstroom et al., 1422-. Toether, all these re!orts
indicate the usefulness of Gamun and its !hytochemicals as a astro!rotective aent
and em!hasi/e the need for detailed investiations.
G. ANTIDIARRHEAL EFFECTS
5iarrhea which may be observed as a mild and ino!!ortune illness, at times in its
severe state causes malnutrition, !articularly amon the children. .ccordin to the
;orld 'ealth Orani/ation *;'O-, annually, diarrhea causes 2.C< million deaths,
es!ecially in the underdevelo!ed countries, and its !revention is a !riority for both
international and national aencies *Boschi-#into et al., 144C-. $ukherGee and
colleaues, in their investiative studies for the first time validated the traditional use
of these !lants as anti-diarrheal aents. The authors observed that administerin the
ethanolic extract of the Gamun tree bark was effective aainst different ex!erimental
models of diarrhea in rats. The extract showed sinificant inhibitory activity aainst
the castor oil-induced diarrhea and !rostalandin E1 *#HE1--induced entero!oolin
and also caused reduction in the astrointestinal motility in charcoal meal studies.
Toether, all these observations em!ha-si/e the usefulness of Gamun as antidiarrheal
aent.
K. ANTIBACTERIAL ACTIVITY
Studies have shown that the hydroalcoholic extract of the leaf *5e Oliveira et al.,
144<-E !etroleum ether, methanolic, and ethyl acetate extract of the leaf *>aneria et
al., 1443-E the a"ueous extract of the leaf *Satish et al., 144C-E the methanolic and
ethyl acetate ex-tracts of seed *Bhuiyan et al., 233D-E the methanolic extract of the
seed *.charyya et al., 1443-E the a"ueous, ethanolic, and acetone extracts of the bark
*Sharma et al., 1443-E and the essential oil *Shafi et al., 1441- have all been shown to
!ossess antibacterial effects. Toether, all these observations clearly indicate that the
Gamun !ossesses antibacterial com!ounds in the extract and warrant detailed
investiation, es!ecially with the isolated !hytochemicals.
L. RADIOPROTECTIVE EFFECTS
)n cancer treatment, the use of radiothera!y althouh beneficial causes severe side
effects by affectin the borderin normal tissues. )n such situations, an aent that can
render a thera!eutic differential between the cancer and normal cell will be beneficial
*:aetia et al., 1440-. Thera!eutic differential may be achieved with chemical
com!ounds that may selectively !rotect the normal cells from the deleterious effects
of radiation termed as radio!rotectors *:aetia et al., 1440-. Studies have shown that
the intra!eritoneal ad- inistration of the dichloromethane extract of Gamun leaf
!ossesses radio!rotective effects. 'isto!atholoical investiations showed that when
com!ared with the concur-rent irradiation control, administerin Gamun leaf increased
the villus heiht and the number of cry!ts and reduced the oblet and dead cells. The
recovery and reeneration were faster in Gamun-!retreated animals than the
irradiation-alone cohorts, and this may have contributed toward the increased survival
of mice *:aetia et al., 144C-.
O. HEPATOPROTECTIVE EFFECTS
Liver diseases remain as one of the most serious health !roblems, and with
satisfactory !rotective drus unavailable in the allo!athic system of medicine, !eo!le
rely on the com!lementary and alternative medicines. #reclinical studies with the
cultured !rimary rat he!atocytes have shown that the !ul! extract of Gamun rich in
anthocyanins *194 m, 244 dry weiht- was effective in !reventin the carbon
tetrachloride *66l
7
--induced liver damae. Treatin he!atocytes with the extract *04M
044 !!m- su!!ressed the 66l
7
- induced release of lactate dehydroenase *L5'-,
decreased the li!id !eroxidation, reversed the toxicant-induced chanes in cellular
lutathione level, and increased the activity of the antioxidant en/yme H#x *Ieias et
al., 144C-. The !ul! extract was also effective in amelioratin the !aracetamol-
induced he!atotoxicity in rats *5as and Sarma, 1443-. ;hen com!ared with the
!aracetamol-alone cohorts, feedin of the !ul! extract at 244 or 144 m,k,day for 24
consecutive days caused a concentration-de!endent decrease in the levels of serum
lll
alanine aminotransferase *.LT-, as!artate aminotransferase *.ST-, .#, and total
bilirubin *5as and Sarma, 1443-. The histo!atholoical findins also su!!orted the
biochemical observations, and a reduction in necrosis and fibrosis was cons!icuous
*5as and Sarma, 1443-.
The a"ueous extract of the leaf was also observed to be effective in !reventin
66l
7
- induced he!atotoxicity in rats when administered either as a sinle dose or
consecutively for < days. .dministerin the extract for < consecutive days caused a
sinificant decrease in the levels of .ST and .LT, while sinle-dose administration
was com!aratively in-effective *$oresco et al., 144<-. .dditionally, administerin the
methanolic extract of the seed *doses 244, 144, and 744 m,k !.o.- also caused a
he!ato!rotective effects aainst the 66l
7
-induced damae as observed from both
biochemical and histo!atholoy-ical observations *Sisodia and Bhatnaar, 1443-.
Wuercetin is also shown to be effective in !reventin the !aracetamol-induced
dam-ae and to reduce the death by 94R. Biochemical studies have shown it to
reduce the serum levels of .ST and .LT *.manlia et al., 144<E :anba/ et al., 1447-.
Wuercetin is also shown to be effective in !reventin the 66l
7
-induced liver cirrhosis
in rats *:anba/ et al., 1447-. ;hen com!ared to the 66l
7
-only cohorts, the
administration of "uercetin *044 Xl,k i.!., 204 Xmol,k body weiht- reduced the
levels of serum .LT, .ST, total bilirubin, conGuated bilirubin, and factor I.
Wuercetin was also effective in increasin the activities of the antioxidant en/ymes
*SO5, 6.T, H!x- and !hase )) detoxification en/yme *HST- and concomitantly
reduced the levels of li!id !eroxidation. The histo-!atholoical observations showed
reduced liver fibrosis indicatin its !rotective effects *.manlia et al., 144<-.
Wuercetin is also shown to be effective in !reventin the ethanol-induced
he!atotox-icity in rats *6hen, 1424-. ;hen com!ared to the ethanol-treated rats, the
administration of "uercetin reduced the ethanol-induced increased levels of .ST,
.LT .5', b-HT, and TH in !lasmaE the levels of cytokines such as )L-2a, )L-2, )L-
D, )L-C, and T&?-c in rats !lasmaE and $5. in liver tissue. Wuercetin increased the
levels of antioxidant HS' content in the liver and )L-24 in !lasma *6hen, 1424-.
Studies !erformed with cul-tured human he!atocytes have shown that "uercetin
!rotected human he!atocytes by !reventin the ethanol-induced de!letion of
lutathione, increase in malondialdehyde, and release of cellular L5' and .ST.
$echanistic studies clearly showed that "uercetin !revented the ethanol-derived
oxidative stress by inducin heme oxyenase-2 via the $.#>,&rf1 !athways *=ao et
al., 144<-.
The !oly!henol ellaic acid is re!orted to be effective in !rotectin the cultured
he-!atocytes aainst the vitamin >9-induced a!o!tosis and necrosis. .nimal studies
have also shown that ellaic acid was effective in concanavalin .-induced fulminant
liver dam-ae in mice *'wan et al., 1424-. .nthocyanins, the !rinci!al colorin
!hytochemical of the !ul!, is shown to reduce the cadmium-induced he!atotoxicity in
rats *>owalc/yk et al., 1449-. In vitro studies have also shown that the tannin
corilain !oses cytotoxic effects on the 'e!9B he!atocellular carcinoma cells, and the
intra!eritoneal administra-tion of the corilain for < consecutive days caused a
sinificant inhibition of the in vivo rowth of xenorafted 'e!9B he!atocellular
carcinoma *'au et al., 1424-. .dditionally, studies have also shown that the corilain
was also effective in !reventin alactosamine- *D44 m,k, s.c.,- and
li!o!olysaccharide *4.0 X,k, i.!.--induced he!atotoxicity in rats throuh
su!!ression of oxidative stress and a!o!tosis *>inoshita et al., 144<-. 6ollec-tively,
all these observations indicate the usefulness of Gamun and its !hytochemicals as a
he!ato!rotective aent and em!hasi/e the need for detailed investiations.
>R.CONCL*SIONS
Scientific studies carried out in the !ast two decades suest the usefulness of
Gamun in amelioratin the various ailments associated with the astrointestinal
system. $ost studies have been with animal models and validated Gamun%s clinical
a!!licability to human. 'owever, studies are warranted to understand the efficacy of
Gamun in humans. .s hu-man beins have been consumin these !lants since time
immemorial, the maGor advan-tae of these dietary inredients over the synthetic
drus lies in the fact that most of them have a low effective dose to hih toxic dose
ratio. These !ro!erties ive immense advan-tae as it can be easily recommended for
human trials and at lesser costs. Toether, all these results suest that Gamun is safe
and has tremendous !otential to develo! as a non-toxic medicinal aent for
astrointestinal ailments.
ACKNOWLEDGMENTS
The authors are rateful to (ev. ?r. #atrick (odrius *director-, (ev. ?r. 5enis
5%Sa *administrator, ?ather $uller $edical 6ollee-, and 5r. :aya!rakash .lva
*dean, ?ather $uller $edical 6ollee- for their unstinted su!!ort.
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on antioxidant activities of six indienous !lants of Banladesh. :ournal of .!!lied
Sciences (esearch 0, 11C0M11CC.
&amba, T.$., Tsune/uka, &.>., 5issanayake, 8.#., 'attori, $., 23C0. Studies on
dental caries !revention by traditional medicines. #art I)). Screenin of .yurvedic
medicines for anti!la"ue action. Shoyaku-aku Nasshi 93, 27D.
(amire/, (.O., (oa :r., 6.6., 1449. The astro!rotective effect of tannins
extracted from duhat *!yBygium cumini Skeels- bark on '6l,ethanol induced astric
mucosal inGury in S!raueM5awley rats. 6linical 'emorheoloy and $icrocirculation
13, 109M1D2.
(a"uibul-'asan, S.$., 'ossain, $.$., .kter, (., :amila, $., $a/umder, $.E.'.,
(ahman, $.E.'., 1443. 5##' free radical scavenin activity of some Banladeshi
medicinal !lants. :ournal of $edicinal #lants (esearch 9, C<0MC<3.
Satish, S., (ahavendra, $.#., (aveesha, >..., 144C. Evaluation of the
antibacterial !otential of some !lants aainst human !athoenic bacteria. .dvances in
Bioloical (esearch 1, 77M7C.
Shafi, #.$., (osamma, $.>., :amil, >., (eddy, #.S., 1441. .ntibacterial activity
of !yBygium cumini and Sy/yium travancoricum leaf essential oils. ?itotera!ia <9,
727M72D.
Sharma, .., #atel, I.>., 6haturvedi, ..&., 1443. Iibriocidal activity of certain
medicinal !lants used in )ndian folklore medicine by tribals of $ahakoshal reion of
central )ndia. )ndian :ournal of #harmacol-oy 72, 213M299.
Sisodia, S.S., Bhatnaar, $., 1443. 'e!ato!rotective activity of %ugenia
Cambolana Lam. in carbon tetrachlo-ride treated rats. )ndian :ournal de #harmacoloie
72, 19M1<.
Su/uki, =., )shihara, $., Seami, T., )to, $., 233C. .nti-ulcer effects of
antioxidants, "uercetin, al!ha-toco!herol, nifedi!ine and tetracycline in rats. :a!anese
:ournal of #harmacoloy <C, 790M772.
Ieias, :.$., &arayan, $.S., Laxman, #.$., &eelwarne, B., 144<. 6hemical
nature, stability and bioeffi-cacies of anthocyanins from fruit !eel of !yBygium cumini
Skeels. ?ood 6hemistry 240, D23MD1<.
Ieias, :.$., Shrivasthava, (., &eelwarne, B., 144C. Efficient amelioration of
carbon tetrachloride induced toxicity in isolated rat he!atocytes by !yBygium cumini
Skeels extract. Toxicoloy )n Iitro 11, 2774M277D.
;an, '.=., Huo, L.$., 6hen, =., et al., 144D. Wuercetin inhibits rowth and
induces a!o!tosis of human astric carcinoma cells. Oi Bao =u ?en Na $ian =i Oue
Na Nhi 11, 0C0M0C<.
;arrier, #.>., &ambiar, I.#.>., (amankutty, 6., 233D. )ndian $edicinal #lants,
vol. 0. Orient Lonman Ltd., 'yderabad, )ndia !!. 110M11C.
=ao, #., &ussler, .., Liu, L., et al., 144<. Wuercetin !rotects human he!atocytes
from ethanol-derived ox-idative stress by inducin heme oxyenase-2 via the
$.#>,&rf1 !athways. :ournal of 'e!atoloy 7<, 109M1D2.
=oshida, $., Sakai, T., 'osokawa, &., et al., 2334. The effect of "uercetin on cell
cycle !roression and rowth of human astric cancer cells. ?EBS Letters 1D4, 24M
29.
Nahorodny, $.)., 1449. Effect of "uercetin on sodium diclofenac-induced
ulceration. Likars%ka S!rava 2, 3DM33.
Nhan, L.L., Lin, =.$., 1443. .ntioxidant tannins from !yBygium cumini fruit.
.frican :ournal of Biotech-noloy C, 1942M1943.
CHAPTER ?E
Pr(+($ti$" th( E3i/(.i& !'
N!$%C!..#$i&ab( Dis(as(s)
A$ O+(r+i(0
A.A. R!bs!$
8niversitQ de Bretane Occidentale, #lou/anQ, ?rance
ABBREVIATIONS
AA .rachidonic acid
ALA .l!ha-linolenic acid
DHA 5ocosahexaenoic acid
EPA Eicosa!entaenoic acid
>. INTROD*CTION TO THE WORLD\S BIGGEST PROBLEM
)n the twentieth century, science and technoloy brouht about !henomenal
chane. 'ue advances were made in all branches of medicine, dianostics, drus and
dru de-livery, ene thera!ies, etc. =et, now in the twenty-first century, there is a
lobal e!idemic of non-communicable diseases *(obson, 1443-. Leadin scientist
#rofessor Steve :ones said the ho!e that enetic research could !rovide a cure for a
host of common diseases *enetic disorders are rare- has !roved to be a false dawn
and that we have wandered into a blind alley and it miht be better that we come out
of it and start aain. )n most cases, hundreds of enes are res!onsible, and often they
have less effect than other factors such as diet, lifestyle, and the environment *:ones,
1443-. The ene code for the coa-ulation factors in humans is much the same as it is
for the !uffer fish, 'ugu rubripes, whose enome dates back 704 million years *:ian
and 5oolittle, 1449-. The rise in death from heart disease M coaulation of the blood M
was not caused by the unchaned enes but by a bad diet o!eratin on ancient enes
*Edward H. 5. Tuddenham, #rofessor of 'aemo!hilia at 8niversity 6ollee London,
!ersonal communication-. The view of diet bein a maGor driver of health and disease
dates back to Sir (obert $c6arrison%s studies in )ndia early last century. This
overview hihlihts the maGor chanes to the modern hu-man diet that are urently
needed in order to !romote health and hel! !revent the lobal e!idemic of non-
communicable diseases.
?. H*MAN DIET
.riculture introduced foods as sta!les for which the human enome had little
evolution-ary ex!erience. $ore im!ortantly, food !rocessin !rocedures were
develo!ed, !artic-ularly followin the )ndustrial (evolution, which allowed for
"uantitative and "ualitative food and nutrient combinations that had not !reviously
been encountered over the course of human evolution. 6ookin oils, cereals, dairy
!roducts, refined suars, fatty meats, alcohol, &a6l salt, and combinations of these
foods fundamentally altered several key nutritional characteristics of ancestral human
diets and ultimately had far-reachin effects on health and well-bein. .s these foods
radually dis!laced the minimally !rocessed, but often cooked, wild foods in human
diets, they adversely affected the fol-lowin dietary indicators+ *2- fatty acid
com!osition, *1- enery density, *9- macronutri-ent com!osition, *7- micronutrient
density, *0- acidMbase balance, *D- sodium *as &a6l-M !otassium ratio, and *<- fiber
content *6ordain et al., 1440E (obson, 1443-. ;ild foods known to be consumed by
hunterMatherers have hiher nutrient concentrations than their domesticated
counter!arts *Brand-$iller and 'olt, 233CE Eaton and >onner, 23C0-, includin the
muscle meat of wild animals *?irst 5ata Bank, 1444-. 'umans may have started
consumin cereal rains *e.., wheat, rice, and mai/e- tens of thou-sands ormore years
ao, but the human immune, diestive, and endocrine systems have not yet fully
ada!ted to cereals, which !rovide 0DR of humanity%s food enery and 04R of its
!rotein *6ordain, 2333-. 6ereal rains are truly humanity%s double-eded sword
*6ordain, 2333-. ?or without them, our s!ecies would likely have never evolved the
com!lex cultural and technoloical innovations which allowed our de!arture from the
hunterMatherer niche. 'owever, because of the dissonance between human evolu-
tionary nutritional re"uirements and the nutrient content of these domesticated
rasses, many of the world%s !eo!le suffer disease and dysfunction directly
attributable to the consum!tion of cereals *6ordain, 2333-.
B. EPIDEMIC OF NON%COMM*NICABLE DISEASES
5iet, lifestyle and environment do not Gust affect a !erson%s health, they also
determine the health of their children and !ossibly the health of their randchildren
*$arsh, 1421E #embrey et al., 144D-. ?ifty seven million deaths occurred lobally in
144C, of those deaths, 9D million M almost two thirds M were caused by non-
communicable diseases. &on-communicable diseases are caused, to a lare extent, by
an unhealthy diet, insuffi-cient !hysical activity, and dru *e.., tobacco and alcohol-
abuse *;orld 'ealth Orani/ation, 1422a-. &on-communicable diseases are a
substantial economic burden today and are !redicted to cost the world economy in the
reion of 8S ]7< trillion over the next 14 years, !ushin millions of !eo!le below the
!overty line *Bloom et al., 1422-. &on-communicable inflammatory diseases, for
exam!le, cardiovascular diseases and non-communicable mental ill health *(obson
1429b- are lobal e!idemics and when combined, they ty!ically afflict 04MD0R of the
!o!ulation in modern societies. 6ardio-vascular diseases are the number one cause of
death lobally *2<.9 million !eo!le died from cardiovascular diseases in 144C,
re!resentin 94R of all deaths-, and it is !roGected that by 1494, almost 19.D million
!eo!le !er year will die from cardiovascular diseases, mainly from heart disease and
stroke *;orld 'ealth Orani/ation, 1422b-. .s !redicted in 23<1 *6rawford and
6rawford, 23<1-, brain disorders have followed the rise in car-diovascular disease,
and the cost of brain disorders has now overtaken those of any other health burden
*6rawford et al., 1443E (obson, 1429bE ;an et al., 1424-. The reason for linkin
heart disease and brain disorders is that durin early develo!ment, the brain relies
heavily on a !re-existin and efficient !lacental vascular and fetal cardiovascular
system. The fetal brain uses <4R of the enery transferred to the fetus from the !la-
centa. The !lacenta itself is a ra!idly rowin vascular system which needs to be in
!lace ahead of the fetal brain rowth s!urt of the last trimester. 'ence, healthy brain
develo!ment is very much de!endent on a ood cardiovascular circulation. #ut sim-
!ly, if the cardiovascular system is under attack in an adult from !oor nutrition, the
brain in the next eneration*s- is likely to suffer *6rawford et al., 1443E cf. $arsh,
1421E #embrey et al., 144D-. The to! !redicted causes of death and disability world-
wide for 1414 *ischemic heart disease and uni!olar maGor de!ression- and the to!
three causes in develo!ed reions *ischemic heart disease, cerebrovascular disease,
and uni!olar maGor de!ression- *$urray and Lo!e/, 233<- have common
denominators in adverse nutrition and are related and relevant to both neuroenesis
and neuron-deeneration *6rawford et al., 1443-.
6ancer is a leadin cause of death worldwide and accounted for <.D million deaths
*around 29R of all deaths- in 144C, and deaths attributable to cancer are !roGected to
continue risin *;orld 'ealth Orani/ation, 1421a-. .n estimated one-third of all
cancer deaths are because of nutritional and lifestyle factors *5anaei et al., 1440-.
5iet-induced inflammation leads to insulin resistance and ty!e 1 diabetes *Solinas et
al., 144<-, and takin into account deaths in which diabetes was a contributory con-
dition *heart disease or kidney failure-, a!!roximately 1.3 million deaths in 1440 were
attributable to diabetes *;orld 'ealth Orani/ation, 144C-. Ty!e 1 diabetes is ra!idly
becomin a disease of children and adolescents. )n 1444, it was estimated that 94R of
boys and 74R of irls born in the 8nited States were at risk of bein dianosed with
ty!e 1 diabetes at some !oint in their lives *)nstitute of $edicine, 1440b-. Hlobally, in
1424, more than 74 million children under the ae of 0 years were over-weihtE in
144C more than 2.7 billion adults, ae 14 years and older, were overweiht and of
these over 144 million men and nearly 944 million women were obese *;orld 'ealth
Orani/ation, 1421b-. )n 144D *;orld 'ealth Orani/ation, 144D-, the ;orld 'ealth
Orani/ation estimated that by 1420, a!!roximately 1.9 billion adults would be
overweiht and more than <44 million would be obese *?iure 10.2- M these
Fi"#r( ?E.> .n obese !erson eatin hih-enery-dense !rocessed food. )t is an
inesca!able fact that consumin more calories than is needed results in weiht ain, even if
there is enetic variation between one !erson and the next *.nthony .. (obson
@
-.
statistics may be underestimated *see obesity statistics above-. Once considered a
!roblem only in hih-income countries *;orld Bank classification+
htt!+,,data.worldbank.or, about,country-classifications-, the !revalence of
overweiht and obese !eo!le is now dramatically on the rise in low- and middle-
income countries, !articularly in urban settins where exercise is o!tional and hih-
enery-dense *`1 kcal
-2
M Ledikwe et al., 144D- fast food is now !lentiful *?iure
10.1-. =et, inflammatory diseases and brain disorders are rare or nonexistent in
hunterMatherers eatin a late #aleolithic diet, that is, a low-enery-dense diet with a
wild !lant-to-animal enery intake ratio 2+2, with fish and shellfish !rovidin a
sinificant !ro!ortion of the animal com!onent *see Eaton et al., 1424-.
Fi"#r( ?E.? Exam!les of widely consumed modern foods with both a hih-enery-
density and a lownutrient- density+ *a- bread, *b- boiled sweets, *c- domesticated !i and
chicken intensively reared on an unnatural diet that is both hih-enery-dense and a low-
nutrient-dense, and *d- ?rench fries *.nthony .. (obson
@
.-
D. INFLAMMATION
8ncontrolled excessive !roduction of !roinflammatory mediators over !roloned
!e-riods of time is associated with heart attacks, thrombotic stroke, arrhythmia,
arthritis, asthma, headaches, dysmenorrhea *menstrual cram!s-, inflammation, cancer,
and oste-o!orosis *Samuelsson, 23<3-. The cardio!rotective effects of anti-
inflammatory 5'. and E#. have been reconi/ed for over 04 years, with the low
incidence of mortality from cardiovascular disease in Eskimos consumin a diet rich
in 5'. and E#. *e.., $akhoul et al., 1424E Sinclair, 230D-. )nflammatory diseases
all seem linked to a lack of anti-inflammatory aents in the diet and excess food
enery *the !ositive imbalance between enery intake and enery ex!enditure-. The
close interaction between d-9 *includin 5'. and E#.- and d-D fatty acids
*includin amma-linolenic acid *2C+9, n-D-, dihomo-amma-linolenic acid *14+9, n-
D-, and .. *14+7, n-D-- on the ability to modify inflammatory markers, !roduction of
!rostacyclin, !rostalandin E2, !rosta-landin )
9
, li!oxins, resolvins, neuro!rotectins,
nitric oxide, and nitroli!ids, and the action of as!irin,
2
statins,
1
lita/ones,
9
and
nitrolycerin
7
on essential fatty acid metab-olism and nitric oxide ex!lains the
relationshi! between both various fatty acids and excess food enery and
cardiovascular disease *Lands, 144CE (obson, 1443-.
.ccordin to the review by Hriffin *144C-, the totality of evidence for the !ositive
effects of 5'. and E#. on various outcomes of cardiovascular disease is almost
incon-trovertible. )t should be noted that the !rimary !revention of cardiovascular
*inflamma-tory- disease starts, crucially, with o!timal adult nutrition before the
ince!tion of !renancy and continues throuhout the life of the newborn and includes
consumin not only more 5'. and E#. but also their cofactors. ?or their
!hysioloical,beneficial actions, 5'. and E#. need many cofactors, not currently
!resent in 5'. and E#. ca!sules, such as folic acid, vitamin B21, vitamin BD,
vitamin 6, tetrahydrobio!terin *B'
7
-, /inc, manesium, calcium,
L
-arinine and small
amounts of selenium, and vitamin E- *(obson, 1443-. )t is im!ortant to note that if
5'. and E#. undero oxidation, it attenuates their beneficial effects *Turner et al.,
144D-. Bioactive !ackain made from nanomaterials can control the oxidation of
foodstuffs *So/er and >okini, 1443-. ?urther, the excessive consum!tion of anythin
may cause disease or !remature death, includin 5'. and E#. *e.., 6hurch et al.,
1443-.
Tumor cells undero a!o!tosis *!rorammed cell death- on ex!osure to 5'. and
E#. because of an increase in intracellular free radical eneration and the formation
of li!id !eroxides *5as, 144C-. 'owever, most e!idemioloical cohort studies have
found no association between 5'. and E#. intake and cancer risk *e.., $acLean et
al., 144D-. But inverse associations with breast cancer have been re!orted in 6hinese
and :a!anese women havin 5'. and E#. intakes u! to 74 times reater than
;estern intakes *e.., Hao-5ominue/ et al., 1449E ;akai et al., 1440-.
)ncreasin human consum!tion of 5'. and E#. and their cofactors, and eatin
less food enery !er meal to lower transient short-lived meal-induced oxidative stress
*e.., Libby, 1441- inflammation, !roliferation, and im!aired nitric oxide *e.., Lands,
144C-, ultimately could have far-reachin effects on health and well-bein. Evidence
leaned over more than three decades now indicates that virtually all so-called
diseases of civili-/ation arise from a com!lex interaction of multi!le nutritional
factors directly linked to the re!lacement of ancestral foods by the excessive
consum!tion of &eolithic and )ndus-trial era foods, alon with other environmental
aents and enetic susce!tibility *(obson, 1443-.
Fi"#r( ?E.B (elationshi! between enery density and water content based on allr food
items !resent in the .ustralian ?ood, Su!!lement and &utrient 5atabase *.8S&8T, 144<-
*enery density = -7.371 u water content + 7.CC3, ?
2,9C79
= 2D0DD.2<, # V 4.442, (
1
= 4.C2-.
The best-fit reression line *solid line- and 30R !rediction intervals *broken lines- are
included.
l
.ll foods and beveraes listed in the database *available from
htt!+,,www.foodstandards.ov.au,- were included for analysis unless the item was listed in a
state that was not normally consumed *e.., !owdered foods that need reconstitution-. )n total,
909D individual foods *includin raw and cooked foods- and 943 beveraes were included in
the analysis.
E. ENERGY DENSITY AND N*TRIENT DENSITY
'uman food !roduction should be linked to human nutritional re"uirements as its
first !riority *(obson, 1421-. Thus, the hih-enery-density and low-nutrient-density
that characteri/e the modern diet must be overcome simultaneously *(obson, 1422,
1421-. #eo!le can develo! !aradoxical nutritional deficiency from eatin hih-
enery-dense foods with a !oor nutrient content *(obson, 1443-. The findin that
!eo!le with a low-enery-dense diet *V2.D kcal
-2
- have the lowest total intakes of
enery, even thouh they consume the reatest amount of food, has im!ortant
im!lications for !ro-motin com!liance with a healthy diet *Ledikwe et al., 144D-. .
farmed and,or !rocessed food that is not both low-enery-dense and of hih-nutrient-
density *?iure 10.9, Table 10.2- is of !oor dietary "uality com!ared to the low-
enery-dense foods of hih-nutrient- density that humans should eat+ the most
nutritious cooked wild !lant and animal foods for humans *Eaton et al., 1424E (obson,
144D, 1424a, 1422-.
#rocessed lowfat foods can have a deleteriously hih-enery-density *cf. (obson,
1429a-. The focus on Gust reducin dietary fat *?arhan 144<E 'sieh and Ofori 144<-,
must be refo-cused on reducin the !ositive imbalance between the intake and the
ex!enditure of food
Tab( ?E.> Enery 5ensity and &utrient 5ensity of a Selection of ?oods
*Ialue !er ram-
DHA Vita.i
$
@_"A
E$(r"y MEPA F(
a
C$ M" Ca
@,&aA @_"A @."A @."A @."A @."A B>? BG C
Oil,
soybean
b
*47477-
C.C 4 2 V2 4 4 4 4 4
&ut, Bra/il
nut *214<C-
D.D 4 17 72 9<D
4
2D4
4
4 2.4 <
6hocolate,
dark *23347-
D.4 4 223 99 11C
4
<94 4.44
9
4.7 4
Twix
h
bar,
$asterfoods
*712C9-
0.0 4 29 3 7D4 294
4
4.44
9
4.7 24
Oat
breakfast bar
*79244-
7.D 4 91 2D 242
4
D44 4 9.0 24
6heese,
cheddar
*42443-
7.4 4 < 92 1C4 <12
4
4.44
C
4.< 4
$ayonnaise,
reular
*4742C-
9.3 4 1 1 14 274 4.44
1
4.1 4
S!ecial >
h
,
>ello%s
*4C4D<-
c
9.C 4 1<4 13 D14 944 4.23
0
D7 D<<
$ayonnaise,
liht *47D72-
9.1 4 9.1 1 14 C4 4 4 4
Bread, white
*2C4D3-
c
1.< 4 9< < 194 202
4
4 4.4C 4
Beef sirloin,
roasted
*29309-
1.2 4 2< 7< 114 234 4.42
0
0.0 4
6hicken
meat, roasted
*40429-
d
2.3 044 21 12 104 204 4.44
9
7.< 4
Beef brain,
cooked
*29914-
e
2.0 C004 19 22 214 34 4.24
2
2.7 240
6lam meat,
cooked
*20203-
e
2..0 1C74 1C4 1< 2C4 314 4.3C
3
2.2 112
E,
!oached
*42292-
f
2.7 724 2C 22 214 094 4.42
9
2.1 4
Oyster meat,
eastern,
wild, cooked
*202D3-
e
2.7 22144 214 2C2
D
304 344 4.90 2.1 D4
$oose meat,
wild, roasted
*2<2<9-
2.9 4 71 9< 174 D4 4.4D
9
9.< 04
;ater
buffalo meat,
wild, roasted
*2<2D2-
2.9 4 12 10 994 204 4.42
C
7.D 4
Shrim!
meat, cooked
*20202-
e
2.4 9204 92 2D 974 934 4.42
0
2.9 11
Banana, raw
*43474-
4.3 4 9 1 1<4 04 4 9.< C<
$ayonnaise,
extra liht
*71239-
4.C 4 2 2 14 D4 4 4 4
S!inach,
boiled
*2270C-
4.1 4 9D C C<4 29D
4
4 1.7 3C
6elery,
boiled
*22277-
4.1 4 7 2 214 714 4 4.3 D2
Entries retrieved from the 8S5. &ational &utrient 5atabase for Standard
(eference, (elease 11 *1443- and are identified by a 0-diit nutrient database number
in !arentheses.
a
@N*MBERINGATwo billion !eo!le, over 94R of the world%s !o!ulation are
anemic, many because of iron deficiency *;orld 'ealth Orani/ation, 1443-.
b
@N*MBERINGASoybean oil !rovides 14R of all calories in the median 8S
diet *Herrior and Bente, 1441-.
c
@N*MBERINGA?ortified with nutrients.
d
@N*MBERINGA )ntensively reared chicken+ if one takes 5'. as the limitin
nutrient for the assessment of "uality, then to obtain the same amount of 5'. today
as can be obtained from one wild chicken, one would need to eat six intensively
reared chickens M inestin somewhere in the reion of 3444 kcal *;an et al., 1424-.
e
@N*MBERINGA?ood with a hih natural nutrient content and a low-enery-
density.
f
@N*MBERINGA Iitamin B21 in es is !oorly absorbed relative to other
foods containin B21 *;atanabe, 144<-.
enery. Low-fat, hih-carbohydrate cereal-based !roducts are often of hih-
enery-density. ?or exam!le, a $asterfoods Twix
h
chocolate biscuit bar+ 0DR
carbohydrate and 1.1R water - =0.0 kcal
-2
, >ello%s S!ecial >
h
+ <2R carbohydrate
and 9R water=9.C kcal
-2
, white bread+ 02R carbohydrate and 9DR water=1.< kcal
-
2
, while roasted wild water buffalo meat+ 4R carbohydrate and D3R water=2.9 kcal
-
2
, shrim! meat cooked in moist heat+ 4R carbohydrate and <<R water=2.4 kcal
-2
and
boiled celery+ 7R carbohydrate and 37R water=4.1 kcal
-2
*cf. ?iure 10.9 and Table
10.2-.
#rocessed food !roducts of !lant oriin such as chocolate bars, biscuits, fruit bars,
and cereal bars have a hih-enery-density !rinci!ally because they have low water
content *(obson, 1422, 1421, 1429a-. Self-assembled, water-filled, edible nanotubes
that self-orani/e into a more com!lex structure, !ossibly a 95 network of nanocel-
lulose, could be incor!orated into many !rocessed foods to lower their enery density
to V2.D kcal
-2
*(obson, 1421E cf. &orton et al., 1443-. &anocellulose is com!osed of
nanosi/ed cellulose fibrils *fiber diameter+ 14M244 nm-, has a water content of u! to
33R and the same molecular formula as !lant cellulose *>lemm et al., 144D-. The
water inside the nanosi/ed cellulose fibrils could contain flavor with few calories, for
exam!le, a cu! of tea without milk = 4.42 kcal
-2
. The sha!e and su!ramolecular
structure of the nanocellulose can be reulated directly durin biosynthesis to !roduce
fleeces, films,!atches, s!heres, and tubes *>lemm et al., 1422-. Other edible materials
can stronly adhere to the surface and the inside of nanocellulose structures such as
fleeces to form edible com!osites *6han et al., 1421-. Taste sensation !er mouthful
could be im!roved by addin flavorin substances !rocessed on the nanoscale
Fi"#r( ?E.D Oysters, 1strea edulis, for sale at a ?rench market. Oysters, es!ecially
cooked wild oysters, are both low-enery-dense and some of the most nutritious foods for
humans on the !lanet. 'owever, they lack the fiber found in !lants *.nthony .. (obson@-.
*increased surface area in contact with taste and smell rece!tors- to edible com!osites
*8ltrafine food technoloy+ Eminate Limited, &ottinham, 8nited >indom-. 5ur-
ethan
h
>81-1D42 !ackain film !roduced by Bayer #olymers, Hermany, is a nano-
com!osite film enriched with silicate nano!articles which is desined to !revent the
contents from dryin out and !revent the contents comin into contact with oxyen
and other ases. 5urethan
h
>8 1-1D42 can !revent food s!oilae *&eethiraGan and
:ayas, 1422- and thus the water content of dehydrated !lant-based food !roducts can
be increased without reducin !roduct shelf life. Therefore, nanocellulose is ex!ected
to be widely used as a nature-based food additive *6han, et al., 1421E>lemm, et al.,
1422-.
The bioavailable nutrient content includin cofactors of !rocessed foods should be
based on the nutritional value of the most nutritious cooked wild foods for humans
*?iure 10.7- and can be increased usin existin bioactive enca!sulation *(obson,
1424a, 1422-. ."uatic biotechnoloy can !rovide the food industry with sufficient
amounts of all the nutrients needed for mass scale o!timal human nutrition includin
!rotein, 5'., E#., .., vitamins, minerals, and fiber *'arun et al., 1424E Liu et al.,
1421E Orti/ et al., 144D-. (educin !article si/e usin nanotechnoloy can further im-
!rove the !ro!erties of bioactive com!ounds *e.., 5'. and E#.-, such as delivery,
solubility, !roloned residence time in the astrointestinal tract, and efficient
absor!tion throuh cells *6hen et al., 144D-.
Tab( ?E.? Suar, #rotein, and ?iber 6ontent of a Selection of Sweet
?oods and 5rinks *Ialue !er 244 -
S#"ar @"A Pr!t(i$ @"A Fib(r @"A
Hranulated suar 33.C 4.4 4.4
*23990-
Brown suar
*23997-
3<.4 4.2 4.4
'oney *2313D- C1.2 4.9 4.1
Ianilla fude
*23249-
<3.C 2.2 4.4
6hewin um
*232D9-
DD.2 4.4 1.7
a
Toffee sweets
*239C9-
D9.0 2.2 4.4
Boiled sweets
*2324<-
D1.3 4.4 4.4
$a!le syru!
*23909-
03.0 4.4 4.4
$arshmallows
*2322D-
0<.D 2.C 4.2
:ellies *23944- 02.1 4.1 2.4
.!ricot !reserve
*23<23-
79.7 4.< 4.9
6reme de menthe
drink *27497-
72.D 4.4 4.4
>ello%s ?rosted
?lakes
h
*4C4D3-
9C.< 7.9 2.C
'ih-fructose corn
syru! *23902-
1D.7 4.4 4.4
#ina colada drink
*2742<-
11.9 4.7 4.9
6hocolate
milkshake *42224-
14.3 9.2 4.9
Ianilla ice cream
*234C3-
14.< 9.0 4.4
6ola drink *2727C- 24.D 4.4 4.4
(ed Bull
h
drink
*27207-
24.2 4.9 4.4
Entries retrieved from the 8S5. &ational &utrient 5atabase for Standard
(eference, (elease 11 *1443- and are identified by a 0-diit nutrient database number
in !arentheses.
a
The fiber in the chewin um is not usually inested.
. reduction in li"uid calorie intake has been found to have a reater effect on
weiht loss than a reduction in solid calorie intake *6hen et al., 1443-. Suar-
sweetened beveraes *SSBs- re"uire little diestion. Hlucose and fructose can be
directly absorbed into the Blood stream without diestion. (educin the enery
density of !rocessed foods, includin SSBs, and simultaneously increasin the cost of
their assimilation makes them more akin to foods consumed by late #alaeolithic
humans. The eneretic cost of the assimilation of !ro-cessed foods can be increased
by increasin their !rotein and fiber content *Table 10.1- *Eaton et al., 1424E (obson,
1424a, 1422-. #rotein has more than three times the thermic effect of either fat or
carbohydrate *6rovetti et al., 233C-, and !rotein has a reater satiety value than fat or
carbohydrate *6rovetti et al., 233CE Stubbs, 233C-. . hih-!rotein diet *!rotein and
carbohydrate intake both bein a!!roximately one-third of total enery intakeE Eaton
et al., 1424- is of vital im!ortance as a weiht-loss stratey for the overweiht or
obese and for weiht maintenance *(obson, 1443E Ieldhorst et al., 144C-. 6linical
trials have shown that calorie-restricted, hih-!rotein diets are more effective than are
calo-rie- restricted, hih-carbohydrate diets in !romotin *Baba et al., 2333E Layman,
1449E Skov et al., 2333- and maintainin *;esterter!-#lantena et al., 1447- weiht
loss in overweiht subGects, while !roducin less huner and more satisfaction
*:ohnston et al., 1447-. ?urthermore, hih-!rotein diets have been shown to im!rove
metabolic control in !atients with ty!e 1 diabetes *Odea, 23C7E Odea et al., 23C3E
Seino et al., 23C9-. ?ood-rade !rotein-based nanotubes *Hraveland-Bikker and 5e
>ruif, 144D- may be used to increase the !rotein content of !rocessed foods that are
currently hih in fat or hih in carbohydrate. ?unctional foods and drinks are re"uired
to simultaneously satisfy the human Ssweet tooth% and almost com!letely remove
added suars such as lu-cose, fructose, and sucrose from the diet *Eaton et al., 1424-.
Savory foods and drinks can be sweetened by addin fruit to them or addin calorie-
free #8(E?(8)T_ *Tate A Lyle- monk fruit *!iraitia grosvenorii- extract *(obson,
1421, 1429a, 1429b-. #8(E-?(8)T_ is a!!roximately 144 times sweeter than suar
and has exce!tional stability.
6ookin has obvious beneficial effects by increasin food safety and im!rovin
diet "uality *6armody and ;ranham, 1443-. 'owever, cookin can reduce the water
con-tent of a hih-enery-dense !rocessed food and, thus, further increase its
deleteriously hih-enery-density, es!ecially if it is cooked twice. ?or exam!le,
toastin whole-wheat bread increases its enery density from 1.0 to 9.2 kcal
-2
as
water content decreases by 27R *data calculated from 8S5. &ational &utrient
5atabase for Standard (eference-. &anoscale science and technoloy are now
enablin us to understand many natural and unnatural !rocesses. Studyin
nanostructures at the cell and 5&. level ives us insiht into the workin of these
!rocesses and how to mani!ulate, !revent, and,or enhance them for the benefit of
mankind.
G. ACIDbBASE BALANCEI NACL SALTI AND FIBER
CONTENT OF THE DIET
The late #aleolithic diet was net base yieldin because of very little cereal
consum!tion *Eaton et al., 1424-. The modern diet is too acidic *6ordain et al., 1440-E
that includes hunter-ather diets such as that of the traditional Eskimo, whose net
endoenous acid !ro-duction is acidic because of very little fruit and veetable
consum!tion *Eaton et al., 1424-. The known health benefits of a net base-yieldin
diet include !reventin and treatin os-teo!orosis *Bushinsky, 233DE Sebastian et al.,
2337-, ae-related muscle wastin *?rassetto et al., 233<-, calcium kidney stones *#ak
et al., 23C0E #reminer et al., 23C0-, hy!ertension *$orris et al., 2333E Sharma et al.,
2334-, exercise-induced asthma *$ickleborouh et al., 1442-, and the !roression of
ae- and disease-related chronic renal insufficiency *.l!ern and Sakhaee, 233<-.
.ddin sufficient amounts of !otassium bicarbonate to cereals and ce-real- based
!roducts will make them net base-yieldin foods.
The addition of manufactured &a6l salt to the food su!!ly and the dis!lacement
of traditional !otassium-rich foods by foods introduced durin the &eolithic and
)ndustrial !eriods caused a 744R decline in !otassium intake while simultaneously
initiatin a 744R increase in sodium inestion *6ordain, 1441E Eaton and >onner,
23C0-. The !otas-siumconcentrations in veetables are four and twelve times those
inmilk and whole rains, res!ectively, whereas in fruit, the !otassiumconcentration is
two and five times that inmilk and whole rains, res!ectively *?irst 5ata Bank, 1444-.
The inversion of !otassium and sodium concentrations in hominin diets had no
evolutionary !recedent and now !lays an interal role in elicitin and contributin to
numerous non-communicable diseases *6ordain et al., 1440-. 5iets lowin !otassium
and hih in &a6l saltmay !artially or directly underlie or exacerbate a variety of
maladies and chronic illnesses, includin hy!ertension, stroke, kidney stones,
osteo!orosis, astrointestinal tract cancers, asthma, exercise-induced asthma,
insomnia, air sickness, hih-altitude sickness, and $eniere%s syndrome *ear rinin-
*6ordain et al., 1440E (obson, 1443-.
The more &a6l salt one uses, the more one needs it in all kinds of foods *e..,
bread, !otatoes, and cheese- because of the damain effect of &a6l salt on taste
buds, which may be irreversible in older !eo!le but is normally recoverable within a
cou!le of months on a low &a6l salt diet *:oossens and Heboers, 23C2-. &ot addin
&a6l salt to *!rocessed- food and the biofortification of cereals and dairy !roducts
with !otassium bicarbonate will hel! alleviate the current sodiumM!otassium
imbalance in the human diet *and the deleterious acidMbase effect *net endoenous
acid !roduction-+ acidic-.
The ty!ical modern diet has a fiber content of 20.2 day
-2
*8.S. 5e!artment of
.riculture, 144C- which is considerably lower than the recommended value of 10M9C
day
-2
*)nstitute of $edicine, 1440a- or the estimated ancestral intake of `<4 day
-2
*Eaton et al., 1424-. (efined suars, cookin oils, dairy !roducts, and alcohol are
devoid of fiber and constitute an averae of 7C.1R of the enery in a ty!ical modern
diet *6ordain et al., 1440-. ?urthermore, fiber-de!leted, refined rains re!resent C0R
of the rains consumed in a ty!ical modern diet, and because they contain 744R less
fiber than whole rains *on an enery basis-, they further dilute the total dietary fiber
intake *6ordain et al., 1440-. ?resh fruit ty!ically contains twice the amount of fiber
in whole rains on an enery basis, and nonstarchy veetables contain almost eiht
times the amount of fiber in whole rains on an enery basis *?irst 5ata Bank, 1444-.
?ruit and veetables known to be consumed by hunterMatherers contain considerably
more fiber than their domestic counter!arts *Brand-$iller and 'olt, 233C-. 5iets low
in dietary fi-ber may underlie or exacerbate consti!ation, a!!endicitis, hemorrhoids,
dee! vein thrombosis, varicose veins, diverticulitis, hiatal hernia, and
astroeso!haeal reflux *Trowell, 23C0-. 5ietary fiber can be added to !rocessed
foods, for exam!le, chocolate *(obson, 1429a-, milk, cheese, ice cream, refined
cereals, and white bread, to increase the fiber content of the modern diet *(obson,
1443, 1421-.
K. ROADMAPPING THE F*T*RE
There are already more humans on Earth than can be sustained by the natural
world. Thus, the nutritional value of !rocessed and farmed foods will be increasinly
based on the nutritional value of the late #aleolithic human diet to hel! !revent diet-
induced disease because unbiased observers aree that nutritional advice from
conventional sources, whether based on e!idemioloic or mechanistic findins, has
not affected com!lex deen-erative disease incidence,!revalence as much as ho!ed
*Eaton et al., 1424-. ?urthermore, modern animal husbandry caused the rise in the
!roduction of hih-fat meat with a low-nutrient- density and it will have to be
corrected because of its neative effects on animal welfare and human nutrition
*.metaG et al., 1424E 5aley et al., 1424E :onsson et al., 144DE ;an et al., 1424-.
?unctional food !roducts and wellness !rorams that hel! !revent the causal
mechanisms of non-communicable diseases will be of reat benefit to mankind
*Lands, 1443E (obson, 1424b-. 'owever, the consum!tion of the most nutritious
cooked wild foods for humans, for exam!le, omnivorous shellfish *(obson, 144D-,
should be encouraed, and emerent technoloies will !robably enhance the
!roduction, utili/e-tion, and food safety of this nutritious resource. Emerent
technoloies will chane society beyond anythin that has one before. This should,
but not with any certainty, eventually slow down the s!iralin increase in healthcare
costs *Tolfree and Smith, 1443-.
L. CONCL*SION
&on-communicable disease is a situation out of control. The causes are
!reventable. &on-communicable disease is a lobal e!idemic because of the
combined effect of the modern diet *includin dru abuse- and a sedentary lifestyle
*(obson 1429b-. 'uman food !roduction must be linked to human nutritional
re"uirements as its first !riority. . low-enery-dense, dru-free diet rich in
bioavailable nutrients-!lus-exercise is most effective for !reventin non-
communicable disease throuhout life. 'ih-enery-density and low-nutrient-density
which characteri/e the modern diet must be overcome simultaneously. 5ru abuse
must be made socially unacce!table. &anocellulose and calorie-free monk fruit
extract could be used to lower the enery density of !rocessed foods,drinks, and their
bioavailable nutrient content includin cofactors can be increased usin bioactive
enca!sulation. ."uatic biotechnoloy can !rovide all the nutrients needed to make
!rocessed foods really nutritious. )n conclusion, the nutritional value of !rocessed and
farmed foods should be based on the nutritional value of the late #alaeolithic human
diet to hel! !revent cardiovascular disease, mental ill health, cancer, obesity, and
other !ost!randial insults *(obson, 1443, 1421, 1429a, 1429b-.
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industries. ?ood and Bio-!rocess Technoloy 7 *2-, 93M7<.
&orton, :., ?ryer, #., #arkinson, :., 6ox, #., 1443. 5evelo!ment and
characterisation of tem!ered cocoa butter emulsions containin u! to D4R water.
:ournal of ?ood Enineerin 30 *2-, 2<1M2<C.
Odea, >., 23C7. $arked im!rovement in carbohydrate and li!id-metabolism in
diabetic .ustralian abori-ines after tem!orary reversion to traditional lifestyle.
5iabetes 99, 03DMD49.
Odea, >., Traianedes, >., )reland, #., et al., 23C3. The effects of diet differin in
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:ournal of the .merican 5ietetic .ssociation C3, 24<DM24CD.
Orti/, :., (omero, &., (obert, #., et al., 144D. 5ietary fiber, amino acid, fatty acid
and toco!herol contents of the edible seaweeds Olva lactuca and (urvillaea
antarctica. ?ood 6hemistry 33, 3CM247.
#ak, 6.=.6., ?uller, 6., Sakhaee, >., #reminer, H.$., Britton, ?., 23C0. Lon-
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297, 22M23.
#embrey, $.E., Byren, L.O., >aati, H., et al., 144D. Sex-s!ecific, male-line
transenerational res!onses in humans. Euro!ean :ournal of 'uman Henetics 27,
203M2DD.
#reminer, H.$., Sakhaee, >., Skurla, 6., #ak, 6.=.6., 23C0. #revention of
recurrent calcium stone for-mation with !otassium citrate thera!y in !atients with
distal renal tubular-acidosis. :ournal of 8roloy 297, 14M19.
(obson, .., 144D. Shellfish view of omea-9 and sustainable fisheries. &ature
777, 2441.
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low-enery-dense diets. &utrition and 'ealth 14, 290M2DD.
(obson, ...., 1424a. 6reatin convenience food based on human nutritional
re"uirements. ./o &anotechnoloy 1D90.
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Iol. 1 Evidence. 'ouse
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(obson, ...., 1422. ?ood nano-technoloy+ ;ater is the key to lowerin the
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than a !roblem[ .ro ?ood )ndustry 'i-Tech 19*1 $onora!hic su!!lement series+
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?oods and 5isease 2M14.
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.mounts 6onsumed !er )ndividual, One 5ay, 1440M144D. .ricultural (esearch
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E.$.(., 1447. 'ih !rotein intake sustains weiht maintenance after body weiht loss
in humans. )nternational :ournal of Obesity 1C, 0<MD7.
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*accessed :uly 29, 1421-.
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.naemia. .vailable from+ htt!+,,www.who.int,nutrition,to!ics,ida,en,!rint.html.
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5iseases 1424. www. who.int,nmh,!ublications,ncdrre!ortrfullren.!df *accessed
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& 92<. Se!tember 1422.
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1421-.
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htt!+,,www.who.int, mediacentre,factsheets,fs922,en, *accessed :uly 29, 1421-.
RELEVANT WEBSITES
htt!+,,www.mccarrisonsociety.or.uk, M The $c6arrison Society for &utrition A
'ealth.
htt!+,,www.mother-and-child.or, M The $other and 6hild ?oundation. ;orkin
for ood health in mothers and children
htt!+,,www.who.int,en, M ;orld 'ealth Orani/ation.
CHAPTER ?G
O.("a B Fatty A&i/s a$/ Bi!a&ti+(
F!!/s) Fr!. Bi!t(&h$!!"y t! H(ath
Pr!.!ti!$
C. F(rr(ri
6onsilio &a/ionale delle (icerche, Bolona, )taly
ABBREVIATIONS
AA .rachidonic acid
DHA 5ocosahexaenoic acid
DPA 5ocosa!entaenoic acid
EFA Essential fatty acids
EFSA Euro!ean ?ood Safety .ency
EPA Eicosa!entaenoic acid
FDA ?ood and 5ru .dministration
LA Linoleic acid
LNA c-linolenic acid
NAFLD &on-alcoholic fatty liver disease
PC #hos!hatidylcholine
PE #hos!hatidyl ethanolamine
PL #hos!holi!id
P*FA #olyunsaturated fatty acids
SDA Stearidonic acid
SREBP Sterol reulatory element-bindin !rotein
TAG Triacyllycerol
>. INTROD*CTION
Since the discovery of the effects of linoleic and linolenic acid deficiencies made
by the Burrs in 2394 *Burr and Burr, 2394E 'olman, 23CC-, essential fatty acids
*E?.- occu!y an im!ortant !lace in health and nutrition. The develo!ment of
analytical methodoloies to follow u! the fatty acid status and fate in bioloical
sam!les, oin from as chromato-ra!hy *H6- of the early 2304s to the modern era
of li!idomics, contributed to ex!and knowlede on omea-9 and omea-D fatty acids,
not only for their roles as com!onents of foods and tissues, but also for their
involvement in crucial ste!s of cell sinalin and metabolic reulation.
Today !olyunsaturated fatty acids *#8?.- belonin to the omea-9 and omea-D
families are an im!ortant subGect of medical research for the !revention and treatment
of several diseases. )n nutrition and health, omea-D and omea-9 intakes are
nowadays discussed in view of the im!ortance of a Sood% balance between these two
families. )n this res!ect, the omea-D !revalence in the diet of industriali/ed societies
has been indicated as a risk factor, motivatin the s!eed-u! of biotechnoloical
develo!ment of omea-9 sources, to im!rove the availability of materials for food
su!!lements and nutra-ceuticals, with conse"uences which also dee!ly influenced
industrial and market rowths.
.s a matter of fact, in the !ast two decades omea-9 fatty acids have re!resented
an im!ortant subGect of research. .n in"uiry on a web data base *)S) ;eb of
>nowlede- by the key word Somea 9 fatty acids% led to almost C444 references in
different disci!lines startin from 23C4. ?rom the ra!hic re!orted in ?iure 1D.2, it is
!ossible to see that !ublications increased in 2334 and a constant number of around
144 !ublications,year was ke!t for 24 years, whereas from 1449 the omea-9 subGect
s!eeded u! with a linear rowth of 244 !a!ers,year, reachin almost C44 !a!ers,year+
more than 1 !a!ers,day a!!ear on omea-9 fatty acids.
The areas s!an from medicine *94M91R- to nutrition *14R-, bioloy and
biochemistry *12R-, food science *21R-, microbioloy *24R-, chemistry *DR-, and
!hysics *1R-, thus showin that this is a true interdisci!linary field of research. )n
fact, the omea-9 subGect can involve bioloical and medical studies, as well as
biotechnoloical issues for the develo!ment of omea-9 factories to increase
availability of these com!ounds. )t also
Fi"#r( ?G.> 5iaram of !ublications,year on Somea-9 fatty acids% *source+ )S) ;eb of
>nowledeE htt!+,, a!!s.isiknowlede.com-.
involves reulatory as!ects of omea-9-based health claims, and economical as!ects
with the ex!onential rowth of the nutraceutical market.
This article will deal with the interdisci!linary scenario reardin omea-9,
discussin some of the most relevant issues and !ers!ectives in the various fields.
?. OMEGA%B FATTY ACIDS AND HEALTH
.reas of rowin research interest include bioloy, nutrition, and medicine, linked
to the characteristic of omea-9 fatty acids to be essential for eukaryotic cell
formation and rowth. )t must be underlined that omea-9 fatty acids are not only
im!ortant !er se, but also in connection with the other essential fatty acid family of
omea-D. )n fact, the two #8?. families are bioloically connected throuh the
cascade of en/ymatic transforma-tions that start immediately after the intake of
!recursors from the diet. $oreover, after atherin evidence of insufficient intake of
omea-9 fatty acids from the diet, the atten-tion to the fatty acid com!osition !resent
in food has increased, thus leadin to an interest in the omea-D,omea-9 balance as a
measure of a healthy diet. The debate is still o!en but the usefulness of omea-9 fatty
acids is continuously !ro!osed in several medical fields, such as dermatoloy,
neuroloy, o!hthalmoloy, and even cancer. . first cause of the beneficial effects on
health status derives from the modulation of eicosanoid !ro-duction, due to the
balance between the liberation of omea-D and omea-9 com!onents from
membranes, which reulate in their turn the !roduction of !rostanoids of the series 1
and series 9, res!ectively. Omea-9 research in bioloy and medicine is continuously
u!dated with new ac"uisitions and the follow-u! of novel as!ects is necessary.
?.>. Ma1!r Bi!&h(.i&a Path0ays !' O.("a%B Fatty A&i/s
?iure 1D.1 summari/es the ste!s startin from a-linolenic acid *L&.-, the
!recursor of the omea-9 family *3cis,21cis,20cis-octadecatrienoic acid, 62C+9
omea-9-, with the en/yme delta-D desaturase *D-desaturase-, that brins to
stearidonic acid *S5., Dcis, 3cis,21cis,20cis-octadecatrienoic acid, 62C+7 omea-9-
by formation of an additional double bond in !osition D. The inter!lay of desaturase
*D and 0- and elonase activities, the latter en/yme elonatin the carbon atom
chain by two carbon units, is needed for the formation of other omea-9 fatty acids,
such as eicosa!entaenoic acid *E#., 0cis$ Ccis,22cis,27cis,2<cis-eicosa!entaenoic
acid, 614+0 omea-9- and docosahexaenoic acid *5'., 611+D omea-9-. ?or the last
ste! of 5'. formation a a-oxidation !rocess is needed.
)n ?iure 1D.1 it is !ossible to see the main features of the metabolism of the
omea families+
?irst of all, the need to transform 62C fatty acids into 614 and 611 fatty acids, in
order to have access to eicosanoids *mediators such as !rostanoids, thromboxanes,
Fi"#r( ?G.? Biosynthetic !athways for omea-D and omea-9 fatty acids.
!rostacyclins, leukotrienes, li!oxins, endocannabinoids- and docosanoids *resolvins-
with crucial roles in cell metabolism. ?iure 1D.1 shows the direct com!etition
between L&. and linoleic acid *L., 3cis,21cis-octadecadienoic acid, 62C+1 omea-D-
for the activity of the same en/yme, 5D-desaturase. This is the key ste! of the two
cascades and, from the seminal work by 'orrobin *2339- on the conse"uences of a
5D-desaturase failure, it is clear that inade"uate levels or im!airment of this en/yme
can alter essential fatty acid levels and cause health conse"uences. The effect of direct
com!etition is influenced by dietary intakes, and therefore the omea-D !revalence
can de!ress the omea-9 bio-synthesis. )t is worth underlinin that the increase of
omea-9 levels can also be stimu-lated without directly enhancin its intake, but
actin indirectly on the omea-D intake, as described for a reime where a hih L.
content was chaned into a low L. content *Liou et al., 144<-.
5esaturase en/ymatic activity can vary in conse"uence of different stimuli+ for
exam-!le, saturated and #8?. fatty acid concentrations, carbohydrates and insulin,
alcohol and trans fatty acids are inhibitors, but not monounsaturated fatty acids. The
en/yme decreases its activity in ain or in the absence of im!ortant cofactors *i.e.,
&.5', ?e, $ and Nn, B
1
, B
9
, B
D
, vitamins-. .nother element to consider for the
E?. effects is that they must be incor!orated at the levels of !hos!holi!ids *#L-,
since it is well known that the sinalin and functions mediated by eicosanoids and
docosanoids start from the membrane-bound fatty acids. The maGor dietary sources
!rovide fatty acids in the form of trilycerides, which have to be !rocessed to #L.
.fter fat absor!tion, these transformations mainly oc-cur in the liver, !rovidin that
fundamental elements and cofactors are !resent *!hos!hate rou!s from .T#, acetyl
6oen/yme ., choline, amon others-.
The !athways de!icted in ?iure 1D.1 were also studied in order to evaluate the
efficacy of other fatty acids of the cascade. ?or exam!le, S5. is a com!onent of fish,
echium, and blackcurrant oils and overcomes the critical D desaturase ste!. ;hen it
enters the metabolic !athway of omea-9, it is ra!idly converted to E#.. S5. is not a
constituent of tissue #L, but it can contribute to enhance the E#.-bound #L in eryth-
rocytes u! to five times of the initial value. The evaluation of the conversion
efficiency has been !erformed also for L&. and E#.. The averae conversion of
L&. to E#. is estimated around CR, whereas the conversion of E#. to 5'. is not
more than 4.2R *;helan, 1443-. Su!!lementation of rams of fatty acids !er day
*from 2 u! to 14M 94 day
-2
- for several weeks *7M21 weeks- have effects of
increasin E#. and 5'. only by choosin fish oil, and not flaxseed oil, as the
dietary source *6ao et al., 144D-.
The conversion from trilycerides or their derivatives *diacyllycerol and fatty
acid esters- to #L brins fatty acids to become constituents of the cell membrane
com!art-mentE after an oil su!!lementation it would be always very im!ortant to
combine the estimation of membrane fatty acid chanes toether with those of
circulatin li!ids. )n most of the !ublished work on dietary reimes or oil
su!!lementations, the analysis often concerns only !lasma li!ids, whereas a com!lete
scenario of metabolic conse"uences could be achieved by includin membrane li!ids.
)n ?iure 1D.9, two alternative !ath-ways of #L synthesis are summari/ed+ *a- the
cou!lin of diacyllycerol and citydine 0%-di!hos!hocoline by the activity of the
en/yme choline !hos!hotransferase. This reaction defines the ultimate ste! in the
>ennedy !athway for the enesis of !hos!hate-dylcholine *#6-, the most im!ortant
#L in mammalsE *b- the cou!lin of lycerol- 9-!hos!hate with two moieties of fatty
acyl-6oen/yme . esters, with formation of !hos!hatidic acid which has the two fatty
acid chains in !ositions 2 and 1 of L-lycerol. This is followed by the insertion of the
!olar heads of choline, serine, inositol, and the formation of the different #L
com!onents.
The lon-chain #8?.s such as omea-9 are usually !resent in the !osition 1 of
the lycerol moiety and one of the maGor !roducts obtained from the de novo #6 and
#E *!hos!hatidyl ethanolamine- biosynthesis has 2D+4 *!almitic acid- in !osition 2
and 5'. in !osition 1. Since carbon-carbon double bonds im!art fluidity to the
membrane, 5'. *with six double bonds- and E#. *with five double bonds- are the
most hihly fluidi/in fatty acids, and in fact are found in hihest concentrations in
the most dynamic membranes *e.., retina, brain, and s!ermato/oa-. Beyond
conferrin membrane fluidity, 5'. and E#. are im!ortant for the homeostatic
reulation of tissue !erformance, renewal, and reeneration also by !roducin
mediators and sinals. On the other hand, L&. is not found in sinificant
concentrations in cell membrane li!ids.
Fi"#r( ?G.B $ain routes for the !hos!holi!id biosynthesis.
)t is worth underlinin that after synthesis #Ls can be remodeled via deacylation-
reacylation reactions, and fatty acid availability from metabolism and diet is crucial to
orient the final #L com!osition. This remodelin !lays an im!ortant role when stress
conditions im!act on membrane fatty acid status, and in this res!ect the well-known
chemical reactivity and sensitivity of #8?. moieties can re!resent a drawback.
Environ-mental conditions, !hysioloical and !atholoical situations such as stress,
inflammation also connected to ut and liver status and immune system, ex!osure to
radiations and liht, use of drus, amon others, can indeed enhance the tendency of
cell com!artments rich in #8?. to oxidation and deradation by free radicals *Else
and 'ulbert, 1449-. .t this !oint the fatty acid fate de!ends also on the individual
status and in !articular the so-called antioxidant network is involved. ?urther insihts
on the omea-9 association with cofactors and antioxidants are needed, which can
contribute to ameliorate fatty acid bioavailability and !rotection from deradation
durin biodistribution, thus leadin to a better understandin of the real !otential of
these #8?. com!onents.
?.?. O.("a%B C!$t($t i$ Ma1!r Nat#ra S!#r&(s
.n abundant, balanced dietary intake of #8?. is an absolute re"uirement for
eukaryotic cells and for ensurin the correct develo!ment of tissues. Some of the
omea-9 sources and contents are dis!layed in Table 1D.2.
Tab( ?G.> Omea-9 ?atty .cid 6ontent in 5ietary Sources
FISH LNA EPA DNA R('
Salmon 4.2 4.7M4.D 4.DM2.1 &ettleton,
2330
Lake Trout 4.7 4.0 2.2 &ettleton
Tuna 4M4.1 4.9M4.7 2.4M2.1 &ettleton
.nchovy 4 4.0 4.3 &ettleton
Sardines
*canned-
4.0 4.7 4.D &ettleton
Swordfish or
sole
4 4.2 4.2 S!iller, 233D
OIL LNA EPA DHA
?laxseed 09.9 4 4 Shahidi, 144C
Linseed 0D.D 4 4 Shahidi, 144C
$enhaden 2.2 22.7 22.9 #alm"uist,
1443
Salmon 2 C.C 21 Exler and
;ehrauch,
23CC
FOOD LNA EPA DHA
S!inach 4.3 4 4 Simo!oulos,
1447
$arine alae 1.< 4.C 10
a
#alm"uist
(ye rass DC 4 4 #alm"uist
;alnuts
b
3.< 4 4 )&(.&, 1444
E yolk
c
4.7 4 4 )&(.&, 1444
a
+21R 5#.
b
content of L.=04R
c
content of L.=29.2RE .(.=1.9R
The omea-9 sources can be divided into two main rou!s+ those !rovidin
mainly L&. and those !rovidin E#. and 5'.. )n the first rou!, flaxseeds and
linseeds are ood sources as oils, whereas seeds can be used in the meals only after
crushin to facilitate release and absor!tion. )n the second rou! fish and fish oils are
!rovidin rich sources of E#. and 5'., whereas a !referential source of 5'. is
!rovided by marine alae.
)n oil manufacturin, the different techni"ues for oil extraction must be taken into
account, as they can affect the "uality of the resultin !roduct. The cold-!ressed tech-
ni"ues with a!!ro!riate mills or !resses are used for small-scale !roductions of edible
oils since old times. ?or lare-scale !roduction, sa!onification, and deodori/ation are
chem.-ical !rocesses which follow the crushin of veetable materials. These
!rocesses reach hih tem!eratures and can affect the content of !recious com!onents
such as antioxi-dants. $oreover, in the deodori/ation !rocess, trans isomers of the
natural cis #8?. are !roduced and this also affects the health safety of these !roducts
*SQbQdio and 6hristie, 233CE ?erreri, 1443E $elchiorre, 1424-. . severe reulation of
trans fatty acid content in food has been introduced by the .merican ?ood and 5ru
.dministration *?5.-.
The source of omea-9 re!resented by krill needs a s!ecial mention. >rill are
marine crustaceans that belon to the order Eu!hausiacea. .lthouh there are many
s!ecies of krill, only .ntarctic krill *%uphausia superba- and #acific krill *%uphausia
pacifica- have been harvested for human consum!tion. The krill li!id com!osition
shows low !ercentaes of saturated *S?.- and monounsaturated fatty acids *$8?.-
and hih #8?.s *a!!roachin 04R of total li!id concentration-, !redominantly E#.
and 5'.. $ore interestinly, #8?. are found !redominantly as #L. .s ex!lained in
the section S$aGor Biochemical #athways of Omea-9 ?atty .cids,% this has a very
im!ortant conse"uence on the bio-availability of essential fatty acids for the
membrane li!id com!osition, which favors #L vs. T.H.
?.B. Ma1!r H(ath E''(&ts !' O.("a%B
The effects of omea-9 on health have been described in different fields. 'ere the
most im!ortant as!ects es!ecially related to acce!ted health claims in Euro!e are
summari/ed. The recently introduced reulation on health claims in Euro!e by the
Euro!ean ?ood Safety .ency *E?S.- has acce!ted L&. for its a!!lication as
maintenance of normal blood levels of cholesterolE in order to bear the claim, a food
should contain at least 20R of the !ro!osed labelin reference intake value of 1
L&. !er day *944 m- *E?S. #anel, 1443-. The hue amount of literature of the
omea-9 effects was screened and health claims of kee!in normal trilyceride levels
*at 1 day
-2
of E#. and 5'.-, normal cardiac functionality, normal blood !ressure
and '5L-cholesterol concentra-tions *104 m day
-2
of E#. and 5'.- have been
acce!ted. Other claims related to the immune system, anti-inflammatory activity,
immuno-modulation, and !rotection from !hoto-oxidative damae need further
studies *E?S. #anel, 144C-. .s ex!lained in the section S$aGor Biochemical
#athways of Omea-9 ?atty .cids%, the su!!lemen-tation of L&. can be considered
much less useful for raisin the levels of E#. and in any case not able to increase
5'. levels. ?or other omea-9 health claims, mixtures of E#., 5'., and 5#.
*docosa!entaenoic acid- have been acce!ted for kee!in blood !ressure and
trilyceride levels at favorable !oints with doses of 1M7 day
-2
.
The most relevant fact to mention for the cardiovascular role of omea-9 is re!re-
sented by the introduction of the Somea-9 index,% which refers to the sum of E#.
and 5'. !ercentaes !resent in erythrocyte membranes. #reviously, other indexes
related to cardiovascular diseases have been !ro!osed, such as the omea-D,omea-9
ratio and its variants *..,E#. and ..,E#.+5'. ratios-. . certain confusion was
oin to arise, since omea-9 levels are evaluated either in !lasma or in blood cells
*!late-lets, erythrocytes-, but it is "uite evident that these a!!roaches !rovide different
infor-mation from circulatin and structural li!ids, res!ectively. )n 1447, von Schacky
and 'arris !ublished the omea-9 index as a sinificant biomarker of cardiovascular
risk, !ointin out its determination in erythrocyte membranes *'arris and von
Schacky, 1447E 'arris, 144<-. )n this way, the omea-9 index succeeded to fulfil
many of the re"uirements for a risk factor includin consistent e!idemioloical
evidence, a !lausible mechanism of action, a re!roducible assay, inde!endence from
classical risk factors, mod-ifiability, and most im!ortantly, the demonstration that
raisin tissue levels will reduce risk for cardiac events. The authors hihlihted the
membrane com!artment as meanin-ful site for the omea-9 index, since it can
re!resent a whole balance of metabolic and dietary contributions. The values
com!rised from 4 to 7R of E#. and 5'. content in erythrocyte membranes are
associated with undesirable risk /one.
Other sinificant health conditions for the essentiality of the omea-9 fatty acids
are !renancy and neuroloical disorders. )n !renancy, the absolute amounts of ..
and 5'. increased by 19 and 01R res!ectively in !lasma li!ids, but this does not
corres!ond to an increase of E?. that is instead decreasin alon !renancy. )t seems
more likely that this rise durin !renancy is due to an increased mobili/ation from
maternal stores to reach the fetal tissues. The de!letion of E?. durin !renancy
involves in !articular 5'., which has a crucial role in the onset of maternal
!ost!artum de!ression *.l et al., 1444-.
Omea-9 de!letion from foods has been clearly associated to the risk of
neuroloical disorders. 5ementia and .l/heimer diseases are associated with low
intakes of fish meals as demonstrated by several studies *?raminham 'eart Study,
(ush-#resbyterian- St. Luke%s $edical 6enter study, etc.-. ;ith 2M1 servins of fish
!er week, risk factors were drastically reduced by 04MD4R *$orris et al., 1449-.
)t is worth !ointin out that not only de!letion of omea-9 can be connected with
cardiac !roblems. )n a recent study of atrial fibrillation, an omea-9 excess was found
in the erythrocyte membranes of 74 !atients, whereas they lacked monounsaturated
fatty acids *Iiviani .nselmi et al., 1424-.
B. OMEGA%B FATTY ACIDS AND BIOTECHNOLOGY
The increased demand for omea-9 fatty acids motivated more research on the
sources of these com!onents. ?ish oils are still a very lare source, but it is not
sufficient to cover the re"uest. 8nfortunately, most of the !roduced fish oil is
hydroenated into mararine and shortenin, so that the valuable omea-9
com!onents are destroyed. $oreover, several !roblems of fish oil raised attention
from customers, such as the !resence of heavy metals or other !ollutants toether with
the !rocessin that can alter the natural com!osition. ?ishy taste and veetarian habits
which avoid animal-derived !roducts are additional fac-tors to !ush for alternative
sources of omea-9.
Biotechnoloical solutions are nowadays considered with the selection of
unicellular oranisms *yeast, bacteria, microalae, and funi-, and study the
differences of marine and terrestrial s!ecies which can be utili/ed to orient !roduction
and to boost the !roductivity of a s!ecific com!onent.
B.>. Bi!t(&h$!!"y '!r I.3r!+i$" O.("a%B Pr!/#&ti!$
$icrooranisms, funi, and alae have been re!orted to !roduce #8?.s with
alternative !athways shown in ?iure 1D.7.
?iure 1D.7 )nter!lay of $8?., omea-D and omea-9 #8?. biosynthesis in
microoranisms and alae.
)t means that the first unsaturated fatty acid to be !roduced is the $8?.
com!ound, oleic acid *3cis-2C+2-, which is then converted to L. by the activity of
delta-21 desaturase and to L&. by the activity of delta-20 desaturase. These two
desaturase en/ymes do not occur in human and animal cells, whereas they are !resent
in different unicellular oran-isms as well as in !lants. .nother im!ortant biochemical
!athway !resent in alae is the !ossibility to Goin omea-D and omea-9 !athways
throuh the transformation of .. into E#. by the activity of a delta2<-desaturase,
which is more active at lower biomass con-centration *?iure 1D.7-. )t is worth
underlinin that this !athway suested molecular bioloy ex!eriments in mammals,
to create transenic s!ecies such as Somea-9- !roducin mice,% ca!able of convertin
omea-D into omea-9 fatty acids and have hih levels of omea-9 in all orans and
tissues, with no need of dietary su!!lementation *Lai et al., 144D-. The balance of
desaturase ste!s also ives the balance of the #8?. !roduc-tion of .., E#., and
5'., which de!ends on the cell ty!e and culture conditions. .fterward, it is also
relevant to know in which li!id molecules the fatty acids are incur-!orated *i.e.,
trilyceride, #L-.
Of the lower funi, #hycomycetes *$ucorales order- is the only !romisin class
for .. and E#. !roduction, which is oriented by the culture tem!erature.
Mortierella alpine at lower tem!erature *21 6- !roduces E#. as the main extractable
fatty acid !roduct *20R-, whereas at 14 6 .. accumulation occurs. 'owever, it must
be also considered that low tem!eratures are disadvantaeous because of the low
rowth rate and hih enery costs for coolin. This can be overcome by combination
with metabolic effects, such as for exam!le lucose feedin durin the rowth of
Mortierella funi, which affords hih E#. !roduction. Hlucose can boost the
!roduction of arachidonic acid, therefore culture conditions must be efficiently tested
in order to reach the desirable final com!osition.
$icroalae are considered a safe veetarian source of E#. and 5'.. )n
!articular !chiBochytrium s!. re!resents a strain which makes hih levels of 5'.
*9<.7R- and low levels of E#. *1.CR-. )t is a member of the kindom 6hromista
*Thraustochryd- that form a !art of the coastal food chains as a food source for
shellfish, re!resentin a sinif-icant !art of human diet in coastal reions around the
world. )t is worth underlinin that these s!ecies are not toxic alae forms, their 5'.-
rich oil is claimed to have no un!leas-ant flavor, no environmental !ollutant, and is
available in several forms also for cookin or as additives. The Thraustochryd
aureum !roduces ood 5'. levels in the !resence of starch, maltose, and lucose.
. lare-scale !roduction of E#. derives from the red ala Prophyridium
cruentum cul-tivated in outdoor !lants. )n winter, E#. constitutes u! to 04R of the
fatty acids whereas in summer it lowers to 2.9R. 'owever, in cultivation also the
biomass is an im!ortant !arameter to evaluate and summer tem!eratures increase the
biomass yield. .lso the ma-rine reen alae Chlorella minutissima and
Chlamydomonas reinhardtii are studied for their metabolic !rocesses and the
!ossibility to boost the omea-9 synthesis. )n 6. minutissima very hih !ercentae of
E#. *34R- can be !roduced. $ore details can be found in several !a!ers and reviews
*Huschina and 'arwood, 144D-. 'ere, the fatty acid contents have been discussed
without considerin the content of other im!ortant alal constituents, classified with
the eneral cateory of Santioxidants.%
B.?. O.("a%B i$ M!/i'i(/ A$i.a Pr!/#&t F!!/s
The search for omea-9 sources involves also modification of the omea-9
content of animal !roducts, includin es, meat, milk. The tasks followed nowadays
in feedstuff for livestock and other domestic animals can be summari/ed as follows+
*a- find a ood and com!lete source of omea-9E *b- address the "uality of !roducts,
in !articular oxi-dative stability and flavorE *c- obtain reasonable costs of !roduction.
5ifferent strateies have been followed de!endin on the !roducts *#alm"uist, 1443-.
#oultry industry was the first to be enaed in amelioratin the omea-9 content
with the so-called Sdesiner es% !resent on the market. Layin hens are fed with
flaxseeds which linearly increase the L&. content and also have effects on 5'.
content. The L&. content can reach 144 m,e by feedin 24R of flaxseeds. The
effect of feedin menhaden or marine alae,fish oil *9MDR- to hens is also re!orted to
ive a 5'. content of 144 m,e *#alm"uist, 1443-. 5rawbacks can be found in the
fishy off-flavors of the es, and a reater tendency of animals to develo! liver
hemorrhaes.
?or !oultry and meat a similar a!!roach is followed and the su!!lementation with
different oils has been re!orted. Two to four !ercent linseed oil additive is used and
the increase of L&. in broiler muscles can be detected u! to 27R. 8sin mixtures of
soybean, sunflower, linseed, and fish oils, the E#. and 5'. levels can also be
increased. 'owever, in this case the follow-u! of indicators of tissue li!id
!eroxidation detected an increased content of malondialdehyde correlated to E#. and
5'. increases. This su-ested to cou!le the oil feedin with some amounts of
vitamin E, which could exert a !rotective effect on the li!id !eroxidation.
Other animal meat such as !ork follows an enriched feedin, and by usin
flaxseed or ra!eseed oils toether with a-toco!herol acetate *044 m k
-2
-, the
omea-9 contents could be increased. Systematic studies of the tissue li!id content are
re!orted *#alm"uist, 1443-.
Even in the fish farms the need for !rovidin fish oil su!!lement was evidenced.
The inclusion of veetable oil in the fish diet has been tested as alternative to fish oil.
'ow-ever, the total substitution of dietary li!ids !rovided by veetable oils brouht to
the reduction of E#. and 5'. concentrations by 94 and 9DR, res!ectively. )t is
interestin that in fish su!!lemented by echium oil it was found out that the ene
ex!ression of liver fatty acid elonase and delta-0 desaturase *?.50- were
u!reulated and it correlated with an increased E#. levels in the liver *#alm"uist,
1443-.
)n the scenario of food modifications, a cautious word must be added for the
extensive use of seeds and oils that do not make !art of the natural diet of the animal
s!ecies. )n this res!ect, the use of oils, such as fish oils, for !oultry and other animals
should be considered somehow adverse, not only because the corres!ondent "uality of
the animal !roducts is affected, but also because the fish source is unnatural for them.
D. OMEGA%B FATTY ACIDS AND N*TRACE*TICALS
5r. Ste!hen 5e?elice, founder and chairman of the .merican ?oundation for
)nnova-tion in $edicine, coined the term S&utraceutical% from S&utrition% and
S#harmaceutical% in 23C3. The oriinal definition of nutraceutical is+ Sa food *or !art
of a food- that !rovides medical or health benefits, includin the !revention and,or
treatment of a disease.% Therefore, the term nutraceuticals indicates that it must not
only su!!lement the diet but should also aid in the !revention and,or treatment of
disease and,or disorder. This im!lies that nutraceuticals need su!!ort of sinificant
clinical trials to !rove their effects and, obviously, absence or reduced side effects. )t
can be a mistake to consider nutraceu-ticals less demandin for scientific evidences
than !harmaceuticals. $oreover, studies have to be !erformed by a!!ro!riate
!rotocols, and therefore in vitro effects are not enouh to !rove the in vivo activity
and, more im!ortantly, the activity in humans. ;hile ?5. has !ointed attention to the
ood manufacturin !ractice in nutraceutical )ndus-tries, in Euro!e attention has been
addressed to health claims, by an E?S. reulation *E8 (eulation &. 2317,144D- that
re"uires evidence-based studies satisfyin the followin criteria+
the study has to be referred to humans, with attention to ae and metabolic
statusE
the diet followed by the rou! has to be mentionedE
com!liance must be monitoredE
the data must be statistically evaluated and sinificantE
the real end !oints can be also re!resented by metabolic biomarkers.
?uture !ros!ects of nutraceuticals o toward the rationali/ation of their indications
and uses, and overall it can also be ex!ected that the consciousness of !roducers
should im!rove.
The lobal nutraceutical market is estimated to be around ]224M204 billion and
fore-casts are of an annual DMCR rowth. .round ]224M204 billion is the world
nutraceutical inredient industry. These are drivin forces for new !roducts and
a!!lications to be introduced, but a cautionary word would be to s!end by takin
consumers% needs into consideration, which should become the !rimary focus. 'ow
much and how lon the consum!tion of a nutraceutical must be effected[ 5ue to the
essentiality of the fatty acid intake, !reventive strateies with nutraceutical
su!!lementation can be hel!ful to avoid deficiencies, althouh the su!!lementation
must not be considered substitute of an healthy diet. 'owever, as !reviously
mentioned in the section S$aGor Biochemical #ath-ways of Omea-9 ?atty .cids,% it
would be advisable that the real need and the status of the subGect, related to li!id
metabolism and the !resence of oxidative conditions, be carefully considered.
D.>. N#triti!$ V(rs#s S#33(.($tati!$
)n this article the situation in develo!ed countries is treated. 5es!ite the rowin
avail-ability of foodstuff, the !ast decade has shown that essential elements are not
sufficiently !rovided and it is much easier than in ancient times to fall in the omea-9
deficiency. On the other hand, health awareness is increasin due to mass media
diffusion and this drives more consumers to take a !roactive role in manain their
health.
.s shown in Table 1D.2, a 244 *c. 9.0 ounce- servin of fatty fish !rovides about
2 of omea-9 which is com!arable to an averae commercial fish oil ca!sule.
Takin into account that in fish food the fatty acid content is not only trilycerides,
but also #L, mixed in a cocktail with many other nutrients, it is really understandable
why nutrition has to be considered much more and before the su!!lementation.
The im!ortance of nutrition for the omea-9 intake has been first underlined by
Simo!oulos *1447-, who !ro!oses that a drastic chane occurred durin centuries in
the "uality of fats, oin from the hunter-atherer *from #aleolithic and ancient times-
to the aricultural !o!ulations *u! to 2344- and to the industriali/ed societies *after
2344 to modern era-. . constant diminution of omea-9 fats, toether with an
increase of saturated fats, de!letion of antioxidant and of other im!ortant nutrient
contents, was established in a relatively short !eriod *less than a century-. )t can be
estimated that the current ;estern diet is very hih in omea-D fatty acids which are
in the ratio with omea-9 of 24M14 to 2. There are some !o!ulations around the world
which are safer for the omea-9 intakes due to consum!tion of fish *:a!anese and
Eskimo !o!ulations- or wild veetables *e.., 6rete inhabitants for the consum!tion of
!urslane, a veetable rich in L&.-. The less incidence of cardiovascular death in
Eskimo !o!ulations makes !art of the history of the omea-9 health benefits. )n
Euro!e the dietary intakes are considered !rimary !revention with E#. at 104M044
m day
-2
, 5'. in !renancy,lactation at 244M144 m day
-2
, and5'.for children%s
vision acuity at 04M244 m day
-2
. .lthouh there are no official (5.s, the ade"uate
intake *.)- is considered by several orani/ations and medical associations+ for
exam!le, the )nternational Society for the Study of ?atty .cids and Li!ids
recommends 044 m day
-2
omea-9, whereas the 8S. &ational )n-stitute of 'ealth
recommends D04 m day
-2
E the Euro!ean aency E?S. ives a diet recommendation
for children and adults to have at least two !ortions of fish !er week, or 104 m day
-2
of E#. and 5'.. The .merican ?5. also recommends not to exceed 9 day
-2
of
omea-9, because of adverse effects related to lycemic control, increased bleedin
tendencies, and elevation of low-density li!o!rotein cholesterol. )t is also worth
underlinin that s!ecial conditions, such as allery to fish food or the choice for a
ve-etarian dietary reime with exclusion of fish meat, re"uire s!ecific attention for
cones-"uent deficiencies of the omea-9 intakes.
)t would be desirable that the need of a fatty acid su!!lementation be established
by a !ersonali/ed a!!roach, throuh the estimation of the !ersonal status in
combination with the familial and dietary information. The combination between the
nutritional re"uire-ment and the li!id status is nowadays named nutrili!idomics, and it
is estimated to become a science-based a!!roach, ho!efully influencin in the future
the !roductive food chain and nutraceuticals *?erreri, 1443-.
D.?. O.("a%B Fatty A&i/ S#33(.($tati!$) A D!#b(%E/"(/
S0!r/U
The su!!lementation of omea-9, as well as of other fatty acids, must be
considered not only from the !oint of view of beneficial effects, but also from the
!ossible side effects which can reduce the ex!ected benefits. Because of the
!o!ularity of omea-9 su!!le-mentation for its anti-inflammatory effects, the most
diffuse !erce!tion is that omea-9 can be taken for lon !eriods at hih doses without
!roblems. )ndeed, several commercial !roducts containin variable "uantities of
#8?.s are sold as self-!rescri!tion. )n the sec-tion S&utrition Iersus
Su!!lementation% the recommended dose ranes have been indi-catedE however any
severe restriction for excessive intake is !erceived by the consumers.
Examinin literature data, the su!!lementation with natural oils containin #8?.
families a!!ears indeed to be a double-eded sword, because a contradictory scenario
emeres from !a!ers, for exam!le in the cardioloy or dermatoloy fields, re!ortin
excellent results in some cases but not always *Hrundt and &ilsen, 144C-. Surveyin
the results and !ayin attention to the methodoloies used in the individual selection
and data, it emeres that #8?. su!!lementation to !atients is enerally !erformed
without ascertainin their metabolic status or condition of oxidative stress in the
subGects. The !resence of low antioxidant defences or a com!romised oxidative status
*due to ain, or health conditions such as inflammation, e..- can dee!ly affect the
availability and bio-distribution of the omea-9 su!!lementation even at the suested
doses. )t would be advisable to et more information on the effects of syneric
antioxidants and #8?. in a !ro!er combination and delivery form, toether with a
careful screenin of the human cohort.
$oreover, additional factors have to be taken into consideration durin #8?.
su!-!lementation+ *a- the hydro!hobicity of these com!ounds, which have a very low
excre-tion and tend to de!osit es!ecially at the level of adi!ose tissues. 6onsiderin
that the adi!ose tissue enerally contains V1R of omea-9 #8?., the enrichment of
these com-!onents should brin to a chane of the functionality and an unnatural
elevated oxidation !otentiality of this tissueE *b- the #8?. incor!oration at the level
of membrane fatty acids which can alter the !ermeability and fluidity !ro!erties in the
sense of hih disordered structures, resultin also in alteration of ion channels and
levelsE calcium, !otassium, and sodium levels are very im!ortant !arameters in the
reulation of im!ulse transmission and en/ymatic activities, such as that of
!hos!holi!ase en/ymesE *c- the membrane #8?. has its influence on the release of
bioactive molecules as #8?. metabolites, as well as on the functionin of membrane
!roteins. )t is also worth recallin that #8?. can directly link to nuclear rece!tors,
and therefore a com!lex sinalin cascade can occur which ulti-mately influences
ene ex!ression and modulation of the whole cell metabolism.
Omea-9 fatty acids are ex!ected to stay in a normal ratio of a!!roximately 2+ 7M0
with the omea-D levels, the latter bein !redominant in most of tissues. Only a few
tis-sues like retina show an inverted 1+2 ratio in favor of omea-9. )n the ;estern
diets the ratio is estimated to be as hih as 20M14+2 omea-D+omea-9 and this would
certainly lead to overcome the desirable 7M0+2 ratio in tissues. On the other hand,
when omea-9 su!-!lementation is followed for lon !eriods, without wash-out, an
accumulation can lead to reverse the ratio between omea-D and omea-9, and also in
this case the normal tissue functionality results to be altered.
)n the !ast decade, li!idomics has been develo!ed as a molecular dianostic tool
with !ractical a!!lication to health. Hiven the levels of fatty acid families that are
characteristic of each tissue, membrane li!idomics allows for the follow-u! of the
individual fatty acid status includin essential fatty acids *omea-D and omea-9-, and
the individuation of unbalance or loss of com!onents. Erythrocyte membranes, as
!reviously mentioned for the omea-9 risk index, re!resent a taret tissue with a
known com!osition of fatty acids related to healthy subGects. Table 1D.1 summari/es
the !ercentae intervals of the maGor fatty acids estimated from the analysis of
erythrocyte membrane #L in healthy sub-Gects *?erreri and 6hatilialolu, 1443E )orio
and ?erreri, 1443-.
Tab( ?G.? ?atty .cid #ercentae )ntervals of Erythrocyte $embrane
#hos!holi!ids in 'ealthy SubGects
?atty acid
a
#ercentae interval *R-
2D+4 2<M1<
2D+2 *n-3- 4.1M4.0
2C+4 29M14
3t-2C+2 4M4.9
3c-2C+2 3M2C
22c-2C+2 4.<M2.9
3c,21c-2C+1 *L.- 3M2D
0c,Cc,22c,27c-14+7 *.(.- 29M2<
trans 14+7 4M4.7
14+9 omea-D *5HL.- 2.3M1.7
14+0 *E#.- 4.0M4.3
11+D *5'.- 0M<
S?.,$8?. 2.<M1
OmeaD,omea9 9.0M0.0
Total trans 4M4.7
a
The !ercentae interval values have been obtained by a literature survey with
ada!tation from the literature data re!ortin cis and trans fatty acids analy/ed by
standard !rotocols from isolated erythrocyte membrane !hos!holi!ids of healthy
subGects *?erreri and 6hatilialolu, 1443E )orio and ?erreri, 1443-.
)t can be foreseen that there is a lare a!!licability of membrane li!id analysis in
order to check the individual status and needs, which can motivate further
develo!ment in the desin of !ersonali/ed intervention strateies by nutritional
elements.
D.B. Th( D(+(!3.($t !' O.("a%B N#tra&(#ti&as i$ Li+(r
Dis(as(s
The omea-9 fatty acid activity on he!atic ene transcri!tion has been
documented. )t is exerted by the activation of !eroxisome !roliferator-activated
rece!tor al!ha, causin u!reulation of enes associated with fatty acid oxidation and
li!id turnover. The omea-9 activity contem!oraneously involves S(EB#-2 *sterol
reulatory element-bindin !rotein-2- with the inhibition of de novo li!id !roduction,
as well as other nuclear hormone rece!tors that !lay a role in fat metabolism. 5ue to
this basic reulation, omea-9 are candidates in liver diseases that involve fat
accumulation, first of all in the so-called non-alcoholic fatty liver disease, a disease
affectin 24M90R of the !o!ulation worldwide. .dditional effects of omea-9 are
re!orted at the level of he!atocyte mem-brane *and mitochondria- #L com!osition
and functionin *$asterton et al., 1424-.
Studies in murine models and humans ascertained that throuh the above-re!orted
rece!tor interactions and activities, an effective reduction of liver steatosis occurs.
The doses re!orted for human studies rane from 2 day
-2
to 1M1.< day
-2
, and even
3 day
-2
for several months *DM21 months-. .lthouh an incom!lete set-u! of the
!rotocols emeres *lack of a sinificant !lacebo or nonblindin of !artici!ants and
invest-tiators, etc.-, in all cases steatosis was reduced by D4MC4R, sinificantly in
com!arison with !lacebo. Other !arameters of liver functionality and eneral status
can accom!any steatosis reduction, such as im!roved serum liver tests, increased
insulin sensitivity, and anti-inflammatory activity. The effects of omea-9 on
he!atocytes can also involve met-abolic transformation to other li!id mediators. ?or
exam!le, 5'. su!!lementation to liver cells has been shown to exert a !rotective
effect toward necrosis caused by the toxic aent carbon tetrachloride *Hon/Kle/-#Qri/
et al., 144D-, due to the formation of 5'.-derived metabolites, s!ecifically 2<S-
hydroxy-5'. and !rotectin 52, the latter bein already re!orted for nervous cells as
neuro!rotectin 52. These omea-9-derived li!id mediators dis!lay !otent anti-
inflammatory action in vivo, and can be !roduced by detachment of 5'. from
membrane li!ids. They attenuate 5&. damae and oxidative stress in liver cells and
key markers in macro!haes, thus suestin the !otential use of 5'. as !rotective
aent in necroinflammatory liver inGury.
These results, toether with the hih tolerability of omea-9, motivate further
studies with riorous methodoloy in order to affirm the nutraceutical omea-9
a!!roach to liver diseases.
E. CONCL*SIONS
The overview of omea-9 fatty acids and bioactive foods iven by this article
summari/ed the relevant subGects in this area and !rovided several hints for further
develo!ments, hihlihtin the im!ortance of a multidisci!linary context that involves
science and society issues. .!!lications of omea-9 in health cannot be achieved
without ex!andin knowlede on their molecular effects, with an increasin attention
to the membrane com!artment which is a crucial site of the omea-9 activity. The
motivation for an im!roved consum!tion of omea-9 sources cannot be dissociated
from the individuation of the real needs by analysis of the individual status, in order to
also im!rove consumers% consciousness and enhance benefits of these essential food
com!onents.
This a!!roach needs coo!eration from different !artners, oin from scientists to
health o!erators and overnmental orani/ations, as !erfectly summari/ed by the
words used in the $arch 1422 issue of /ature iotechnology on its 20th anniversary+
It)s time to realign the interests of companies$ patients and payors so that innovation
is prioritiBed#
ACKNOWLEDGMENTS
The author wishes to acknowlede the stimulatin environment and the su!!ort
iven by the 6OST .ction 6$4D49 S?ree radicals in chemical bioloy,% which
created the interdisci!linary context to develo! most of the conce!ts associated with
this article.
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Boca (aton. Iiviani .nselmi, 6., ?erreri, 6., &ovelli, I., et al., 1424. ?atty acid
!ercentae in erythrocyte membranes of atrial flutter,fibrillation !atients and controls.
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RELEVANT WEBSITES
htt!+,,www.efsa.euro!a.eu, M E?S..
htt!+,,www.eufic.or M E8?)6.
htt!+,,www.cfsan.fda.ov,dms,"atrans1.html M ?5..
htt!+,,www.inran.it,D7D,tabellerdircom!osi/ionerdeliralimenti.html M )&(.&
*)talian )nstitute of &utrition-.
htt!+,,www.li!idlibrary.co.uk,li!id.html M The Li!id Library.
www.li!idma!s.or M Li!id$a!s.
CHAPTER ?K
Car!t($!i/s) Li+(r Dis(as(s Pr(+($ti!$
M. S#"i#ra
&ational )nstitute of ?ruit Tree Science, Shi/uoka, :a!an
>. O=IDATIVE STRESS AND CAROTENOIDS
>.>. OHi/ati+( Str(ss a$/ Li+(r Dis(as(s
The liver is a vital oran and has a wide rane of functions, includin
detoxification, !ro-tein synthesis, !roduction of biochemicals necessary for diestion,
and maintenance of normal lucose concentrations durin fastin. This oran !lays an
im!ortant role in the metabolism of lycoen storae, !lasma !rotein synthesis,
hormone !roduction, and detoxification. Es!ecially, the liver is a maGor site of insulin
clearance and the loss of a direct effect of insulin to su!!ress he!atic lucose
!roduction, and lycoenolysis in the liver causes an increase in he!atic lucose
!roduction *$ichael et al., 1444-.
6hronic liver disease is a worldwide common !atholoy. .bnormal liver function
is characteri/ed by an inflammatory and fibrotic !rocess that leads to a !roressive
evolution from chronic he!atitis to cirrhosis and liver cancer. .lcohol, virus,
xenobiotics, and,or unusual li!id and carbohydrate metabolism such as obesity,
insulin resistance, and ty!e 1 diabetes are widely known causes of chronic liver
disease *Louercio et al., 1442-.
Oxidative stress !lays a maGor role in the !athoenesis of liver inGuries. The maGor
source of reactive oxyen s!ecies in the liver are the activated inflammatory cells,
such as macro!hae and >u!ffer cells, the mitochondrial en/ymes, and cytochrome
#704 of damaed liver cells. The excessive reactive oxyen s!ecies in the liver affects
not only the transcri!tion of biochemical mediators such as cytokines which modulate
tissue and cel-lular events but also deeneration of li!ids, !roteins, 5&.,
carbohydrates, and other bio-molecules *#arola and (obino, 1442E Til and 5iehl,
1444-. )n such circumstances, antioxidant micronutrients, such as carotenoids, may
!lay im!ortant roles in defendin aainst oxidative stress by efficiently "uenchin the
!roduction of sinlet oxyen and free radicals and inhibitin the !roression of liver
diseases.
>.?. R!( !' A$ti!Hi/a$t Car!t($!i/s
.ntioxidant micronutrients, such as vitamins and carotenoids, exist in abundance
in fruit and veetables and have been known to contribute to the body%s defense
aainst reactive oxyen s!ecies *Stanner et al., 1447-. (ecently, it became known that
antioxidant
Fi"#r( ?K.> Oxidative stress in the !athoenesis of liver diseases and roles of antioxidant
carotenoids.
vitamins and carotenoids are reduced in several liver diseases, such as he!atitis and
cir-rhosis *:ain et al., 1441E Leo et al., 2339E Ian de 6asteele et al., 1441E ;ard and
#eters, 2331-. Oxidative stress is thouht to !lay a key role in the !athoenesis of
liver inGury. Therefore, antioxidant carotenoids would be ex!ected to !rotect aainst
liver inGury *?iure 1<.2-. )nested carotenoids from foods exist in several human
orans *Stahl et al., 2331-. 6arotenoids are mainly accumulated in the liver and
combined into li!o!rotein for release into the blood circulation. )nested carotenoids
could !artici!ate in an anti-oxidant defense system when !resent in hih
concentrations of free radical s!ecies in the liver, and these !hysioloical functions of
carotenoids could inhibit the develo!ment of liver dysfunction. )n fact, recently, many
studies have been re!orted that carotenoids, such as a-carotene, lyco!ene, lutein, and
a-cry!toxanthin, have antioxidant effects aainst li!id !eroxidation in rat liver *6hen
and Ta!!el, 233DE ;hittaker et al., 233D-.
?. ALCOHOLIC LIVER DISEASE AND CAROTENOIDS
)t is well known that alcohol induces the eneration of free radical s!ecies durin
its metabolism *>och et al., 1447-. The absorbed ethanol is oxidi/ed to acetaldehyde
by acetaldehyde dehydroenase in mitochondria. )n habitual drinkers, the microsomal
ethanol-oxidi/in system is increased by en/yme induction and is also res!onsible for
the !roduction of acetaldehyde. The eneration of hih concentrations of free radical
s!ecies durin the metabolism of alcohol may exceed the ca!acity of the antioxidant
defense mechanisms and cause the develo!ment of liver dysfunction.
?.>. Ci$i&a Cas(bC!$tr! St#/i(s
$any studies of the antioxidant status of alcohol-induced he!atitis or cirrhosis
!atients have re!orted on the measurement of the blood concentrations of antioxidants
or markers of oxidative stress, such as a-toco!herol, ascorbic acid, carotenoids, or
lutathi-one *Leo et al., 2339E Ian de 6asteele et al., 1441E ;ard and #eters, 2331-.
;ard and #eters *2331- examined the !lasma antioxidant values of alcoholic
!atients. They found that the alcoholic !atients% rou! showed sinificant decreases in
the mean !lasma values of a-carotene, /inc, and selenium when com!ared to the
control subGects. ;hen the !atients were subdivided accordin to their liver histoloy,
a-carotene showed a !roressive decrease in !lasma concentration with increasin
liver damae, whereas c-toco!herol levels were only de!leted in the !atients with
cirrhosis.
Similarly, Ian de 6asteele et al. *1441- also have investiated whether various
anti-oxidant !arameters in blood are affected in different staes of alcoholic liver
disease and how s!ecific the chanes are relative to nonalcoholic cirrhosis. )n this
study, !atients with alcohol abuse without cirrhosis, with alcoholic cirrhosis, and with
nonalcoholic cirrhosis stratified by 6hildM#uh scores *., B, and 6- were studied.
The 6hildM#uh score is used to assess the !ronosis of chronic liver disease, mainly
cirrhosis. Levels of reduced lutathione and lutathione !eroxidase activity in blood,
erythrocytic su!eroxide dismutase activity and carotenoids, c-toco!herol and
malondialdehyde in !lasma were measured. .s a result, they found that levels of
reduced lutathione were sinificantly decreased in 6hildM#uh score 6 cirrhotics,
alcoholic or not in oriin, whereas oxidi/ed lutathione and lutathione !eroxidase
activity were not affected. Su!eroxide dismutase activity and a-toco!herol levels were
not sinificantly different in the various rou!s. )n contrast, total carotenoid levels *c-
carotene, a-carotene, lyco!ene, cry!toxanthin, lutein, and /eaxanthin- were
sinificantly lower in alcoholic cirrhotics *6hildM#uh score 6- versus controls.
$alondialdehyde levels were elevated only in cirrhotics% 6hildM#uh score 6,
alcoholic or nonalcoholic *Table 1<.2-.
On the other hand, Leo et al. *2339- examined the carotenoid levels in diseased
liver. )n this study, they measured six carotenoid contents in diseased liver of !atients
with alcoholic cirrhosis, less severe alcoholic liver disease, and with nonalcoholic
liver disease and com!ared them with control subGects. .s a result, they found that all
carotenoid levels were extremely low at all staes of liver disease. #atients with
alcoholic cirrhosis had 14- and 10-fold decreases of levels of lyco!ene and c- and a-
carotene, res!ectively. Even
Tab( ?K.> Blood .ntioxidant Levels in 'ealthy 6ontrols and #atients
with .lcoholic 'e!atitis
S(r#.
a$ti!Hi/a$ts
@_.!
%>
A
A&!h!
ab#s(
0ith!#t
&irrh!sis
A&!h!i& &irrh!sisI Chi/%P#"h
s&!r(
H(athy
&!$tr!s
A B C
n 12 27 3 0 2C
Lutein,/eaxanthin 2.4 *4.9M
7.1-
4.< *4.2
M
2.3-
2.4 *4.0
M
2.9-
4.0 *4.4
M
1.2-
4.9 *4.4
M
2.1-
l
6ry!toxanthin 4.0 *4.4M
2.4-
4.4 *4.4
M
4.2-
l
4.4 *4.4
M
4.1-
l
4.4 *4.4
M
4.4-
l
4.4 *4.4
M
4.1-
l
Lyco!ene 2.4 *4.2M
9.D-
4.40 *4.2
M
1.4-
4.0 *4.4
M
4.3-
4.7 *4.4
M
4.<-
4.2 *4.4
M
4.D-
l
c-6arotene 4.2 *4.4M
4.0-
4.4 *4.4
M
4.1-
l
4.2 *4.4
M
2.4-
4.2 *4.4
M
4.9-
4.4 *4.4
M
4.1-
l
a-6arotene 4.D *4.2M
2.3-
4.1 *4.4
M
4.9-
l
4.7 *4.1
M
4.D-
4.9 *4.2
M
4.7-
4.2 *4.4
M
4.0-
l
Total carotenoids 9.7 *2.2M
<.7-
2.D *4.9
M
9.D-
1.2 *4.C
M
1.7-
2.1 *4.0
M
9.2-
2.4 *4.1
M
2.1-
l
(etinol 7.1 *2.9M
D.2-
9.2 *4.7
M
<.7-
4.3 *4.<
M
2.<-
2.9 *4.1
M
7.7-
4.0 *4.<
M
2.<-
l
c-Toco!herol 2C *27M
D1-
94 *24M
<D-
72 *14M
73-
2D *3M
93-
2D *4M
D9-
!ource+ $odified from !revious data by Ian de 6asteele, $., Naman, N., Neeers,
$., et al., 1441. Blood antioxidant levels in !atients with alcoholic liver disease
correlate with the deree of liver im!airment and are not s!ecific to alcoholic liver
inGury itself. .limentary #harmacoloy and Thera!eutics 2D, 3C0M331, !ublished by
Blackwell Science Ltd.
l
# V .40 vs. healthy control subGects.
5ata are mean and rane.
in subGects with less severe alcoholic liver disease *steatosis, !erivenular fibrosis, and
!ortal fibrosis- and in !atients with nonalcoholic liver disease, levels were four to six
times lower than those in normal subGects.
These clinical caseMcontrol studies !rovided su!!ort for the hy!othesis that
antiox-idant carotenoids may !rotect aainst oxidative stress induced by alcohol
consum!tion.
?.?. Obs(r+ati!$a E3i/(.i!!"i&a St#/i(s
2.1.1. 7erum liver en3ymes with carotenoids
)n contrast, some observational e!idemioloic studies on normal livin subGects
about the associations of serum carotenoid concentrations and liver functions have
been re!orted. )n these e!idemioloic studies, investiators measured serum liver
en/yme activities in the blood. The damae of liver cells accom!anies the release of
liver function en/ymes, such as b-lutamyltransferase *b-HT#-, alanine
aminotransferase *.LT-, and as!artate aminotransferase *.ST- into the blood.
6linically, these en/ymes are often used as biomarkers for liver inGury or liver
diseases. (ecently, several e!idemioloic studies have shown that serum b-HT# is
associated with risk factors of cardiovascular disease, suestin the !ossibility of a
close relationshi! between oxidative stress and chronic diseases *Lee et al., 1447E
&akanishi et al., 1449-.
b-HT# exists widely in various tissues, es!ecially in the liver and kidneys, and it
cataly/es the transfer of a b-lutamyl rou! from -lutamyl !e!tides to other
!e!tides, thereby !rovidin a su!!ly of constituent amino acids for u!take and
reutili/ation in intracellular lutathione synthesis. )n a normal metabolism, this
en/yme !lays an im!ortant role in antioxidant defense systems on a cellular level.
.lthouh serum b-HT# is not a s!ecific indicator of liver inGuries due to alcohol, it is
widely used as a screenin test for alcohol-induced liver dysfunction *(yback et al.,
23C1-.
. recent e!idemioloical study has re!orted the inverse association of serum b-
HT# with serum-carotenoid concentrations both cross-sectionally and lonitudinally
*Lee et al., 1447-. )n this study, the inverse associations between total serum
carotenoid con-centration and serum b-HT# were examined amon subrou!s
includin race, sex, body mass index *B$)- levels, tobacco use, and vitamin
su!!lement usae. ;ith reard to alcohol consum!tion, althouh inverse associations
between total serum carotenoid concentration and serum b-HT# were found in
drinkers, they were not found in non-drinkers. 'owever, the associations of the serum
carotenoid concentration and serum b-HT# with ethanol intake were not discussed in
detail accordin to the stratification of the ethanol intake level. ?urthermore, the
associations of serum concentration of each carotenoid with serum b-HT# were not
ex!lained in detail.
2.2.2. Alcohol,induced increases o" serum liver en3ymes with
carotenoids
On the other hand, Suiura et al. *1440- examined the associations of six main
serum carotenoids and serum b-HT# with alcohol intake level. )n this study, the daily
ethanol consum!tion of study subGects was estimated !recisely from the data obtained
in the "ues-tionnaire concernin food fre"uency. Therefore, these data make it
!ossible to evaluate the detailed association of serum carotenoid concentrations and
serum b-HT# with alcohol intake level. They evaluated the association of serum b-
HT# as a marker of oxidative stress induced by alcohol consum!tion and serum
carotenoids stratified by alcohol intake level in :a!anese men with normal liver
function.
The subGects were divided into three rou!s stratified by ethanol intake levels
defined as nondrinkers *less than 2 of ethanol daily-, liht drinkers *2, V10 of
ethanol daily-, and moderate and heavy drinkers *10 of ethanol daily-. The subGects
were further subcateori/ed into three rou!s accordin to the tertile of serum
carotenoid concentrations after bein stratified by ethanol intake levels. The
multivariate-adGusted eometric mean and 30R confidence interval of the serum b-
HT# concentrations by tertiles of the serum carotenoid concentration were calculated
after adGustin for confounders usin analysis of covariance.
The multivariate-adGusted eometric means of serum b-HT# concentrations
associated with the tertiles of each serum carotenoid concentration stratified by
ethanol intake level are shown in ?iure 1<.1. )n liht drinkers, the adGusted means of
serum b-HT# were slihtly low in accordance with tertiles of serum a-carotene and a-
cry!toxanthin concentration but the rou! difference was not statistically sinificant.
)n moderate and heavy drinkers, adGusted means of serum b-HT# were sinificantly
low in accordance with the tertiles of serum lyco!ene, c-carotene, a-carotene, and a-
cry!toxanthin. On the other hand, sinificant inverse associations were not observed
in lutein and /eaxanthin.
These results suest that carotenoids may act as a su!!ressor aainst liver cell
damae and inhibit the !roression of liver dysfunction induced by alcohol. 'owever,
the data obtained here consist of cross-sectional analyses. To determine whether
serum antioxidant carotenoids are effective in increasin serum b-HT# in alcohol
drinkers, further cohort studies or intervention studies will be re"uired.
?.B. Ci"ar(tt( S.!,i$" EHa&(rbat(s D(3(ti!$ !' S(r#.
Car!t($!i/s I$/#&(/ by A&!h!U
.s mentioned earlier, alcohol induces the eneration of free radical s!ices durin
metab-olism in the liver. )n such circumstances, carotenoids may !lay im!ortant roles
as antioxidants in defendin aainst oxidative stress. That is to say, carotenoids may
be con-sumed by free radical s!ecies. On the other hand, active smokers are ex!osed
to reactive free radicals that are !resent in ciarette smoke. Therefore, smokin is also
a !otent oxidative stress in humans. 'owever, there is limited information about the
syneristic interaction of ciarette smokin and alcohol drinkin with serum
carotenoid concentrate-ions. The differences in the chane amon six maGor serum
carotenoid concentrations
?iure 1<.1 6onfoundin factors adGusted means of serum b-HT# stratified by alcohol
intake levels *Suiura et al., 1440-. .dGustments were made for ae, B$), total cholesterol,
triacyllycerols, current smokin, and habitual exercise.
l
# V .40,
ll
# V .442 versus the lowest
carotenoid tertile in Bonferroni multi!le com!arison test. O!en circle+ nondrinkers *V2 day
-
2
-, closed circle+ liht drinkers *2M10 day
-2
-, closed trianle+ moderate to heavy drinkers
*`10 day
-2
-. *Modified from previous data by !ugiura$ M#$ /a&amura$ M#$ I&oma$ M#$ et al#$
455:# "igh serum carotenoids are inversely associated *ith serum gamma-
glutamyltransferase in alcohol drin&ers *ithin normal liver function# 7ournal of
%pidemiology 9:$ 985;986$ published by 7apan %pidemiological ,ssociation#-
aainst oxidative stress induced by ciarette smokin and alcohol drinkin have not
been thorouhly studied while controllin for dietary carotenoid concentrations.
2.'.1. 7ynergistic interaction o" cigarette smoking and alcohol
drinking with serum carotenoids
Iery recently, Suiura et al. *1443- tested the hy!othesis that smokin and
drinkin reduce the serum carotenoid concentration syneristically. )n this survey, the
subGects were divided into six rou!s accordin to alcohol intake *nondrinkers, V2
day
-2
E liht drinkers, 2, V10 day
-2
E moderate to heavy drinkers, 10 day
-2
- and
smokin status *nonsmokers and current smokers-. The dietary intakes and serum
concentrations of six carotenoids *lyco!ene, c-carotene, a-carotene, lutein, a-
cry!toxanthin, and /ea-xanthin- within each rou! were evaluated cross-sectionally.
(esults showed that the multivariate-adGusted means of the serum carotenoid
concentrations in nondrinkers did not differ between nonsmokers and current
smokers. )n contrast, the adGusted means of serum c-carotene, a-carotene, and a-
cry!toxanthin were sinificantly lower than those with increased alcohol intake, and
these lower serum carotenoids amon alcohol drinkers were more evident in current
smokers than in nonsmokers. Serum lyco!ene of moderate to heavy drinkers was
sinificantly lower than that of nondrinkers, but it was not influenced by smokin.
&either smokin nor drinkin was associated with the serum concentrations of lutein
and /eaxanthin. These differences of serum carotenoid concen-trations amon six
rou!s were observed after adGustin for intakes of each carotenoid. ?rom this study,
it was observed, interestinly, that serum c-carotene, a-carotene, and a-cry!toxanthin
in moderate to heavy drinkers amon current ciarette smokers were about half the
levels of those in nondrinkers amon nonsmokers even thouh their intake of
carotenoids was the same. These results suest that smokin and drinkin may
reduce the serum c-carotene, a-carotene, and a-cry!toxanthin concentrations in a
syneristic manner *?iure 1<.9-.
2.'.2 8i""erences among si carotenoids against oidative stress
induced %y cigarette smoking and alcohol drinking
)t is known that a transformin reaction from !ro-vitamin . to retinol is induced
by smokin. On the other hand, alcohol is known to !romote increased oxidation of
vitamin . com!ounds and reduce liver stores. )t can be !ostulated that alcohol intake
may also accelerate the conversion of !ro-vitamin . to retinol. ?rom amon the six
maGor serum carotenoids, c-carotene, a-carotene, and a-cry!toxanthin, are !ro-
vitamin .. These three carotenoids are converted to retinol in the body. Therefore, the
serum concentrations of c-carotene, a-carotene, and a-cry!toxanthin miht be more
easily influenced by ciarette smokin and alcohol drinkin than lyco!ene.
Suiura et al. *1443- also found that the serum lutein and /eaxanthin
concentrations were not influenced not only by alcohol drinkin but also by ciarette
smokin. )t miht be difficult to ex!ose lutein and /eaxanthin aainst oxidative stress
or that the differences amon the six serum carotenoids observed occurred by chance.
One !ossible ex!lanation is that the differences in the associations of the six serum
carotenoids with ciarette smok-in and alcohol drinkin miht be attributed to the
!olar characteristics of each carotene-oid. )t is conceivable that the tissue distribution
and locali/ation in the cell membranes of carotenoids differ in each carotenoid.
Es!ecially, the chemical structure of a carotenoid may determine its locali/ation in a
cell membrane. 'ydrocarbon carotenoids, such as lyco!ene, c-carotene, and a-
carotene, are located within the hydro!hobic membrane core with multi!le
orientations, whereas xantho!hylls, such as lutein and /eaxanthin, have a more riid
membrane-s!annin orientation. Therefore, the antioxidant defense
?iure 1<.9 .dGusted serum carotenoid concentrations stratified by smokin status and
daily alcohol intake level *Suiura et al., 1443-. .dGustments were made for ae, sex, B$),
total cholesterol, total enery intake excludin alcohol, and dietary intake of corres!ondin
carotenoid. a# V .40,
b
# V .42, and
c
# V .442 versus nonsmokers amon nondrinkers,
d
# V .42
and
e
# V .442 versus nonsmokers who have the same alcohol intake,
f
# V .42 and
# V .442
versus current smokers amon nondrinkers by Bonferroni multi!le com!arison test. O!en
circle+ nonsmokers, closed circle+ current smokers. *Modified from previous data by !ugiura$
M#$ /a&amura$ M#$ 1ga*a$ D#$ et al#$ 455<# !ynergistic interaction of cigarette smo&ing and
alcohol drin&ing *ith serum carotenoids concentrations@ findings from a middle-aged
7apanese population# ritish 7ournal of /utrition 954$ 9499;949<$ published by Cambridge
Oniversity Press#-
system by carotenoids aainst li!id !eroxidation in a cell membrane may de!end on
the !olar characteristics of each carotenoid.
B. NONALCOHOLIC LIVER DISEASE AND CAROTENOIDS
The adverse im!act of overweiht, obese, and,or !hysical inactivity is well
documented as risk factors for diabetes, cardiovascular disease, cancer, and
musculoskeletal disease. &onalcoholic fatty liver disease *&.?L5- !resents a
com!rehensive histoloical as!ect which results from the de!osit of trilycerides into
he!atocytes. .lthouh the !atholoy-ical alterations in &.?L5 are similar to those of
alcoholic liver disease, it occurs in non-alcoholic individuals. These !atholoical
alterations vary from sim!le steatosis to nonalcoholic steatohe!atitis *&.S'-,
fibrosis, and cirrhosis. The !revalence of &.?L5 has risen in !arallel with obesity
and diabetes, and it is becomin the most common cause of liver disease in ;estern
countries.
B.>. N!$a&!h!i& Li+(r Dis(as( a$/ OHi/ati+( Str(ss
The role of oxidative stress and mitochondrial dysfunctions in nonalcoholic liver
diseases is well documented *Basaranolu et al., 1424-. b-Oxidation within the normal
liver takes !lace in mitochondria, but this !rocess in the context of &.?L5 can
become over-whelmed as a result of increased free fatty acid *??.- load. )ncreased
??. ives rise to reactive oxyen s!ecies. (eactive oxyen s!ecies induce oxidative
stress and activate inflammatory !athway. .lthouh antioxidant carotenoids may also
act as su!!ressors to oxidative stress in nonalcoholic liver diseases, the associations of
carotenoids with non-alcoholic liver diseases have not been thorouhly studied.
B.?. R(ati!$shi3 B(t0(($ S(r#. Li+(r E$-y.(s a$/
Car!t($!i/s Ass!&iat(/ 0ith N!$a&!h!i& Li+(r Dis(as(
One lare observational e!idemioloic study has been re!orted about the inverse
association of serum carotenoid concentrations with abnormal serum liver en/yme
activity. (uhl and Everhart *1449- analy/ed the associations of serum antioxidants
with abnormal serum .LT activity from the third 8S &ational 'ealth and &utrition
Examination Survey *&'.&ES )))- usin a total of 29,D40 adult subGects. .ccordin
to results, they found that abnormal .LT risk was associated neatively with an
increase of c-carotene, a-carotene, a-cry!toxanthin, lutein,/eaxanthin, and combinin
0 carotenoids. They also examined the associations of serum carotenoid concentration
with the risk for abnormal .LT level amon subcateori/ed subGects by obesity,
waist-to-hi! ratio, and diabetes. Sinificant inverse association of combined 0
carotenoids with the risk for abnormal .LT level was observed amon obese subGects
*B$), 10- but not amon non-obese subGects. The same inverse association was also
observed amon subGects whose waist-to-hi! ratio was hiher *4.C<- but not amon
normal subGects. ?rom these results, one may conclude that carotenoids may act as
su!!ressors aainst abnormal liver function such as nonalcoholic liver disease
associated with visceral adi!osity.
B.B. Hy3(r"y&(.ia%I$/#&(/ I$&r(as(s !' S(r#. Li+(r
E$-y.(s 0ith Car!t($!i/s
On the other hand, chronic hy!erlycemia leads to the auto-oxidation of lucose
and causes the nonen/ymatic lycation of !roteins throuh $aillard%s reaction
*Hiuliano et al., 233D-. )n these !rocesses, reactive oxyen s!ecies are !roduced.
'y!erlycemia enhances oxidative stress, for exam!le, the increase of li!id
!eroxidation. The relation-shi! between the !athoenesis of diabetes mellitus and
oxidative stress is unclear, but a close relationshi! exists between the !athoenesis of
diabetic com!lications and tissue inGury from free radicals. To avoid oxidative stress,
antioxidant en/ymes, such as catalase, su!eroxide dismutase, and lutathione
!eroxidase, !lay an im!ortant role aainst oxidative stress. 'owever, the eneration
of hih concentrations of free radical s!ecies in hy!erlycemia also causes
nonen/ymatic lycation of these antioxidant en/ymes *IiGayalinam et al., 233D-.
These facts indicate that hy!erlycemia-induced oxidative stress may also cause liver
cell damae, and increased oxidative stress in hy!erlycemia causes an increase in
serum liver en/yme even at !hysioloical concentrations. Therefore, an antioxidant
defense system aainst oxidative stress induced by chronic hy!erlycemia may !lay
an im!ortant role in the earlier !athoenesis of liver disease amon hy!erly-cemic
subGects. )f so, carotenoids may act as su!!ressors to inhibit the !roression of liver
disease induced by hy!erlycemia, and this will eventually result in the !revention of
nonalcoholic liver disease.
(ecently, Suiura et al. *144D- examined the hy!othesis that hy!erlycemia-
induced increases of serum liver en/ymes at !hysioloical concentrations would be
inversely associated with the serum carotenoid concentrations. The associations of the
six serum carotenoid concentrations with serum liver en/yme stratified by the lucose
tolerance status were evaluated cross-sectionally.
Table 1<.1 shows the serum .ST and .LT stratified by the lucose tolerance
status. These serum liver en/yme concentrations in the im!aired fastin lucose
Tab( ?K.? 6haracteristics of the Study SubGect Stratified by Hlucose
Tolerance Status
N!r.a 'asti$" I.3air(/ 'asti$"
"#&!s( "r!#3 "#&!s( "r!#3
a
"#&!s( "r!#3
a
n <43 <3 D3
$ale *R- 13.0 72.C 00.2
.e
*years-
07.D *24.4- 03.2 *C.4-
lll
03.7 *C.9-
lll
Body
mass
index *k
m
-1
-
11.< *9.2- 19.< *9.2-
l
17.9 *1.C-
lll
?astin
!lasma
lucose
*m dl
-2
-
32.1 *<.0- 24C.1 *C.C-
lll
279.9 *90.9-
lll
.LT *)8
l
-2
-
2C.4 *C.3- 12.7 *C.0-
ll
1C.3 *23.2-
lll
.ST *)8
l
-2
-
14.2 *0.<- 11.2 *0.3-
l
1D.7 *20.4-
lll
!ource+ $odified from !revious data by Suiura, $., &akamura, $., )koma, =.,
et al., 144D. Serum carotenoid concentrations are inversely associated with serum
aminotransferases in hy!erlycemic subGects. 5iabetes (esearch and 6linical #ractice
<2, C1M32.
l
# V .40,
ll
# V .42 and
lll
# V .42 vs. normal rou! in 5unnett%s test.
.ll data are re!resented as means *standard deviation- or !ercent.
a
224M210 m dl
-2
of fastin !lasma lucose and,or 0.DMD.4R of 'b.2c.
b
21D m dl
-2
of fastin !lasma lucose and,or D.2R of 'b.2c and,or history of
diabetes.
*)?H- and diabetes rou!s were sinificantly hiher than those in the normal fastin
lucose *&?H- rou!. The multivariate-adGusted eometric means of the serum .LT
concentrations associated with tertiles of each carotenoid concentration stratified by
lucose tolerance status are shown in ?iure 1<.7. The means of the serum .LT
concentrations in each tertile were calculated after adGustin confounders. )?H and
diabetic rou!s were combined to form a hy!erlycemic rou!. The serum .ST
concentration in the hy!erlycemic rou! was sinificantly low in accordance with
the tertiles of serum a-carotene and a-cry!toxanthin concentrations. On the other
hand, serum .LT concentration in the hy!erlycemic rou! was sinificantly low in
accordance with the tertile of the serum a-cry!toxanthin concentration *?iure 1<.7-.
These results showed that serum a-carotene and a-cry!toxanthin concentrations
were inversely associated with serum .ST and .LT concentrations in the
hy!erlycemic subGects. The inverse associations of serum carotenoid concentrations,
es!ecially in a-cry!toxanthin, with serum .ST and .LT were !roressively stroner
in lucose intolerance. a-6arotene and a-cry!toxanthin may act as a su!!ressor
aainst liver cell damae and inhibit the !roression of liver dysfunction in
hy!erlycemia.
Fi"#r( ?K.D 6onfoundin factors adGusted means of serum .LT stratified by lucose
tolerance status *Suiura et al., 144D-. .dGustments were made for ae, B$), systolic blood
!ressure, total cholesterol, triacyllycerols, current smokin, and habitual exercise.
l
# V .40
versus the lowest carotenoid tertile in the Bonferroni multi!le com!arison test. O!en circle+
normal subGects rou!, closed circle+ hy!erlycemic subGects rou!. *Modified from previous
data by !ugiura$ M#$ /a&amura$ M#$ I&oma$ M#$ et al#$ 4556# !erum carotenoid concentrations
are inversely associated *ith serum aminotransferases in hyperglycemic subCects# (iabetes
.esearch and Clinical Practice$ G9$ 84;<9$ published by %lsevier LT(#-
D. LIVER CANCER AND CAROTENOIDS
.lthouh the !otential roles of antioxidant carotenoids in cancer !revention have
been demonstrated at various cancer sites *5ruesne-#ecollo et al., 1424-, the
association with he!atocellular carcinoma *'66- remains unclear *;orld 6ancer
(esearch ?und, .merican )nstitute for 6ancer (esearch, 144<-. (ecently, some lare
cohort studies about the association of carotenoid intake with the risk of liver cancer
and an intervention study were re!orted.
D.>. Lar"( C!h!rt St#/y
>urahashi et al. *1443- have re!orted the inverse associations of intakes of reen
veetables or carotenoids with the risk for '66 usin 23,33C men and women
*190,C22 !erson-years of follow-u!-. .s a result, they found that borderline inverse
as-sociations were seen between total veetables and reen-yellow veetables and
'66, with multivariable ha/ard ratios *'(s- for the hihest versus the lowest tertile
of 4.D2 *30R confidence interval *6)- e 4.9DM2.49, # for trend e .4<- and 4.D0 *30R
6) e 4.93M2.4C, # for trend e .4D-, res!ectively. )n !articular, reen leafy veetable
consum!tion showed an inverse dose-de!endent association with '66 *'( e 4.03,
30R 6) e 4.90M2.42 for hihest versus lowest tertile of consum!tion, # for trend e .
47-. On the other hand, a slihtly neative association was seen between c- and a-
carotene and '66, with res!ect to multivariable '(s for the hihest versus the lowest
tertile of 4.D3 *30R 6) e 4.71M2.20- and 4.D7 *30R 6) e 4.9CM2.4C-. ?urthermore,
they found that these inverse associations of veetable and carotenoid intakes with the
risk for '66 were noted es!ecially amon those who were never ciarette smokers
*hihest versus lowest+ '( e 4.92, 30R 6) e 4.29M4.<D for a-carotene-.
D.?. I$t(r+($ti!$ St#/y
$eanwhile, &ishino et al. *1443- examined the effectiveness of combinational
admin-istration of multi!le carotenoids aainst liver cancer in he!atitis virus-infected
!atients with cirrhosis. )n the !ast, they found that !alm oil carotene, which consists
of 94R c-carotene, D4R a-carotene, and 24R others *b-carotene, lyco!ene, etc.-,
remarkably su!!ressed s!ontaneous liver carcinoenesis in 69','e male mice, more
effectively than c- or a-carotene alone *$urakoshi et al., 2331-. Therefore, they
examine the hy-!othesis that a carotenoid mixture would be effective to su!!ress the
develo!ment of liver cancer in !atients with he!atitis 6 virus-induced liver cirrhosis,
the hih risk rou! of '66. .s a result, they found that the administration of
hydrocarbon carotenoid mix-ture *lyco!ene 24 m, a-carotene D m, and c-carotene 9
m- resulted in sinificant su!-!ression of tumor develo!ment. ?urthermore, recently,
they found that combined a!!lication of :a!anese mandarin orane Guice containin 9
m of a-cry!toxanthin with
Tab( ?K.B Liver 6ancer #revention by 6arotenoids $ixture 6a!sule and
a-6ry!toxanthin-Enriched :a!anese $andarin Orane :uice
C#.#ati+(
i$&i/($&( !' i+(r
&a$&(r
I$hibiti!$ @PA
Gr!#3 n
6ontrol rou! 70 11.1
6arotenoids
mixture rou!
7D 29.4 72.4
6arotenoids
mixture !ulse a-
cry!toxanthin rich
17 7.1
l
C2.4
Guice rou!
!ource+ $odified from !revious data by &ishino, '., $urakoshi, $., Tokuda, '.,
Satomi, =., 1443. 6ancer !revention by carotenoids. .rchives of Biochemistry and
Bio!hysics 7C9, 2D0M2DC, !ublished by Elsevier Ltd.
l
# V .40 vs. control rou!.
6arotenoids mixture ca!sules *lyco!ene+ 24 m, a-carotene+ 9 m, a-carotene+ D
m-.
a carotenoid mixture *lyco!ene 24 m, a-carotene D m, and c-carotene 9 m- showed
to be more effective than a carotenoid mixture alone *Table 1<.9-.
?rom these results, various carotenoids and combinations of these elements seem
to be !romisin for the !revention of a wide variety of chronic liver diseases, not only
liver cancer but also alcoholic and nonalcoholic diseases, althouh further extended
clinical trial is needed to confirm and im!rove the efficacy.
E. CONCL*SIONS
Systemic inflammation and oxidative stress a!!ear to be involved in the
!roression of liver dysfunction. .lcoholic and nonalcoholic fatty liver diseases are
conditions associated with hiher levels of inflammatory !roteins, increased markers
of oxidative stress, and lower !lasma concentrations of antioxidants. On the other
hand, !ros!ective cohort studies have linked the consum!tion of fruit and veetables
to a decreased risk of liver disease, cardiovascular events, metabolic syndrome, and
ty!e 1 diabetes, which suests a !rotective effect of dietary antioxidant carotenoids.
)ndeed, !ublic health authorities have been recommended a diet of five servins of
fruit and veetables each day. ?ruit and veetables are the main dietary sources of
carotenoids. )nested carotenoids could !artici!ate in an antioxidant defense system
when !resent in hih concentrations of free radical s!ecies in the liver, and these
!hysioloical functions of carotenoids could inhibit the develo!ment of liver
dysfunction. 'owever, even if antioxidant carotenoids are thouht to !lay a key role
in disease !revention, the results of intervention studies with sinle antioxidants
administered as su!!lements have been !oor so far. The consum!tion of carotenoids
in !harmaceutical forms for the treatment or !revention of these chronic diseases
cannot be recommended, because some lare randomi/ed controlled trials did not
reveal any reduction in cancer, cardiovascular events, and,or ty!e-1 diabetes with a-
carotene *Liu et al., 2333E Toornwall et al., 1447-. 'ih doses of carotenoids used in
the su!!lementation studies could have a !ro-oxidant effect *El-.amey et al., 1447-.
Therefore, it miht be favorable to consume carotenoids from foods throuh the
com-bination of other nutrients such as vitamins, minerals, or !hytochemicals, and not
by su!!lements.
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rats with dietary iron overload. &utrition and 6ancer 10, 223M21C.
;orld 6ancer (esearch ?und,.merican )nstitute for 6ancer (esearch, 144<.
?ood, &utrition, #hysical .ctivity, and the #revention of 6ancer+ . Hlobal
#ers!ective. .merican )nstitute for 6ancer (esearch, ;ashinton, 56.
CHAPTER ?L
O.("a%B Fatty A&i/s a$/ Eary Li'(
N#triti!$a Pr!"ra..i$") L(ss!$s 'r!.
th( A+ia$ M!/(
G. Ch(ria$
Oreon State 8niversity, 6orvallis, O(, 8S.
>. ESSENTIAL OMEGA%B FATTY ACIDS
.ll mammals synthesi/e saturated fatty and monounsaturated fatty acids de novo
from sim!le !recursors such as lucose or ketoenic amino acids. 'owever, mammals
cannot insert double bonds more !roximal to the methyl end than the ninth carbon
atom. Thus, two fatty acids havin their first double bonds at the Dth and 9rd carbon
atoms, namely, linoleic *2C+1 n-D- and al!ha-linolenic acid *2C+9 n-9-, res!ectively,
cannot be synthe-si/ed de novo. Therefore, these fatty acids have to be su!!lied
throuh the diet and are called essential fatty acids. 5enotin the !osition of the first
double bond !roximal to the methyl end of the fatty acid chain, essential fatty acids
are also classified as omea- D *n-D- and omea-9 *n-9- fatty acids. . list of the most
common n-9 and n-D fatty acids and their systemic, common name, and shorthand
notation is shown in Table 1C.2. .s early as the2394s, the essentiality of linoleic acid
*2C+1 n-D- and al!ha-linolenic acid *2C+9 n-9- in rat diets was identified *Burr and
Burr, 2394-. 'owever, the essentiality of n-9 fatty acids in humans was first
demonstrated only in the early 23C4s *'olman et al., 23C1-.
?. OMEGA%B FATTY ACIDS) DIETARY S*PPLYI
SYNTHESISI AND NEED
)n humans, dietary su!!ly of al!ha-linolenic acid is from terrestrial sources such
as oils from flax and canola. Other food !roducts *e.., es, meat- obtained from
animals fed with s!ecialty diets containin flax may also substantially contribute
al!ha-linolenic acid to the human food chain. ?or exam!le, es from hens that were
fed 24R flax could !rovide over 144 m of al!ha-linolenic acid *6herian, 144C-. On
consum!tion, dietary al!ha-linolenic acid serves as the substrate for the synthesis of
loner-chain 14- and 11-carbon n-9 olyunsaturated fatty acids *#8?.s-. To
synthesi/e lon-chain #8?.s from dietary al!ha-linolenic acid, two key reactions
must occur+ elonation and desatura-tion. )n both the reactions, the carbon chain is
successively extended by two carbons !er
Tab( ?L.> The Systematic &ame, Trivial &ame and Shorthand &otation
of Some of the 6ommon n-D and n-9 ?atty .cids
Syst(.i& $a.( C!..!$ $a.( Sh!rtha$/ $!tati!$
n,- .olyunsaturated "atty acids
all-cis-3,21-
Octadecadienoic acid
Linoleic acid 62C+1n-D
all-cis-D,3,21-
Octadecatrienoic acid
Hamma-linolenic acid 62C+9n-D
all-cis-22,27-
Eicosadienoic acid
Eicosadienoic acid 614+1n-D
all-cis-C,22,27-
Eicosatrienoic acid
5ihomo-b-linolenic acid 614+9n-D
all-cis-0,C,22,27-
Eicosatetraenoic acid
.rachidonic acid 614+7n-D
all-cis-<,24,29,2D-
5ocosatetraenoic acid
.drenic acid 611+7n-D
all-cis-7,<,24,29,2D-
5ocosa!entaenoic acid
5ocosa!entaenoic acid 611+0n-D
n,' .olyunsaturated "atty acids
all-cis-3,21,20-
Octadecatrienoic acid
c-Linolenic acid 62C+9n-9
all-cis D,3,21,20-
Octadecatetraenoic acid
Stearidonic acid 62C+7n-9
all-cis-0,C,22,27,2<-
Eicosa!entaenoic acid
Eicosa!entaenoic acid 614+0n-9
all-cis-<,24,29,2D,23-
5ocosa!entaenoic acid
5ocosa!entaenoic acid 611+0n-9
all-cis-7,<,24,29,2D,23-
5ocosahexaenoic acid
docosahexaenoic acid 611+Dn-9
reaction while more double bonds are added to the !arent al!ha-linolenic acid. The
!ro-cess of elonation and desaturation of al!ha-linolenic acid occurs mainly in the
liver and includes delta-D desaturation, chain elonation, and delta-0 desaturation.
Thus, the !ar-ent al!ha-linolenic acid is converted to eicosa!entaenoic acid *E#.,
14+0 n-9-, which is subse"uently converted to docosa!entaenoic acid *5#., 11+0 n-9-
*Brenner, 23<2-. The final metabolite, docosahexaenoic acid *5'., 11+D n-9-, is
synthesi/ed by chain elon-ation, delta-D desaturation, and !eroxisomal beta-
oxidation of 5#. *11+0 n-9-. 5ue to the com!etition between linoleic and al!ha-
linolenic acids for desaturases, the lon-chain #8?. formation from al!ha-linolenic
acid is de!endent on factors such as ratio of linoleic acid as well as ae and disease
conditions *BarcelJ-6obliGn and $ur!hy, 1443E 5as, 1440, 144D-.
)n a ty!ical ;estern diet, al!ha-linolenic acid !rovides 2.7 !er dayE lon-chain
n-9 fatty acids, 4.1 !er day. The dietary ratio of linoleic acid to al!ha-linolenic acid
is in the rane of 27+2 *BarcelJ-6obliGn and $ur!hy, 1443E >ris-Etherton et al.,
1444-. The wide dietary n-D+n-9 fatty acid ratio in the ;estern diet is reflected in the
!lasma li!ids as well as breast milk of women consumin ;estern diet *)nnis, 144<a-.
Low circulatin levels of 5'. are observed in newborns, breast-fed infants, and !re-
school children in the western countries com!ared to those in fish-eatin countries
*)nnis, 144<b-. 5'. is the most abundant #8?. in the central nervous system of
mam-mals. The accretion of5'.is at its !eak durin !eriods of ra!id brain rowth,
such as the last trimester of !renancy and first DM24 months after birth in human
infants *6landinin et al., 23C4a,b-. 5urin these !eriods, maternal diet, breast milk, or
artificial formula serves as the source of 5'. to the fetus or the newborn. The su!!ly
of 5'. to the neonate durin !eriods of !eak rowth may be ham!ered in !reterm
and newborn infants fed with !lant-oil-based formulas lackin 5'. as well as in
those infants nursed by mothers consumin a ty!ical western diet. Several studies
have demonstrated that the lack of 5'. in infant formula leads to lower 5'. levels
in infant brain, (B6, and !lasma *6arlson et al., 23CDE $akrides et al., 2337E #utnam
et al., 23C1-. ?or these reasons, it is critical that the correct ac"uisition of 5'. occurs
durin !renatal and early !ostnatal life.
B. WHAT IS EARLY LIFE PROGRAMMINGU
Early life or in utero !rorammin is the conce!t that !erturbations durin critical
!renatal or early !ostnatal life can have lastin im!acts on the develo!ment of chronic
diseases later in life as !ro!osed by the SBarker fetal oriin of diseases% hy!othesis
*Barker, 2330E ;aterland and Har/a, 2333-. These !rorammed chanes may be the
oriins of a number of diseases in later life, includin coronary heart disease and the
related disorders such as stroke, diabetes, and hy!ertension *Bertram and 'anson,
1442E ?owden et al., 144D-. E!idemioloical and ex!erimental studies in humans and
animal models have broadened the understandin of in utero !rorammin
*Hluckman et al., 144CE Lucas, 2332-. Throuh such studies, it has been demonstrated
that the timin, duration, and nature of !erturbations durin critical !eriods of
develo!ment are im!ortant determi-nants of s!ecific !hysioloical outcomes in the
!roeny *>orotkova et al., 1440E #atel and Srinivasan, 1441-. ?or instance, even a
minor variation in maternal nutritional status !roduces shifts in the fetal environment
*:ackson, 1444-. &utrition-related factors drive these !rocesses by disturbin
!lacental function, includin control of maternofetal endocrine exchanes, or the
e!ienetic reulation of ene ex!ression *Schwart/ and $orrison, 1440E Neisel,
1443-.
D. ANIMAL MODELS FOR EARLY LIFE PROGRAMMING
RESEARCH
5ue to ethical concerns, animal studies have been of !ivotal im!ortance in
advancin knowlede of in utero !rorammin and !roeny health. The most
commonly used animal models for investiatin n-9 fatty acids in in utero nutritional
!rorammin are rodents or !is *6ha!man et al., 1444E Bertram and 'anson, 1442E
)nnis, 1440-. )n mam-malian s!ecies, the fetus has continuous ex!osure to fatty acids
and other nutrients throuh maternal circulation via the !lacenta. The !lacenta may
transfer, synthesi/e, or selectively trans!ort certain fatty acids to the fetus, which
creates a !roblem in eval-uatin the contribution of maternal diet in fetal n-9 #8?.
accretion. The !lacental role in meetin the fetal su!!ly of n-9 and n-D #8?.s in the
mammalian model is shown in ?iure 1C.2. )n rodents, for exam!le, u! to 04R of the
fatty acids in the fetal circulation are derived from the maternal circulation throuh
the !lacenta *6oleman, 23CD-. . five-fold increase in fetal and !lacental 5'.
com!ared with the 5'. content of maternal
Fi"#r( ?L.> #olyunsaturated n-9 and n-D fatty acid su!!ly to the fetus in mammalian
models.
serum has been re!orted in rodents *6hen et al., 2331-. )n humans, !lacental transfer
of !reformed 5'. from maternal blood to the fetus is a maGor source of fetal brain
5'. *6arlson and Salem, 2332-. This selective transfer may cause sinificant
reduction in 5'. levels in maternal !lasma durin late estation *'olman, 2332-.
Thus, in mammals, !lacental contribution creates difficulty in understandin the role
of maternal diet in modulatin the #8?. com!osition of !roeny.
E. AVIAN MODEL) A *NI;*E RESEARCH TOOL
8se of the avian model to study n-9 fatty acids and early life !rorammin has
been very limited. )n chickens, the tissue or e #8?. com!osition can be altered
readily by dietary mani!ulation *6herian, 144C-. ?urthermore, chickens are a uni"ue
ex!erimental animal in that they !rovide an automatic daily bio!sy *e- without
causin !ain or sacrificin the animal. )n addition, in ovi!arous s!ecies, embryonic
develo!ment is outside the host. Therefore, the develo!in embryo is absolutely
de!endent on nutrients that were !re-!ackaed in the es !rior to lay. The fertili/ed
e serves as the only source of #8?. needed for sustainin rowth and develo!ment
of the hatchlin. Thus, the develo!in chick is in a Scontrolled% or Sse!arate%
environment and is not influenced by maternal su!-!ly of fatty acids or other nutrients
throuh the !lacenta, as would be the case in mam-mals. ?ertili/ed es de!leted of or
enriched with n-9 fatty acids can be !roduced within a short !eriod of 1M9 weeks. The
hatched chick can be used to study the effect of maternal *e- or neonatal diet *chick
diet- on metabolic effects and,or other behavioral chanes in the !roeny.
?urthermore, as incubation takes only 12 days, multieneration !roeny varyin in
#8?. content can be obtained in a short !eriod. )n summary, short eneration
interval, self-contained nutritional environment, tem!oral se!aration of maternal and
embryonic !hase of li!id translocation, noninvasive sam!le collection *e-, and
Tab( ?L.? .dvantaes and Limitations in 8sin #oultry $odels for
?atty .cid &utrition (esearch
.dvantaes
Strict control of dietary li!ids and fatty acids
Lon term multi-eneration studies !ossible within short time s!an
5aily e collection can be done in an invasive way
E fatty acid com!osition can be used as a natural marker for investiatin effect of
diet
5ietary intake can rane from extreme deficiency to toxicity
Embryonic develo!ment outside host
&o nutrient transfer throuh !lacenta as in mammals
Limitations,5isadvantaes
5ue to selection of !oultry for fast rowth, metabolic !athways, membrane
com!osition and
nutrient re"uirements may not be the same in all classes of !oultry
5ifferences in staes of develo!ment !re- and !ost-hatch
ex!erimental cost make avians a uni"ue and an attractive tool to ex!lore the role of
#8?. in early life nutritional !rorammin *Table 1C.1-. )n addition to these uni"ue
features, many other similarities exist between mammalian and avian s!ecies in fatty
acid utili/ation durin early develo!ment. ?or exam!le, durin embryoenesis, there
is an intense transfer of 5'. from e yolk to the chick brain durin the third week
of in-cubation *6herian et al., 233<-. The disa!!earance of 5'. from e durin
avian em-bryonic develo!ment is shown in ?iure 1C.1. . similar !henomenon has
been re!orted in human infants durin the third trimester of estation *6landinin et
al., 23C4a,b-. Thus, des!ite the obvious develo!mental difference between mammals
and avians, there are
?iure 1C.1 5ocosahexaenoic acid *11+D n-9- disa!!earance from the e durin the 12-
day incubational !eriod *5ay 2 throuh 5ay 20 re!resents embryonic ae of the develo!in
chick-.
uni"ue similarities between mammals and avians in the content and u!take of lon-
chain #8?. durin the develo!mental !eriod *6herian et al., 233<E &oble and
6occhi, 2334-.
G. EARLY E=POS*RE TO $%B FATTY ACIDS) ST*DIES
WITH THE AVIAN MODEL
The avian model that includes the hen, fertili/ed e, and hatched chicks was used
to investiate in ovo !rorammin as affected by n-9 fatty acids. The method involved
feed-in hens with diets deficient in or enriched with n-9 fatty acids, !roducin n-9
#8?.-enriched or #8?.-de!leted es, and feedin !roeny birds with diets
deficient in or enriched with n-9 fatty acids durin rowth. . flowchart of the avian
model studies is shown in ?iure 1C.9. 8sin this model, several as!ects of n-9 #8?.
metabolism as well as immune and inflammatory res!onses were investiated in the
!roeny.
G.>. Eary EH3!s#r( t! $%B P*FA a$/ Tiss#( R(t($ti!$ i$ th(
Pr!"($y
Ex!eriments were conducted to investiate the effects of an early ex!osure of n-9
fatty acids throuh the e *in ovo- on tissue retention of n-9 fatty acids when faced
with a diet deficient in n-9 fatty acids durin rowth. To address this, hens were fed
diets containin
Fi"#r( ?L.B ?low chart of the studies with avian model to investiate in ovo nutritional
!rorammin.
Fi"#r( ?L.D Effect of maternal diet hih or deficient in n-9 fatty acids on the retention of
lon chain n-9 fatty acids in the cardiac tissue of broiler birds fed an identical diet lackin in
lon chain n-9 fatty acids.
l
'ih or &o re!resent maternal diet containin 9.0R fish oil *n-9-
or 9.0R sunflower oil *n-D-. The !roeny from both 'ih and &o maternal diets were fed a
similar diet lackin in lon chain n-9 fatty acids durin 71 days of rowth. Ialues re!orted as
!ercent of total fatty acids.
9.0R menhaden *fish- *hih n-9- or 9.0R sunflower oil *low n-9-. ?ertili/ed es
*hih n-9 or low n-9- were incubated, and the hatched chicks from both treatments
were fed an identical diet lackin in lon-chain n-9 or n-D fatty acids but containin
9R c-linolenic acid. 6hicks hatched from breeder hens fed with the hih-n-9 diet
retained hiher levels of 5'. and other lon-chain n-9 fatty acids in the tissues when
com!ared with chicks hatched from hens fed with the low-n-9 diets. ?or instance,
increase in the retention of n-9 fatty acids *!redominantly 5'.- was evident u! to
day 71 of rowth in the cardiac tissue of chicks hatched from hens fed with hih-n-9
diets when com!ared to those from hens fed with hih-n-D diets *#V4.40- *?iure
1C.7-. .rachidonic acid *14+7 n-D- concentration was hiher u! to 27 days !ost hatch
in chicks from hens fed with low n-9 than those from hens fed with hih-n-9 diet
*6herian et al., 1443-.
G.?. Eary EH3!s#r( t! $%B P*FA) I$ O+! +s. Eary
P!sthat&h A&&(ss
)n another ex!eriment, the effectiveness of early n-9 #8?. nutrition throuh in
ovo vs. !osthatch su!!lementation in enhancin tissue n-9 fatty acid status was
investiated. To investiate this, fertili/ed es enriched with or deficient in n-9 fatty
acids were obtained by feedin breeder hens diets containin menhaden fish oil *'- or
sunflower oil *L-. The oils were included at a 9.0R level in a corn-soy-based breeder
hen diet.'ih- and low-n-9 hatched chicks were divided into two treatments each and
were fed with hih-n-9 *'- or no-n-9 *L- diet u! to 74 days of ae. Thus, there were a
total of four treatments *'M', 'ML, LM', and LML-. )n treatments where chicks
received the hih-n-9 !osthatch diets *'M' and LM'-, the content of 5'. was hiher
in 'M' than in LM' in the liver until day 74 of rowth and in the brain u! to 14 days.
Similarly, arachidonic acid concentration was lower *#V4.40- in the brain of 'ML than
LML chicks u! to day 74 of rowth.
G.B. Eary EH3!s#r( !' O.("a%B Fatty A&i/s) A3ha%i$!($i&
A&i/ +s. DHA
5'. is the most abundant #8?. in the central nervous system of avians. The
chicken embryo !referentially accumulates 5'. in the brain durin the last week of
incubation *6herian and Sim, 2331E 6herian et al., 233<-. The accretion of 5'.
durin embryo-enesis occurs from maternal sources *e yolk- and !ost hatch
throuh chick starter diet, similar to maternal !lasma *estation-, breast milk, or infant
formula *!ostnatal- in the human infant. $ost infant formulas as well as the diets of
veetarians !rovide only al!ha-linolenic acid. 8sin the avian model, the efficacy of
al!ha-linolenic acid vs. 5'. on brain tissue 5'. accretion was investiated. Es
with hih levels of or no al!ha-linolenic acid were obtained by feedin hens diets
containin flax oil *hih n-9- or !alm oil *low n-9-. The e content of al!ha-linolenic
acid was <.0 and 4.1R, res!ectively, in the hih and low rou!s. The newly hatched
chicks obtained were divided into three rou!s and fed diets containin flax oil, fish
oil, or !alm oil for 74 days. The retention of 5'. was sinificantly hiher *over 2.<-
fold- in the chicks hatched from hih-n-9 es *#V4.40-. &o difference was observed
in the brain 5'. content of chicks hatched from hih-n-9 and low-n-9 es from
hens fed a flax- or fish-oil-based diet !osthatch, su-estin the role of al!ha-linolenic
acid in meetin 5'. need durin early rowth. These results may have im!lications
on the diet of veetarians, as their diets are lackin lon-chain n-9 fatty acids such as
5'.. This study confirmed that dietary al!ha-linolenic acid in the hen diet was
elonated to 5'. in the chicks and that maternal dietary status *e- miht im!act
the ability of the brain or other tissues to convert al!ha-linolenic acid to 5'.. The
ability of chicks to retain 5'. or arachidonic acid as observed in the studies re!orted
demonstrates that an early ex!osure to al!haMlinolenic acid, 5'., or ara-chidonic
acid may have a S!rorammin% or Sconditionin% effect on the en/ymes
*desaturases,elonases- affectin their activities thereby causin a lon-term im!act
on tissue n-9 and n-D #8?. com!osition. This observation is Gustified by !revious
research demonstratin the modulation of delta-D desaturase en/yme activity in the
liver of chicks hatched from es hih in n-9 #8?. *6herian and Sim, 1442-. The
same !henomena have been re!orted in other s!ecies suestin a bioloical
!rorammin of en/ymes involved in li!id metabolism *6ha!man et al., 1444-.
G.D. I$ O+! EH3!s#r( !' $%B Fatty A&i/s) E''(&ts !$
Ei&!sa$!i/ G($(rati!$ a$/ I$'a..at!ry Pr!&(ss(s i$ Br!i(r
Bir/s
$etabolites derived from 62C and 614 fatty acids are collectively known as
eicosanoids. These include !rostalandins, thromboxanes, and leukotrienes.
Eicosanoids are li!id mediators of inflammation. Eicosanoids derived from n-9 fatty
acids *!rostalandin E
9
, thromboxane B
9
, and leukotriene B
0
vLTB
0
w- are less
inflammatory and are less !otent than n-D derived eicosanoids *!rostalandin E
1
and
leukotriene B
7
vLTB
7
w-. The effects of an in ovo su!!ly of n-9 fatty acids on
eicosanoid !roduction in !osthatch chicks were assessed. ?ertili/ed es with hih or
low levels of n-9 fatty acids were obtained by feed-in hens diets with menhaden
*hih n-9- or sunflower oil *low n-9-. Total n-9 fatty acids constituted 21.3 and 2.0R
for hih-n-9 and low-n-9 es, res!ectively. The chicks hatched from both treatments
were fed an identical diet lackin in E#., 5'., arachi-donic acid, or other lon-
chain n-9 and n-D fatty acids. )t was observed that the !roduc-tion of !rostalandin E
1
*!roinflammatory eicosanoid- by !eri!heral blood mononuclear cells was
sinificantly lower in <-day-old chicks hatched from hih-n-9 es *6herian et al.,
1443-. Similarly, it was observed that leukotriene B
7
*a !roinflammatory eicosa-noid-
!roduction by thrombocytes from 12-day-old chicks hatched from low-n-9 es was
reater than that from chicks hatched from hih-n-9 es *#V4.40- *'all et al., 144<-.
6onsiderin the role of eicosanoids in the !athobioloy of various disease condi-tions,
an early ex!osure to n-9 #8?. may cause Snutritional im!rintin% or conditionin in
chicks that can affect the health of birds.
G.E. I$ O+! N#triti!$ a$/ Tra$s'(r !' A$tib!/y t! Pr!"($y
Chi&,s
)n mammals, !assive immunity is transferred to the neonate throuh the !lacenta
and colostrum. )n ovi!arous s!ecies, the newly hatched chick heavily relies on
antibodies transferred from the e before shiftin to its own immune system, which
enerally takes about two weeks *Brambell, 23<4-. The effects of e n-D to n-9
#8?. ratio and transfer of total )H and antibody )H were investiated usin the
avian model. Total )H and BS.-s!ecific antibody )H levels in the serum of
hatchin chicks were sinificantly decreased when the ratio of n-D to n-9 in the e
was increased from 2.4 to 17.4 *;an et al., 1447-. Similarly, in another study with
broiler chickens, the same authors re!orted that the inflammatory res!onse, as
measured by delayed-ty!e hy!ersensitivity at win-web, was su!!ressed sinificantly
by n-9 #8?. concentration in the hen diet and e *;an et al., 1441-. Broilers
hatched from es laid by hens fed hiher levels of n-9 #8?. had sinificantly lower
delayed-ty!e hy!ersensitivity res!onse at both 1 and 7 weeks !ost hatch.
)nflammatory res!onse is im!ortant for animals or humans to maintain "uick immune
res!onses. Therefore, the results re!orted suest that the avian model could be used
to further ex!lore the role of maternal diet in !roeny immune health.
K. RESEARCH ON AVIAN MODEL) E=TRAPOLATION OF
INFORMATION
These results obtained from an avian model may also have a!!lications in human
infant health. The effect of in ovo nutrition in meetin the 5'. su!!ly as well as
affectin eicosanoid !roduction in chicks when fed a 5'.-deficient diet will be of
maGor im!ortance in reachin a better understandin of the relationshi!s between
maternal and !roeny diets. This conce!t could be extra!olated to humans. The diet
of !renant or nursin women in western countries is low in lon-chain n-9 fatty acids
with a wide ratio of n-D+n-9 fatty acids, and infants are fed formulas deficient in 5'.
*)nnis, 144<a,b-. )n addition, the !ostnatal synthesis of lon-chain #8?. from 62C
!recursors is neliible durin the first 7 months followin birth *)nnis, 144<a-.
Therefore, a low su!!ly of lon-chain n-9 #8?. from maternal source *human breast
milk- and infant formulas may re-sult in low fetal and neonatal accretion with
!ossible im!airment of brain develo!ment. 'owever, the differences amon s!ecies
in nutrient re"uirements, metabolism, severity and duration of the dietary treatment,
and tissue rowth velocity should be considered before extra!olatin results to
humans.
)n summary, studies usin avian models can !rovide im!ortant information to
dee!en our understandin of the im!ortance of n-9 and n-D #8?. in the maternal diet
durin !renancy, lactation, and early !ostnatal life. 'owever, s!ecies differences, in
nutrient source *e.., milk vs. yolk fatty acids- and nutrient metabolism should be
taken into con-sideration when such information is extra!olated to human
re"uirements. &evertheless, one must weih the benefits of ex!erimental desin,
control of diet, different sam!les available for investiation, and short !eriod for
multieneration studies that could be accom!lished with avian models. ?urthermore,
usin the avian model in in ovo !roram-min events altered by maternal ex!osure to
environmental stressors other than nutrition *e.., drus, tem!erature, !athoens,
toxicants- or maternal health status *e.., disease, disease resistance- could also be
investiated. (esults obtained from such research can also enhance bird health, meat
"uality, disease resistance, and other traits that are !artic-ularly im!ortant for animal
ariculture.
ACKNOWLEDGMENTS
This article is dedicated to :eon S. Sim, Emeritus #rofessor, 5e!artment of
.ricultural ?ood and &utri-tional Sciences, 8niversity of .lberta, Edmonton,
.lberta, 6anada, who introduced me to omea-9 fatty acid research in !oultry. ) also
thank the Oreon State 8niversity, ;alther '. Ott #rofessorshi! in #oultry Science.
REFERENCES
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CHAPTER ?O
Pr(bi!ti&sI Pr!bi!ti&sI a$/ H(ath
Pr!.!ti!$) A$ O+(r+i(0
B. D#$&a$
The 8niversity of .ri/ona, $el and Enid Nuckerman 6ollee of #ublic 'ealth,
Tucson, .N, 8S.
ABBREVIATIONS
AAD .ntibiotic-associated diarrhea
AD .to!ic dermatitis
CI 6onfidence interval
GI Hastrointestinal
GIT Hastrointestinal tract
I"A )mmunolobulin .
NEC &ecroti/in enterocolitis
RCT (andomi/ed controlled trial
RR (elative risk
.>. DEFINITIONS
#rebiotics were defined by Hibson in 2330 as Tnon-diestible food inredients
that benefit the host by selectively stimulatin the rowth and,or the activity of one or
more of a limited number of bacteria in the colon and thus im!rove healthU *Hibson
and (oberfroid, 2330-. )n 1447, Hibson modified the definition as Ta selectively
fermented inredient that allows s!ecific chanes, both in the com!osition and,or
activity in the astrointestinal *H)- microbiota that confers benefit u!on host
wellbein and healthU *Hibson et al., 1447-. #rebiotics encourae or !romote the
!roliferation of beneficial bacteria already in residence in the astrointestinal tract
*H)T-.
#robiotics as defined by the ?ood and .ricultural Orani/ation of the ;orld
'ealth Orani/ation are Tlive oranisms that when inested in ade"uate amounts
confer a ben-efit to the hostU *?ood and .riculture Oranisation and ;'O, 1441-. )t
is !recisely these oranisms that !rebiotics encourae to row and !roliferate. Some
oranisms do not survive the !assae throuh the intestinal tract and are merely
transient residents and even when inested in lare "uantities may not reach sufficient
density in the colon for any beneficial effect to be reali/ed.
Synbiotics is a newer term and refers to a combination of !rebiotics *nondiestible
foods- and !robiotics *beneficial bacteria-. $ore studies are emerin to determine
the health benefits of the effectiveness of ivin live bacteria alon with a source of
nutrition to enhance their survival and hasten their coloni/ation.
?. THE GIT ECOSYSTEM
The H)T ecosystem constitutes a com!licated interaction between everythin
*livin and nonlivin- that is in the lumen of the H)T with both the structure and
function of what defines the lumen, the intestinal wall.
The lumen of the H)T is the home to between 044 and 2444 s!ecies of livin
bacteria. The density of oranisms chanes alon the track as many do not survive the
acid envi-ronment of the stomach and others do not survive the bilious contents of the
!roximal small bowel. Of those in the colon, the anaerobes outnumber the aerobes by
a factor of 2444 to 2. )t is the ratio of Bacteroides to ?irmicutes that !lays an
im!ortant role in the health of the host. The ratio chanes from infancy to adulthood
and another chane oc-curs as one aes. The term infant is born with a H)T that is
erm free but is "uickly col-oni/ed by bacteria inested durin the descent throuh
the birth canal. The !reterm infant%s ac"uisition of Snormal flora% is delayed and this
is felt to be a sinificant factor in the !reterm infant%s develo!ment of necroti/in
enterocolitis *&E6-. Breast feedin results in the coloni/ation of an abundance of
beneficial bacteria+ bifidobacteria and lac-tobacillus. On the other hand, the
!redominant oranisms in the formula fed infant are the !otentially more harmful
bacteria, %scherichia coli and Bacteroides. )t is not until 17 months of ae or so that
the child%s H)T assumes the microbiota of the adult micro flora. On ain, the colon
ex!eriences a decrease in anaerobic and bifidobacteria density and an increase in the
numbers of enterobacteria, !articularly %# coli.
Bacteria of the Bacteroides !hylum include B. fragilis and B. vulgates and are
obliate anaerobic saccharolytic oranisms whose !rimary end !roducts from
fermentation of nondiestible carbohydrates are volatile fatty acids, !redominately
acetate, !ro!ionate *from succinate-, and butyrate. The lowered colonic !' from the
short chain fatty acids inhibit the rowth of more harmful bacteria such as Salmonella
enteritidis and !higella flexineri and the bile salts are toxic to oranisms such as
Clostridium botulinum. Bacteroides become harmful when they !enetrate the
intestinal wall and infect the !eritoneal cavity with abscess formation and, althouh
considered a commensal oranism, these bacteria can also cause diarrhea. The more
friendly and beneficial ?irmicutes *stron wall- !hylum includes the enera of
Lactobacillus, 6lostridium, and Bacillus, which also ferment non-diestible
carbohydrates with similar end !roducts of metabolism.
$any of the myriad of s!ecies cannot be cultured but identifyin the residents of
the lumen of the H)T has recently taken a lea! forward with the use of innovative
techni"ues. (ather than relyin on culturin, these techni"ues include ene
identification of bacteria usin ribosomal 2DS and 5&. se"uencin. )t is estimated
that there are ten times more bacteria in the H)T than cells in the human body and that
the combined enome of these bacteria is 04 times reater than the human enome. )n
the healthy H)T ecosystem, there is a symbiotic relationshi! between the host and
beneficial bacteria. The host su!!lies the nonlivin nutrients while the bacteria assist
with diestion and the host in turn utili/es some of the metabolites from the
fermentation of these nutrients. The col-oni/ation and metabolism of beneficial
bacteria results in *2- the !roduction of short chain fatty acids with a resultant dro! in
!' that enhances absor!tion of the minerals calcium, manesium, /inc, and ironE *1-
!rotection aainst not only the invasion by !athoenic bacteria but also their
!roliferation with the !roduction of toxic substances such as am-monia, amines,
!henols, and indolsE and *9- the control of ut e!ithelium !roliferation and
differentiation and induction of reulatory T cells in ut lym!hatic follicles allowin
the host to tolerate a lare number of antiens *Huarner et al., 144D-. . symbiotic
rela-tionshi! within the H)T ecosystem and a !ro!er balance between beneficial and
harmful bacteria ensure a state of homeostasis. The relationshi! is mutualisticE both
!artners ben-efit. These !robiotic microbiota residents of the colon do no harm. They
metaboli/e undiested nutrients and the by-!roducts of their metabolism !lay an
im!ortant role in the health of the individual. 'owever, with an imbalance where the
numbers of harmful bacteria exceed beneficial bacteria, the stae is set for the host%s
susce!tibility to disease.
5ifferent microbial s!ecies coloni/e the H)T, different s!ecies in different
sements and in different densities. Hastric acid and bile salts kee! the density down
in the u!!er sements of the ecosystem with the maGor coloni/ation occurrin in the
colon. Hastric by-!ass surery reatly alters the resident bacteria throuhout the H)T.
6holecystectomy and alteration of bile acid secretion not only chane the chemical
com!osition of the H)T but also chane the resident bacteria. Exocrine !ancreatic
insufficiency results in an over-rowth of bacteria in the !roximal small bowel.
#athoenic and commensal bacteria com!ete for limited resources and their relative
densities determine the "uantity of adverse or beneficial metabolites.
The surface of the e!ithelial linin of the lumen of the H)T ecosystem exceeds the
ex!osed surface of the skin and luns and the number of enteric immune cells exceed
the number of immune cells in the rest of the body. The intestinal wall offers a critical
barrier to !rotect the host from ex!osure to a vast array of antiens, the invasion by
harm-ful bacteria, and the absor!tion of toxic chemicals. )ntracellular and
extracellular reca!-tors allow the H)T to distinuish the bad from the ood, between
!athoenic andcommensal bacteria. $anaement strateies initially !rimarily
involved antibiotics to eliminate harmful bacteria. This cha!ter deals with more recent
a!!roaches that involve enhancin the rowth of beneficial bacteria with !rebiotics
and the administration of !robiotics to set u! com!etition and to o!timi/e the
ecosystem in an attem!t to im!rove the health of the host.
B. MECHANISMS OF BENEFICIAL EFFECTS
)nested nondiestible carbohydrates enter the colon and they are fermented by
co-lonic bacteria. The result is an increase in biomass, the !roduction of short-chain
or-anic acids, lactic and butyric, which lower the colonic !', and an environment
less conducive to the rowth of !athoenic bacteria. )n addition, the lower !' aids ion
absor!tion. There is an increase in intestinal e!ithelial cells, !articularly oblet cells
whose mucus secretion coats the intestinal wall !rovidin a thicker coat of !rotection.
The lenth and width of intestinal cry!ts is increased, !rovidin an enlared area for
absor!tion for bothmacro- and micronutrients. This !hysioloical !rocess alters
enery metabolism, li!id and cholesterol levels, and ene ex!ression. The interaction
between microbiota and lym!hatic cells is critical for o!timal functionin of the
immune system. The H)T ecosystem has a role in infection, inflammation, allery,
!erha!s chronic H) diseases, colorectal cancer, and obesity. Evidence or lack of it for
the effect on the health of the individual in these conditions is discussed from both the
stand!oint of !rebiotics and !robiotics.
D. PREBIOTICS
.ll !rebiotics are not the same. Their health effects vary. 5ifferent indiestible
carbohy-drates !roduce different levels of volatile acids *lactic, acetic, !ro!ionic, and
butyric- and hence different derees of acidification of the H)T ecosystem. 5ifferent
!rebiotics have variable effects on mineral absor!tion and osmotic action and on
lucose and insulin con-trol. There is a difference in stool volume or biomass and
stool consistency, the increase in the deree of !eristalsis, the amount of as
!roduction, the selection of bacterial rowth, and hence the "uantitative and
"ualitative inhibition of toxin-!roducin bacteria that in-fluence the !revention of H)
infection or colonic cancer or intestinal inflammatory disease.
The !rinci!al !rebiotics are inulin, oliosaccharides *fructo-, alacto-, soya-,
xylo-, isomalto--, and lactulose. These com!lex carbohydrates cannot be hydroly/ed
by the human body system and are resistant to mammalian diestive en/ymes. They
reach the co-lon essentially unchaned where they are fermented by colonic bacteria,
!rimarily the beneficial mucosal bacteria, bifidobacteria and lactobacilli. These
oranisms transform the carbohydrates into biomass with the beneficial effect of
!reventin consti!ation. Short-chain fatty acids *lactic and butyric- are !roducts of
their metabolism, which decrease colonic !', an environment adverse to the rowth
of harmful bacteria such as %# coli, 6lostridia, Campylobacter CeCuni, Salmonella, and
Shiella.
)nulin occurs naturally in some foods such as leek, onion, arlic, wheat, chicory,
artichoke, and bananas. )t is used as a su!!lement in some low-fat dairy !roducts,
bakery oods, butter-like !roducts, and cream cheeses. )t can re!lace sinificant
amounts of fat and its sweet taste allows re!lacement of suar. $ost of the inulin used
on an industri-ali/ed scale comes from the chicory root. The chicory root also
contains a fairly lare amount of oliosaccharides as do the so-called :erusalem
artichokes, a member of the sunflower family. These indiestible carbohydrates share
a s!ace with inulin in onions and other members of the Sonion family% such as leeks
and arlic, leumes, wheat, as!ar-aus, and Gicama. The diet of &orth .mericans
contains about 2M9 of inulin, which is "uite a bit less than the Euro!eans% diet of 9M
24 .
Oliosaccharides, the bifidoenic substance *actively metaboli/ed by
bifidobacteria- constitutes u! to one-fourth of the carbohydrates in human colostrum
and more than 20R in mature human milk for the first cou!le of months, considerably
hiher than that in cow%s milk. )t is !re!ared commercially and has been used in :a!an
as a food inredient for over 94 years. )t is available in Euro!e as a syru! or !owder
but it is not readily avail-able in the 8S.
Lactulose is an isomer of alacto-fructose, cannot be hydroly/ed, and reaches the
colon intact where it is fermented by intestinal microbiota, saccharolytic bacteria, bifi-
dobacteria, and lactobacilli. The rowth of these beneficial oranisms is !romoted in
!reference to the rowth of !roteolytic bacteria such as Bacteroides, 6lostridia,
Salmo-nella, 6oliforms, and Eubacteria that !roduce !otentially toxic substances.
6ommer-cially, lactulose comes either as a syru! or a !owder and both are resistant to
heat and acidity. ;hen added to infant formulas, lactulose chanes the intestinal
micro flora, resultin in a stool consistency similar to that of the breast-fed infant.
E. PROBIOTICS
5ietary chanes can affect the com!osition of the micobiotic flora with the
inestion of inulin and oliosaccharides favorin the rowth of beneficial bacteria.
The oral inestion of !robiotics adds to the "uantity of oranisms in the colon
de!ends on their ability to survive the acid environment of the stomach and the bilious
and en/yme-filled environ-ment of the small intestine. )n eneral, inested bacteria
can be detected in hih "uantities only durin the time of inestion and will ra!idly
disa!!ear within 2 week followin feedin. The s!ecific s!ecies and the "uantity of
!robiotic colonic bacteria have varyin beneficial influences on the health and well-
bein of the host.
#robiotics are usually inested in !owder form as an additive to foods or dissolved
in drinks. 6urrently, dairy drinks and yourt lead the list of foods containin
!robiotics but com!anies are beinnin to su!!lement soy, cereals, and fruits. )n the
!ast 0MD years, there has been a 04R rowth in the lobal retail market for these
dietary su!!lements. The challenes to the food industry and the studies on the health
effects include the selection of the strain*s-E the sensory !ro!erties of the oranismsE
the ty!e *fro/en or !ow-dered- and amount of inoculumsE how the inoculate is storedE
survival throuh the intestinal tract, subse"uent rowth in the colon, and com!etitive
outcome with harmful bacteria. .ll of these influential factors will determine the
eventual colonic colony counts. Some of these challenes have been circumvented
with micro-enca!sulation of !robiotics, im!rovements in the stability of bioactive
!articles durin !rocessin and storae, maskin of un!leasant odors and tastes, and
!rotection of the oranisms aainst an adverse environment in the H)T ecosystem.
Bifidobacteria are Hram-!ositive, nonmotile, nons!oreformin, catalase neative,
!olymor!hic rods in a = or I sha!e and hence the name Sbifid.% They are obliate
anaerobes thouh some can tolerate low levels of oxyen. )nested bifidobacteria can
!ass throuh the stomach%s acid and the unfriendly bile salts and once in the colon,
they bind to the e!ithelial cells and to the intestinal mucin. Their density in the human
H)T varies with ae, diet, lifestyle, and activity. The colons of breast-fed infants are
coloni/ed with hih "uantities of bifidobacterium but recent evidence indicates that
(uminococcus is also in abundance. &ewborns on formula have a varied micobiotic
flora but far less of these friendly bacteria. The !rominent intestinal flora in adults
con-sists of Bacteroides, Enterococci, %scherichia coli, and fewer numbers of
bifidobacteria and lactobacilli.
Bifidobacteria s!ecies are able to ferment oliosaccharides and other com!lex
non-diestible carbohydrates such as resistant starches, raffinose, lactulose, and
intestinal mu-cin. )n cataboli/in oliosaccharides, they !roduce lactic acid and acetic
acid and do not !roduce as. 8! to 94 different s!ecies have been re!orted, isolated
from sewae, human and animal feces, rumen of cattle, dental caries, and honey bees.
# longum is the most fre"uently re!orted Bifidobacterium as havin health benefits.
#rotective functions in-clude com!etin with harmful bacteria for nutrients,
coloni/ation numbers, and adherence to the intestinal e!ithelium. Tro!ic functions
include control of e!ithelial cell !roliferation and differentiation and homeostatic
reulation of the immune system. These beneficial bacteria ex!and the number of
mucosal lym!hocytes, the si/e of ermi-nal centers in lym!hoid follicles, and there is
some research indicatin a role in the induction of reulatory T cells in lym!h
follicles.
Lactobacilli *acido!hilus, casei, rhamnosus, salivarius, and others- are Hram-
!ositive lactic acid !roducin rod-sha!ed bacteria. They are !art of but not the
dominant s!ecies of the normal flora of the mouth, the lower small bowel, colon, and
vaina in some but not all individuals. L# acidophilus and bifidobacteria constitute
34R of the colonic oran-isms in breast-fed infants. L. casei sinificantly enhances
the immune system and stimulates the !roduction of )mmunolobulin . *).-. The
fermentation of nondiestible carbo-hydrates constitutes their !rinci!le source of
enery !roduction and some, notably L# acidophilus and L# Cohnsonii, contain
!roteinases and are able to derade the !oly!e!tides of harmful bacteria. Lactobacilli
are im!ortant in the food industry where they are used in the !icklin !rocess and in
cheese and yourt !roduction.
!accharomyces boulardii is yeast and considered a !robiotic but is not a normal or
usual resident of the H)T ecosystem. )f used, it must be iven continuously as within
D h after the last dose it cannot be found in the intestinal lumen.
G. HEALTH BENEFITS
8nfortunately, investiators who have used !robiotics as intervention in treatment
of the same disease or condition have not used the same s!ecies of bacteria but often
different combinations of oranisms, different "uantities, and varied lenths of
thera!y. This has often resulted in conflictin results and difficulties in inter!retin
the deree of benefits to health. Several criteria are im!ortant in selectin which
!robiotic miht be a!!ro!riate for a iven study. The deree of tolerance to acid and
bile determines survival of the inested beneficial bacteria. Survival of harmful
bacteria is influenced by which bacteria can better adhere to intestinal cells and which
bacteria have the reater ability to metab-oli/e nutrients not diested by the host.
Survival in the com!etitive environment is also de!endent on which !robiotics
!roduce bacteriocin, a !roteinaceous antimicrobial com-!ound that !rotects aainst
!athoenic bacteria and which bacterium is a better scavener of iron and can thus
de!rive other bacteria of this vital mineral.
)n an attem!t to summari/e the data on the rowin number of investiations
relative to the health benefits of s!ecific conditions usin !rebiotics and !robiotics, a
search was done in #ub$ed limitin it to only systematic review articles of the
s!ecific condition that had been !ublished in the !ast 9 years *144CM1422-. )n most
instances, the authors had limited their searches to the 6ochrane S!eciali/ed
(eistries and often $E5L)&E, E$B.SE, L)L.6S, and 6)&.'L data bases and
the results were usually subGected to meta-analysis.
@B*LLET MISSINGAImmune function+Two inde!endent studies
involved 271 elderly individuals who were iven either yourt *34 -
fermented with Lactobacillus delbruec&ii or milk *244 ml- daily over an CM21-
week !eriod. The increase in natural killer cell activity was hiher in the
yourt rou! *!4.41C- and their risk for catchin the common cold was 1.D
times lower than in the milk rou! *$akino et al., 1424-. 6hildren 7M17
months of ae attendin a day care center iven daily oliofructose for D
months had less-severe diarrhea e!isodes, fewer febrile illnesses and cold
sym!toms, took fewer antibiotics, and had fewer absentee days *Saavedra and
Tschernia, 1441-. Oliofructose !romotes the rowth of bifidobacteria,
beneficial intestinal bacteria that !lay a role in the local immune system. The
known mechanisms include synthesi/in bacteriocins, an anti-microbial
substanceE !roducin butyric acid, an intestinal nutrientE im!rovin intes-tinal
barrier functionE and com!etin with !athoenic bacteria *$an/anares and
'ardy, 144C-. #robiotics are enerally safeE however, Lombardo offers a
cautionary note citin re!orts of bacteremia and enodcarditis where
Senetically unstable% lacto-bacilli have been iven to neutro!enic !atients
durin chemothera!y and to !ediatric !atients with a astroGeGunostomy
*Lombardo, 144C-. 6aution is also advisable with children who have
conenital heart disease and diarrhea and with children who have a shortened
ut.
@B*LLET MISSINGA,cute infectious diarrhea+ .llen and colleaues
evaluated the results of D9 studies *0D in-volved infants and youn children-
involvin C427 individuals that met the inclusion criteria of a randomi/ed or
"uasi-randomi/ed controlled trial of diarrhea either !roven or !resumed to be
caused by an infectious aent. #robiotics alon with rehy-dration thera!y
shortened the course of the diarrhea by 17 h and by the second day, a decrease
in stool fre"uency. The authors stressed the im!ortance for research to uide
the a!!ro!riate !robiotic reimen *.llen et al., 1424-.
@B*LLET MISSINGATravelers) diarrhea+ $c?arland !ublished a meta-
analysis of 21 randomi/ed, controlled, blinded, efficacy trials !ublished in
!eer-reviewed Gournals involvin 7<43 individuals. Two trials used
!accharomyces boulardii and seven trials tested various ty!es of lactobacilli
*L# rhamnosus HH, L# acidophilus, L# bulgaricus, and L# fermentum-. The
results showed inconsistent efficacy, influenced by which !robiotic was iven,
the amount iven, and the destination of the traveler. 'owever, the !ooled
estimate indicated a case !revention rate of C0R. The author concluded that
!robiotics were both safe and effective for the !revention of traveler%s diarrhea
*$c?arland, 144<-.
@B*LLET MISSINGA,ntibiotic-associated diarrhea (,,(-+ The
mechanism of ..5 is !oorly understood but is !robably secondary to
alteration in fecal fermentation with a chane in !'E the by-!roducts of
carbohydrates resultin in osmotic diarrheaE and the overrowth of !ath-
oenic bacteria such as !taphylococcus aureus$ Dlebsiella oxytoca, or
6andida. $c?arland conducted a meta-analysis from 10 trials with a total
!o!ulation of 1C24 individuals. Seven of the 2D adult trials showed an efficacy
of 77R and in six of the nine trials that involved children, the efficacy rate was
D<R. The author concluded that some !ro-biotics !articularly L# rhamnosus
HH as it !roduces bacteriocin, the yeast !accharomyces cerevisiae, and
bifidobacteria are effective in !reventin ..5 but the studies are in-
conclusive as to the effectiveness in the treatment of ..5 *$c?arland, 144D-.
>ale-#radhan and associates did a meta-analysis of ten randomi/ed, blinded,
!la-cebo- controlled trials investiatin the efficacy of Lactobacillus as a
sinle-aent re-imen. The studies, six adult and four children involved 2CD1
!atients. The dose varied but was administered throuhout the antibiotic
course *0M27 days-. The reimen was effective in lowerin the risk ratio for
adults but not for children. These two re!orts em!hasi/e the im!ortance of
considerin how different strains of !robiotics may re-sult in different results
*>ake-#radhan et al., 1424-.
:ohnston and colleaues conducted a meta-analysis of six randomi/ed
!lacebo-controlled trials that assessed the efficacy of !robiotics iven to
children who were receivin antibiotics *total n of <4<-. The combined results
showed sinificant benefit usin !robiotics over !lacebo *relative risk v((w
4.79-. The intention-to-treat analysis was not sinificant *(( 2.42-. There was
stron evidence with narrow confidence interval *6)- for usin Lactobacillus
HH, L# sporogens, or !# boulardii subrou! to !revent ..5 in children
*:ohnston et al., 144<-.
Clostridium difficile rowth results in the most severe form of ..5 and can
result in colitis, !seudomembranous colitis, or toxic meacolon. There is no
clear evidence of efficacy of !robiotics to !revent first e!isode of 6. difficile
diarrhea, but a systematic review by Tun and colleaues suested
!accharomyces boulardii may be hel!ful in !reventin recurrent 6. difficile
diarrhea *Tun et al., 1443-.
.adiation-induced diarrhea+ ?uccio and colleaues !erformed a meta-analysis
on three clinical trials involvin D91 !atients that evaluated the !reventive
effects of !robiotics on radiation-induced diarrhea. 5ifferent !robiotics
reimens were used in the studies. The analysis failed to show a difference
between the !robiotic and the !lacebo rou!s *?uccio et al., 1443-.
/ecrotiBing enterocolitis */%C-+ &E6 is an acute inflammatory and
necroti/in condi-tion of the small and lare bowel. The etioloy is
multifactorial but most often occurs in !reterm infants less than 9D weeks
estation. The damaed intestinal wall allows invasion of bacteria with
resultant se!sis. )t is a maGor cause of morbidity and mortality in !reterm
infants whose H)T is coloni/ed with a different !o!ulation of bacteria than
that of full-term infants. Breast-fed infants have a lower incidence of &E6
than formula-fed infants !resumably due to the hih levels of oliosaccharides
in colostrum and mature milk that !romote the rowth of lactobacilli and
bifidobacteria.
)n 1443, 5esh!ande and associates !reformed a systematic review of
(andomi/ed controlled trials *(6Ts- where su!!lemental !robiotics were
started within the first 24 days of life and continued for < days in very low
birth weiht infants. The out-come effect was stae 1 &E6. The analysis of
22 clinical trials with 12<D infants showed a 94R reduction in the incidence of
&E6 and a sinificant reduction in mor-tality in those infants who received the
su!!lement. . variety of !robiotics were used, some trials used a sinle
oranism and some used a mixture of different oranisms *ifidobacterium
breve$ Lactobacillus HH$ !accharomyces boulardii$ ifidobacteria infantis$
!treptococcus thermophiles$ ifidobacterium bifidus$ Lactobacillus
acidophilus$ Lactobacillus casei$ ifidobacterium lactis$ and ifidobacterium
longum-. There were no serious adverse side effects. The authors concluded
that Tadditional !lacebo-controlled trials are unnecessary if a suitable !robiotic
!roduct is availableU *5esh!ande et al., 1424-.
Constipation@ 8ndiested carbohydrates add biomass and should be beneficial
in allevi-atin functional consti!ation. Lactulose is widely used for this
condition and is "uite effective. )ts use increases the bulkin and osmotic
effect resultin in increased water in bowel lumen and a softer stool. Studies
accessin other !rebiotics re!ortmixed results.
6hmielewska and S/aGewski re!orted an analysis of five (6Ts in 1424 that
studied !robiotics for safety and efficacy in functional consti!ation. Three of
the investia-tions involved 1DD adults and re!orted im!roved stool fre"uency
and consistency usin ifidobacterium lactis$ Lactobacillus casei Shirtoa, and
%scherichia coli &issle. The other two investiations involved 222 children
and re!orted favorable outcome with L. casei rhamnosus Lcr90 but not with L.
rhamnosus HH. This cha!ter hihlihts different results when usin different
bacteria. The authors suested that without more studies at this time, the use
of !robiotics for consti!ation Sshould be considered investiational%
*6hmielewska and S/aGewska, 1424-.
"elicobacter pylori eradication+ S/aGewska and associates conducted a
systemic review of (6Ts that evaluated the effectiveness of the yeast,
!accharomyces boulardii, as a su!-!lement to tri!le thera!y to eradicate
"elicobacter pylori. The authors analy/ed five(6Ts involvin 294<
!artici!ants. There was a sliht increase in eradiation rate *((2.29- and a
larer decrease in adverse side effects *(( 4.7D-, !articularly of diarrhea in the
rou!s that had received the yeast as com!ared to the !lacebo rou!s
*S/aGewska et al., 1424-.
Nou and 5on did their systematic review usin Lactobacillus as the
su!!lement to tri!le thera!y. They identified eiht (T6s with a total of 29<1
!atients. This !ro-biotic was more effective than the control rou! in
im!rovin the eradication rate of "# pylori3 C1.1DR versus <D.3<R. .s with !#
boulardii, diarrhea was less in the rou! that received the Lactobacillus *Nou
et al., 1443-.
,cute pancreatitis+ Several systematic reviews have been conducted involvin
!rebi-otics, !robiotics, and synbiotics. &one have found these aents to have a
beneficial effect on acute !ancreatitis *Sun et al., 1443E Nhan et al., 1424-.
Inflammatory bo*el disease+ $ennien and Bruewer reviewed the theoretical
basis for the use of !robiotics in inflammatory bowel disease. These beneficial
bacteria offset some of the chanes created by harmful bacteria such as
!reservin the Stiht Gunc-tion%, !reventin the decline in transe!ithelial
resistance, and thus decrease e!ithelial !ermeability. L. bacillus decreases the
secretion of cytokines and hence decreases e!-ithelial cell a!o!tosis, increases
mucin secretion, and com!etes with the Sbad% bacteria for !laces to adhere to
the mucosal surface *$ennien and Bruewer, 1443-.
Irritable bo*el syndrome+ Several systematic reviews that evaluated the
efficacy of !robiotics in the irritable bowel syndrome in adults and children
em!loy the words Scaution% or Smay benefit% in their conclusions. $c?arland
and 5ublin conducted a meta-analysis of 19 (6Ts involvin 2747 subGects
and found an (( of 4.<< for a lobal im!rovement in sym!toms and an (( of
4.<C of less abdominal !ain in subGects treated with !robiotics as com!ared to
the !lacebo rou! *$c?arland and 5ublin, 144C-. . more recent re!ort by
$oayyedi and colleaues identified 23 (6Ts that involved 2D04 !atients with
the outcome of lobal im!rovement and abdominal !ain. These authors
concluded that !robiotics were hel!ful but the deree of benefit and the most
a!!ro!riate strain of bacteria was uncertain *$oayydei et al., 1424-. Brenner
and colleaues% review suested that Bifidobacter-ium infantis 90D17 was
most effective but there was inade"uate information with other !robiotics to
define their effectiveness *Brenner et al., 1443-. 'uertas-6eballos and
colleaues% systematic review of studies evaluatin the efficacy of fiber
su!!le-ments, lactose-free diets, and Lactobacillus concluded that there was
no evidence to su!!ort the use of these aents in children with recurrent
abdominal !ain *'uertas-6eballos et al., 1443-.
Olcerative colitis+ There are limited studies and the use of different strains of
!robiotics and different dose schedules have made a systematic review
difficult.
Crohn)s disease+ . similar statement can be made for the use of !robiotics in
6rohn%s disease. Shen and colleaues% systematic review found six (6Ts with
a total of 903 !atients on which the authors !erformed a meta-analysis to
determine if Lactobacillus was su!erior to !lacebo in maintainin remissions
from 6rohn%s disease. The (( for adults was 2.20 and for children the (( was
2.C0. L# rhamnosus was more effective than L# Cohnsonii *(( 2.DC and 4.32
res!ectively- *Shen et al., 1443-.
Infantile ecBema+ Nhu and colleaues !erformed a meta-analysis on 21 (T6
trials, seven of which re!orted that lactic acid bacteria but only when used in
combination with other !robiotics had a !ositive effect on the !revention of
ec/emaE com!ared to !lacebo, the((was 4.<3 *Nhu et al., 1424-. The
systematic review and meta-analysis by Boyle and others did not find a
beneficial effect in the re!orts from 21 trials in-volvin <C2 !atients. ?ive of
the 21 showed no reduction of ec/ema sym!toms and the other seven usin
investiator-rated severity as the outcome measure found no difference
between !robiotics and !lacebo. These authors also noted the re!ort of serious
adverse side effects+ se!sis and bowel ischemia. They could not recommend
its use unless novel strains of !robiotics miht !rove otherwise *Boyle et al.,
1443-.
,topic dermatitis+ . systemic review that evaluated the efficacy of !robiotics
and a sinle trial that evaluated the efficacy of a combination of !rebiotics and
!robiotics *synbiotics- both concludedthat this thera!ywasbeneficial in
thetreatmentof ato!ic dermatitis *.5-. The first re!ort analy/ed ten studies
with a total of D<C !artici!ants and found an overall im!rovement in the
Scorin of .to!ic 5ermatitis Severity Score *S6O(.5- and su-ested that
the children withmoderately severe disease weremost likely to im!rove.The
sinle trial involved 34 children between 2 and 9 years of ae with moderate-
to-severe .5. The ex!erimental rou! received both L# acidophilus and
fructo-oliosaccharide for C weeks. The children who received 9C9ymbiotic
thera!y decreased their S6O(.5 by 99.<Ras com!ared to the control rou!
whose score decreased 23.7R and the symbiotic rou! used less to!ical
corticosteroids. These chanes were also associatedwith a chane in
lym!hocyte subsets *Herasimov et al., 1424E $ichail et al., 144C-.
acterial vaginosis+ . 6ochrane database systematic review by Oduyebo and
associates of 17 (6Ts that involved 7711 !artici!ants with the ex!eriment
rou! receivin antibiotics with or without Lactobacillus. ;hen iven
vainally as a elatin tablet, this !robiotic was more effective than oral
metronida/ole with an (( of 4.14. ;hen iven orally in combination with
oral metronida/ole, the (( was 4.99 as com!ared with metronida/ole alone
*Oduyebo et al., 1443-.
,bsorption of ions+ Both animal and a few human studies investiatin the
effect of inestion of oliosaccharides or inulin on the absor!tion of minerals
re!orted a !ositive balance, !articularly calcium *6oudray et al., 233<-. The
mechanisms !ostulated include a decrease in !' secondary to bacterial
fermentation of the nondiestible carbohydrates with the !roduction of short-
chain fatty acidsE an increase in the absor!-tive surface due to the !roliferation
of enterocytes under the stimulus of fermentation !roducts, !articularly lactate
and butyrateE and an increase in calcium-bindin !roteins. .brams and
colleaues fed youn adolescents a combination of inulin and oliofructose for
a year and re!orted hiher body bone density and mineral content. This may
have a !lace in the !revention of osteo!orosis *.brams et al., 1440-.
Colorectal cancer (C.C-+ 6olorectal cancer is the fourth most fre"uent
cancer-related mortality in the world. The cause is believed to be related to
enetics and diet. 'iher rates are associated with obesity, !rocessed meat,
alcohol, and a low-fiber diet. . low-fiber diet results in a lower concentration
of saccharolytic bacteria with a corres!ondin abundance of !roteolytic
bacteria that !roduce toxic and carcinoenic metabolites. Lower rates of 6(6
are associated with a diet hiher in fiber, arlic *contains inulin-, milk, and
calcium. 8ndiested carbohydrates *!rebiotics- increase the amount of fiber in
the lower colon and stimulate the rowth of Bifidobacterium and
Lactobacillus. &ot only is the ecoloic balance of harmful and beneficial
bacteria altered but also these !re-biotics fermented by !robiotics with the by-
!roduct of short-chain fatty acids such as butyrate that has antitumor
!ro!erties *(after et al., 144<-.
#ool-Nobel and Sauer have been conductin in vitro and in vivo
investiations, the S=&6.& !roGect, in both animal models and human
clinical trials to test this loic. Bacteria were incubated with a !rebiotic
mixture of oliofructose and inulin *Synery-. The fermentation su!ernatant
contained a lare "uantity of butyrate and was !laced in a tube with human
'T1 cancer cells. Survival of tumor cells was im!aired and !rolifer-ation of
cells was inhibited. (ats iven colon carcinoens and fed inulin-ty!e fructans
showed a marked reduction in the incidence of colon cancer. 'umans with
colonic !oly!s iven a 9C7ymbiotic reimen showed a clear reduction in
cellular 5&. damae. These authors !ro!ose lon-term !ros!ective trials to
determine if such a dietary chane can reduce the rate of colon cancer *#ool-
Nobel and Sauer, 144<-.
1besity+ #rebiotics are low enery bulkin nondiestible foods that re!ortedly
!ro-mote satiety and decrease food intake. Su!!lements increase !lasma ut
lucaon-like !e!tides with a resultant decrease in a!!etite and an increase in
!lasma lucose *6ani et al., 1443-.
The H)T ecosystem may be a fertile round for weiht manaement as there
seems to be an obesoenic ut environment. The ut microbiota and its micro-
biome *ene content- is "uite different in an individual on a diet hih in fat
and refined carbohydrates *obese individuals- than those on a low-fat and low-
carbohydrate diet *lean individuals- *Ley et al., 144C-. Obese individuals have
a re-duced number of intestinal Bacteroidetes and an increase in ?irmicutes
resultin in an increase in fermentation with an increase in enery harvest
from the diet *Turnbauh et al., 144D-. This fermentation !rovides otherwise
lost enery from the host that can result in as much as 044 kcal !er day. These
bacteria also !lay an im!ortant role in the enterohe!atic circulation of bile
throuh transformin un-used bile that reaches the colon into secondary bile.
This bile may be useful in enery absor!tion from fat that reaches the colon
and can be reabsorbed and trans-!orted to the liver. The increased enery
harvest results in an alteration of fatty acid metabolism and a de!osition in
adi!ose tissue and the liver. . hih fat diet reduces the density of
bifidobacteria with resultant increase in ut !ermeability and a hiher
li!o!olysaccharide level in the !lasma. 6oloni/in erm-free animals with
colonic bacteria from obese animals resulted in obese animals des!ite
inestion of less food *Turnbauh et al., 144D-.
Lare-scale alterations or a reversal in the ratio of Bacteroidetes to ?irmicutes
result in a corres!ondin weiht reversal des!ite no chane in food intake
*animals and humans- *Ley, 1424-. .nimal studies indicate ut microbiota
reulate entero-endocrine cells influencin release of ut hormones that can
increase release of insulin from the !ancreas, slow astric em!tyin,
!romotion of satiety, and weiht loss *Ley, 1424-.
K. S*MMARY STATEMENT
This is an ex!lodin field of in"uiry. )nconsistent methodoloies used in assessin
the health benefits from !rebiotics and !robiotics on an increasin number of
conditions make inter!retation of results difficult and at times confusin. That was the
loic behind !resentin articles that have synthesi/ed the literature. )t is difficult to
kee! abreast of the chanin scene but worth the Gourney. ?or a com!rehensive
backround and under-standin of this relative new thera!eutic direction, the two-
volume text edited by 5. 6haralam!o!oulos and(. (astall, #rebiotics and #robiotics
Science and Technoloy. S!riner, &ew =ork, &=. *1443- is hihly recommended.
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Oduyebo, O.O., .norlu, (.)., Ounsola, ?.T., 1443. The effects of antimicrobial
thera!y on bacterial vainosis in non-!renant women. 6ochrane 5atabase of
Systematic (eviews 9, 6544D400.
#ool-Nobel, B.L., Sauer, :., 144<. Overview of ex!erimental data on reduction of
colorectal cancer risk by inulin-ty!e fructans. The :ournal of &utrition 29< *Su!!l
22-, 10C4SM10C7S.
(after, :., Bennett, $., 6aderni, H., et al., 144<. 5ietary synbiotics reduce cancer
risk factors in !oly!ec-tomi/ed and colon cancer !atients. The .merican :ournal of
6linical &utrition C0, 7CCM73D.
Saavedra, :.$., Tschernia, .., 1441. 'uman studies with !robiotic and !rebiotics+
6linical im!lications. The British :ournal of &utrition C< *Su!!l 1-, S172MS17D.
Shen, :., (an, '.N., =in, $.'., et al., 1443. $eta-analysis+ The effect and adverse
events of Lactobacilli versus !lacebo in maintenance thera!y for 6rohn disease.
)nternal $edicine :ournal 93, 249M243.
Sun, S., =an, >., 'e, O., et al., 1443. #robiotics in !atients with severe acute
!ancreatitis+ . meta-analysis. Lanenbeck%s .rchives of Surery 937, 2<2M2<<.
S/aGewska, '., 'orvath, .., #iwowarc/yk, .., 1424. $eta-analysis+ The effects of
Saccharomyces boulardii su!!lementation on 'elicobacter !ylori eradication rates
and side effects durin treatment. .limentary #harmacoloy and Thera!eutics 91,
24D3M24<3.
Tun, :.$., 5olovich, L.(., Lee, 6.'., 1443. #revention of 6lostridium difficile
infection with Saccharo-myces boulardii+ . systematic review. 6anadian :ournal of
Hastroenteroloy 19, C2<MC12.
Turnbauh, #.:., Ley, (.E., $ahowald, $..., et al., 144D. .n obesity-associated
ut microbiome with increased ca!acity for enery harvest. &ature 777, 241<M2492.
Nhan, $.$., 6hen, :.W., Lu, =.(., et al., 1424. 8se of !re-, !ro-, and synbiotics
in !atients with acute !ancreatitis+ . meta-analysis. ;orld :ournal of
Hastroenteroloy 12, 93<4M93<C.
Nhu, 5.L., =an, ;.O., =an, '.$., 1424. $eta-analysis of lactic acid bacteria as
!robiotics for the !rimary !revention of infantile ec/ema. Nhonuo 5an 5ai Er >e
Na Nhi 21, <97M<93.
Nou, :., 5on, :., =u, O., 1443. $eta-analysis+ Lactobacillus containin "uadru!le
thera!y versus standardtri!le first-line thera!y for 'elicobacter !ylori eradication.
'elicobacter 27, 3<M24<.
CHAPTER BR
Gastr!3r!t(&ti+( E''(&ts !' Bi!a&ti+(
F!!/s
M. D(yI M. Th!.as
South 5akota State 8niversity, Brookins, S5, 8S.
ABBREVIATIONS
ACF .berrant cry!t foci
AIDS .c"uired immunodeficiency syndrome
CD 6rohn%s disease
DHNA 2,7-5ihydroxy-1-na!hthoic acid
GI Hastrointestinal
GERD Hastric eso!haeal reflux disease
GMP Hlycomacro!e!tide
HIV 'uman immunodeficiency virus
IBD )nflammatory bowel disease
NDM &ondialy/able material
P*D #e!tic ulcer disease
PEITC #henethyl isothiocyanate
PEO #E)T6 essential oil
PPI #roton-!um! inhibitors
*C 8lcerative colitis
WHO ;orld 'ealth Orani/ation
>. INTROD*CTION
Hastrointestinal *H)- diseases and diestive disorders, hereafter referred to as H)
diseases, affect the alimentary tract, liver, biliary system, and !ancreas. )ncreasinly,
H)-related ambulatory care visits and hos!itali/ation were re!orted in 90R of the 8S
!o!ulation in 1447 *Everhart, 144C-. .nnual H) disorder-related healthcare
ex!enditure was esti-mated at 272 billion dollars in the 8S for 1447 *Everhart, 144C-.
5iestive diseases accounted for 24R of all deaths in the 8nited States *Everhart,
144C-. H) diseases result in loss of work days, reduced "uality of life, decreased life
s!an, and also !ose an economic burden to the individual as well as to the society.
6hronic H) diseases have multifactorial etioloy and only sym!tomatic treatments are
available. )nfectious H) diseases that are treated usin antibiotics are increasinly
develo!in resistance toward these drus. &u-tritional manaement offers a !ramatic
alternative for !revention and treatment of H) diseases. But the "uantity and
com!osition of the food and fre"uency of intake could influence the !roression or
!revention of !atholoical conditions. . better understand-in of nutrients and non-
nutritional com!ounds in the food and knowlede about their mechanisms for
bioloical activities in the context of health and diseases are necessary for ado!tin
nutrition as a tool to manae health. The .merican 5ietetic .ssociation defines
Sbioloically active% *bioactive- food com!onents as T!hysioloically active
constituents in foods or dietary su!!lements derived from both animal and !lant
sources, includin those needed to meet basic human nutrition needs, that have been
demonstrated to have a role in health and to be safe for human consum!tion in
intended food and dietary su!-!lement uses.U Bioactive com!ounds must contribute to
better health in addition to any nutritional role these com!onents miht !ossess.
Bioloically active com!ounds from !lants are often !roducts of a !lant%s
secondary metabolism. $any of these com!ounds have evolved over centuries as the
!lant%s defense mechanism aainst !ests, !athoens, and !redators *6owan, 2333-.
Exam!les of bioactive com!ounds obtained from !lants are !oly!henols, !hytosterols,
carotenoids, ses"uiter-!ene lactones, toco!herols, tocotrienols, oranosulfur
com!ounds includin isothiocyanates, soluble and insoluble fibers, inulin, and
oliofructosaccharides. #oly!henols are the most abundant amon !lant bioactive
com!ounds. There are more than C444 !oly!he-nols *O!ara and (ockway, 144D- of
which flavonoids, isoflavones, theaflavins, and catechins are widely used for
treatment of diseases. ?ruits, cereals, leumes, nuts, rains, and veetables are ood
sources of !oly!henols *O!ara and (ockway, 144D-. $ilk and whey !rotein are
excellent sources of bioactive com!ounds that are of animal oriin. ?er-mented dairy
!roducts contain bacteria that are beneficial to human health *Hhosh and #layford,
1449-. These bacteria are desinated as !robiotic and are considered as bioactive food
com!onents *Hhosh and #layford, 1449-. .lthouh many of these food com!onents
have been !art of human diet for aes, their use for !revention and treatment of
various diseases is a relatively new conce!t in Snutrition and health% research.
Ex!eriments on model animals and human clinical trials have demonstrated the
beneficial role of bioactive com!ounds in manain H) health. )n this cha!ter,
scientific information evidencin H) health !rotection from the use of bioactive
com!ounds is discussed. .ll maGor diseases of the H)-tract for which interventions
with bioactive food com!onents are known have been covered here. 'owever,
diseases of the associated orans such as the allbladder and liver have not been
discussed here, in an attem!t to stay within the word limit.
?. ORAL DISEASES
The mouth or oral cavity is the anterior o!enin of the diestive tract *$artini,
144D-. )t is bound by the li!s anteriorly, hard and soft !alate dorsally, and tonue
ventrally. The oral cavity contains two layers, each of teeth and alveolar ride or um.
The inside of the mouth is lined by mucus membrane. Salivary lands o!en into the
oral cavity and secrete saliva. The normal functionin of these body !arts is im!ortant
in initiatin the diestion of food.
Oral diseases are !revalent amon all !o!ulations and affect eneral health and
"uality of life. The most common conditions are dental caries and !eriodontal
diseases. Hlobally, 0M20R of the !o!ulation has severe !eriodontal diseases and sins
of inivitis. .ccordin to ;orld 'ealth Orani/ation, D4M34R of school children
and a maGority of adults have dental caries *#etersen et al., 1449-. 6ommon sym!toms
include halitosis, orofacial !ain, reduced salivary flow, loose teeth, and altered sense
of taste and smell. )t has been dem-onstrated that oral lesions are associated with
cardiovascular diseases, diabetes mellitus, cancer, chronic obstructive !ulmonary
disease, and human immunodeficiency virus, ac"uired immunodeficiency syndrome
*#etersen et al., 1449-.
Biofilm formation in the mouth is critical in develo!in dental caries and
!eriodontal diseases. Biofilm is a com!lex arranement of multi!le communal
bacteria and can lead to !la"ue formation that remains adherent to the teeth. Toxic
!roducts and virulent factors from !la"ues can elicit inflammatory res!onses in the
host and damae soft tissues and bones leadin to inivitis and !eriodontal diseases.
Bacteria in the biofilm ferment the suars in the food !roducin oranic acids, which
will reduce the !', and leads to dental caries *$arsh, 1440-. Thus reducin biofilm
formation is critical to !revent den-tal caries and !eriodontal diseases. The inhibitory
effect of food-based bioactive com-!ounds on biofilm formation is well documented.
?.>. Ora H(ath B($('its !' Bi!a&ti+( C!.3!#$/s
5ried fruits and cranberry+ 5ried fruits, es!ecially raisins, contain !hytochemicals
known for their antibacterial actions. (aisins contain oleanolic acid, oleanolic
aldehyde, linoleic acid, linolenic acid, betulin, betulinic acid, 0-*hydroxymethyl--1-
furfural, rutin, and their derivatives. These aents can inhibit !# mutans *carioenic-
and Porphyromonas gin-ivalis *!eriodonto!athicE ;u, 1443-. The nondialy/able
material *&5$- in cranberries has a !otent anti-adhesion !ro!erty that !revents
biofilm formation. The &5$ contains D0R !roanthocyanidin-like com!ounds, which
accounts for anti-adhesive !ro!erty. The biofilm formation was inhibited by cranberry
!oly!henol fraction. .lso mouthwash su!-!lemented with &5$ decreased total
bacterial count and !# mutans count. The &5$ also inhibited the adhesion of !#
sobrinus to saliva-coated hydroxya!atite. These ex!er-iments indicate that the
!oly!henol fraction or&5$ in cranberry can !revent or reduce the biofilm formation
mostly by counteractin the bacterial adhesion to dental enamel *#etti and Scully,
1443-. 6ranberry &5$ can also inhibit !eriodontal diseases because of its anti-
inflammatory !ro!erties. The ex!eriments conducted by Bodet and coworkers
suested that &5$ fraction inhibits the !roduction of !roinflammatory cytokines by
macro!haes stimulated with li!o!olysaccharides *Bodet et al., 144C-. 6ranberry
!oly-!henols are suested to !lay a role in reducin the release of bacterial toxic
!roducts. ?iure 94.2 illustrates the mechanisms by which cranberry !revents
!eriodontitis *Bodet et al., 144C-.
$ilk and milk !roducts+ Bioactive !e!tides are embedded in milk !rotein,
es!ecially in the casein fraction, which are ca!able of inhibitin bacterial rowth
*Huenheim et al., 2333-. The diets containin casein could inhibit the rowth of !#
sobrinus and alter overall bacterial com!osition of !la"ue in rats *Huenheim et al.,
2333-. Hlycomacro-!e!tide *H$#-, a maGor com!onent of cheese whey !rotein, can
!revent the adhesion of carcinoenic bacteria and also alter the microbiota of !la"ue
favorably. Other milk !roteins such as lactoferrin, lacto!eroxidase, and lyso/yme also
have antibacterial !ro-!erties. .lso, casein !hos!ho!e!tide can reduce enamel
deminerali/ation and !romote reminer-ali/ation by stabili/in the calcium !hos!hates
in the !la"ue *(eynolds, 233<-.
Tea+ Black tea contains theaflavin that is !roduced by the oxidation of catechins
dur-in the manufacturin !rocess. In vitro and in vivo ex!eriments have shown that
catechins have an inhibitory effect on bacterial en/ymes such as amylase and lucosyl
transferase and thus !revent bacterial !ro!aation and adhesion. .lthouh human
studies have remained inconclusive, some of those studies have exhibited a
correlation between tea drinkin and reduced !la"ue scores *#etti and Scully, 1443-.
'oney *$olan, 1442-+ 'oney has been used for the treatment of skin wounds,
ulcers, and burns throuhout the aes. 'ydroen !eroxide in honey is res!onsible for
the
Fi"#r( BR.> Scheme showin !ro!osed mechanisms by which bioactive com!ounds in
cranberry inhibit locali/ation of !athoens involved in the initiation and develo!ment of
!eriodontitis. Modified from 'igure 4 in odet$ C#$ -renier$ (#$ Chandad$ '#$ et al#$ 4558#
Potential oral health benefits of cranberry# Critical .evie*s in 'ood !cience and /utrition
H8$ 6G4;865$ Taylor and 'rancis -roup$ LLC#
.ntibacterial activity. 'oney also has antioxidants that could reduce the damae due
to free oxyen radicals durin !eriodontitis.
#robiotics+ These are the bacteria that !otentially benefit human health on ines-
tion. Several s!ecies under enus Lactobacillus as well as other enera have been
studied in context of oral health. Some exam!les are L# paracasei$ L# rhamnosus$ L#
lactis$ L# reuteri$ L# brevis$ L# helveticus$+eissella cibaria$ and !treptococcus
thermophilus. #robiotic oranisms inhibit the rowth of !athoenic oranisms, by
com!etin and dis!lacin them from bio-films and thus !revent their adhesion. L#
reuteri can !revent inivitis and um bleedin *>rasse et al., 144D-. #robiotic strains
could also !revent !eriodontal, halitosis, or oral malodor and inhibit the !roduction of
toxins by !athoenic strains of bacteria.
B. ESOPHAGEAL AND GASTRIC DISEASES
The eso!haus *$artini, 144D- is a flattened muscular tube that connects the
!harynx to the stomach. )t is lined by mucosal membrane that secretes mucus to
lubricate and move the food bolus. The !eristaltic movement of the eso!haus !ro!els
the food to the stomach. The lower and u!!er s!hincters in the eso!haus !revent
retrorade move-ment of food. The stomach *$artini, 144D- is the muscular sac lyin
between the eso!h-aus and small intestine. Hlands in the stomach wall secrete
mucus, en/ymes, and hydrochloric acid, which hel! in the diestion of food. The
muscular wall of the stomach aids in churnin and evacuatin its contents into the
small intestine.
B.>. Gastri& Es!3ha"(a R('#H Dis(as( a$/ Barr(t4s
Es!3ha"#s
(eflux of astric contents into the eso!haus *eso!haitis- develo!s from either
dys-functional eso!haeal motility or im!ro!er functionin of lower eso!haeal
s!hincter or both *'erbella and #atti, 1424-. 6ommon sym!tom of astric eso!haeal
reflux dis-ease *HE(5- is heartburn. The incidence of HE(5 is 24M14R amon
;estern !o!-ulation *5ent et al., 1440-. )n .sian !o!ulation, the rate was less than
0R in 1440, but has reached C.0R by 1424 *:un, 1422-. This increase could be a
reflection of chanes in lifestyle and eatin habits in recent years due to chanin
socio-economic structure or due to im!rovement in re!ortin and record kee!in or
both. Occurrence of HE(5 is hihly correlated to obesity and diabetes mellitus,
which are on rise lo-bally *5ent et al., 1440-.
6om!lications of HE(5 include stomach and eso!haeal ulcers and Barrett%s
eso!h-aus. Hastric and eso!haeal ulcers are discussed later under the Section 7.2.
Barrett%s eso!haus is an abnormal benin chane in the e!ithelial cell mor!holoy
*meta!lasia- of the lower eso!haus ty!ically in res!onse to chronic acid ex!osure in
HE(5. $eta-!lastic cells can !otentially !roress to develo! dys!lasia, and then
malinant neo!lasia *cancer-. .bout 24M20R of HE(5 !atients develo! Barrett%s
disease and are, therefore, at an increased risk for develo!in eso!haeal
adenocarcinoma, a !articularly lethal cancer *Oh and 5emeester, 1424-. 6urrent
treatment o!tions for Barrett%s and HE(5 include antacids, '
1
blockers, and !roton-
!um! inhibitors *##)s-. The disease could be better manaed by life style and dietary
chanes such as reducin body weiht, carbonated drinks, citrus fruits, and smokin.
Surery could be beneficial if other treatments fail *Oh and 5emeester, 1424-.
B.?. Bi!a&ti+( F!!/s '!r Es!3ha"(a a$/ Gastri& Dis(as(s
&eem *,Badiracta indica-+ &eem bark extract has shown !otent antisecretory and
antiul-cer !ro!erties in animals and human *Bandyo!adhyay et al., 1447E $aity et al.,
1443E $alfertheiner et al., 1443-. Lyo!hili/ed bark extract at 94-m daily oral dose
for 24 days sinificantly reduced astric acid secretion in !atients with chronic acid
reflux and astric ulcers. ?urther ex!eriments are re"uired to identify the bioactive
com!ounds in neem bark extract.
Morinda citrifolia a"ueous fruit extract+ $orinda fruit *&oni fruit- extract
containin the bioactive com!ound sco!oletin showed antisecretory and antiulcer
!ro!erties in rats *$ahattanadul et al., 1424-.
,sparagus racemosus+ 6rude extract derived from ,sparagus racemosus
administered orally at 244 m k
-2
reduced ulcers in rats that com!ared with the
effects of (anitidine, a current !rescri!tion dru. The extract also decreased astric
acid secretion *Bhatnaar and Sisodia, 144D-.
B.B. H(i&!ba&t(r 3y!ri I$'(&ti!$
"# pylori coloni/e astric mucosa. These oranisms en/ymatically metaboli/e
urea into ammonia, thereby neutrali/in the acidic environment in the stomach
*;roblewski et al., 1424-. The infection is !revalent in 04R of the world !o!ulation
but often do not !roduce a!!arent sym!toms. .mon lon-term carriers, 24R develo!
!e!tic ulcers and 2M9R may develo! astric adenocarcinoma *8emura et al., 1442-.
.lthouh the sym!toms are not s!ecific to "# pylori infection, the disease could be
sus!ected if there is severe abdominal !ain, nausea, vomitin, weiht loss, and
bloatin. Treatment for "# pylori infection is indicated for astric and duodenal ulcer,
dys!e!sia, !atients on lon-term nonsteroidal anti-inflammatory dru *&S.)5-
thera!y, atro!ic astritis, as-tric cancer, unex!lained iron-deficiency anemia, and
astric mucosa-associated lym!hoid tissue lym!homa. .ntimicrobial aents in
combination with ##)s are used successfully to treat "# pylori infection. 'owever,
resistance to these drus is increasin and alternate antimicrobial and astro!rotective
aents are bein develo!ed.
B.D. Bi!a&ti+( F!!/s A"ai$st ). pylori I$'(&ti!$
Bioactive com!onents do not eradicate the bacteria, but are useful when used in
combination with antibiotics. Bioactive foods !rovide an alternate solution for the
rowin antibiotic resistance. The maGor bioactive foods aainst "# pylori infection as
substantiated by research are as follows+
6ranberry and ra!e extracts+ The &5$ fraction of cranberry extract rich in !lant
!oly!henols inhibits "# pylori adhesion to astric mucosa in vitro *Burer et al., 1444-
in an &5$-concentration-de!endent and bacterial strain s!ecific manner. )t was
observed that the bacteria went into a coccoid form after &5$ treatment and were
unable to !ro-liferate likely due to this mor!holoical chane *$atsushima et al.,
144C-. The !oly!he-nolic extracts from ra!es containin resveratrol also showed
inhibitory effect on "# pylori rowth *Brown et al., 1443-.
#robiotics+ #robiotics inhibit the rowth of "# pylori by multi!le mechanisms
*Lesbros-#antoflickova et al., 144<-. Some of the !robiotic oranisms synthesi/e
antibac-terial com!ounds such as bacteriocin, which is ca!able of inhibitin "# pylori
rowth. .lso the end !roducts of bacterial fermentation, es!ecially lactic acid, inhibits
"# pylori urease en/yme, lowers !', and creates unfavorable environment for "#
pylori rowth. .nother !ro!osed mechanism is that !robiotics such as L# Cohnsonii
La9$ L# salivarius, L# acidophilus$ and +# confuse com!ete with "# pylori for
adhesion to astric e!ithelium *Lesbros-#antoflickova et al., 144<-. #robiotic bacteria
also increase the mucin !roduc-tion in stomach. This thickens the astric mucosal
layer, which acts as a !hysical barrier aainst "# pylori coloni/ation *Lesbros-
#antoflickova et al., 144<-. The summary of clin-ical trials that used !robiotics in
combination with antibiotics is iven in Table 94.2. *Hotteland et al., 144D-. )n a
se!arate study where !robiotics were su!!lemented to a standard tri!le thera!y *two
antibiotics and a ##)-, su!!lementation im!roved "# pylori eradication rate, and
lowered side effects such as nausea, diarrhea, and taste disturbance that are enerally
associated with the tri!le thera!y *Son et al., 1424-.
5airy !roducts+ 'uman trials have demonstrated that bovine lactoferrin has
beneficial effect on "# pylori eradication. ;hey !rotein isolates such as H$#, c-
lactalbumin, and lacto!eroxidase could also inhibit " pylori rowth, but further
research is warranted to obtain conclusive results. >efir, a fermented milk !roduct, is
!ro!osed to have antimi-crobial, antimutaenic, and anticarcinoenic !ro!erties
*Bekar et al., 1422- but further research is needed to establish the dose rane and
mechanism of such bioloical activities.
D. INTESTINAL DISEASES
The small intestine is divided into three !arts+ duodenum, GeGunum, and ileum
*$artini, 144D-. $ucosal layer of small intestine is modified into villi, finer-like
!roGections, which increases the surface area for absor!tion of nutrients. The mucus
from the oblet cells in the mucosa !rotects the intestine from acid in the chime
*diesta from the stomach-. 5iestion of food is com!leted in the small intestine and
the diested wastes are moved into the lare intestine. Lare intestine has three !arts+
cecum, colon, and rectum. )lleocecal valve at the Guncture of the two intestines
!revents the retrorade flow of chime from cecum to ileum.
Tab( BR.> Summary of 6linical Trials that used #robiotics in
.ssociation with .ntibiotics for the Treatment of "# pylori 6oloni/ation
St#/y
/(si"$ S#b1(&ts Era/i&ati!$
th(ra3y
Pr!bi!ti& R(s#ts
(6T 5ys!e!tic
adults
(abe!ra/ole,
clarithromycin,
amoxicillin
Lactobacillus
acidophilus LB
for 24 days
E.(.+
increased ..
E.+ no effect
(6T .sym!tomatic
adults
#anto!ra/ole,
clarithromycin,
tinida/ole
L# rhamnosus
-- for 24 days
E.(.+ no effect
.+E.+
decreased
(6T 5ys!e!tic
adults
Lanso!ra/ole,
clarithromycin,
amoxicillin
L# acidophilus
L.0+B. lactis
for 7 weeks
E.(.+
increased
5B#6 .sym!tomatic
adults
(abe!ra/ole,
clarithromycin,
tinida/ole
L# rhamnosus$
!accharomyces
boulardii
E.(.+ no effect
.+E.+
decreased
Lactobacillus+B
. lactis for 1
weeks
5B#6 .sym!tomatic
adults
6larithromycin L# Cohnsonii L.2
acidified milk
for 9 weeks
E.(.+ no effect
(6T 5ys!e!tic
!atients with
resistant "#
pylori
infection
Esome!ra/ole
or
!anto!ra/ole,
ranitidine
bismuth citrate,
amoxicillin and
tinida/ole
L# casei 5H for
24 days
E.(.+ no effect
.+E.+
decreased
5B#6 "# pylori
!ositive
Esome!ra/ole
6larithromycin
.moxycillin
L# casei for 7
weeks
E. (+ no effect
(6T Sym!tomatic
children
#anto!ra/ole,
clarithromycin,
.moxycillin
L# acidophilus$ L
rhamnosus B)5
for 14 days
E.(+ increased
(6T "# pylori
sym!tomatic
.moxycillin,
6larithromycin,
Ome!ra/ole
!# boulardii for 7
weeks
E.(.+
increased
..E.+
decreased
.bbreviations+ E.(., eradication rateE ..E., adverse effectsE (6T, randomi/ed
clinical trialE 5B#6, double-blind !lacebo controlled. )nformation for the table is
obtained from Hotteland et al. *144D-, Son et al. *1424-, and Nou et al. *1443-.
$ost of the water in the diesta is absorbed in the lare intestine, althouh a small
amount of water is absorbed in the small intestine. Lare intestine harbors bacteria
that can ferment carbohydrates and fiber that are not diested in the small intestine.
D.>. P(3ti& *&(r Dis(as(
#e!tic ulcer disease *#85- includes eso!haeal, astric, and duodenal ulcers.
.mon these, eso!haeal ulcers are least common and are mostly associated with
HE(5. 6ommon cause for astric ulcers and !roximal duodenal ulcers is "# pylori
infection *$alfertheiner et al., 1443-. Heneral causes of all ty!es of ulcers include
side effects of drus *&S.)5s, some antibiotics, and metronida/ole-, chronic
vomitin, infections, and idio!athic oriin. )n the elderly, <4R of #85 !atients are "#
pylori !ositive and 74R of !e!tic ulcers are caused by &S.)5 or other drus. .bout
14M10R of #85 incidences are idio!athic of oriin *#ilotto et al., 1424-.The annual
incidence of !hysician-dianosed cases of #85 rane from 4.2 to 4.23R of the lobal
!o!ulation *Sun et al., 1443-.
6linical manifestations for #85 are ae related and often nons!ecific *#ilotto et
al., 1424-. The most common sym!tom is e!iastric !ain. One-third of the !atients
also ex-!erience heartburn. Other sym!toms include fullness, bloatin, satiety, and
nausea. #e!-tic ulcers could lead to bleedin and this occurs more in elderly !atients
*$alfertheiner et al., 1443-. Two-thirds of elderly !atients have aty!ical sym!toms
while only one-third ex!erience e!iastric !ain. The dianosis of #85 could be
delayed in elderly !atients if only aty!ical sym!toms are manifested *#ilotto et al.,
1424-. The treatment of #85 is !lanned accordin to the causative factor. Treatment
reimen for ulcers due to "# pylori and HE(5 are described in the earlier sections.
#e!tic ulcers due to &S.)5 thera!y could be treated with ##)s such as ome!ra/ole
and histamine blockers such as ranitidine accom!anied by discontinued use of the
&S.)5. 8lcers of idio!athic oriin are also trea-ted with ##) and histamine blockers
*$alfertheiner et al., 1443-.
D.?. Bi!a&ti+( F!!/s B($('i&ia i$ P*D
The bioactive com!ounds discussed under "# pylori infection and HE(5 are also
ben-eficial for #85 treatment. Studies have shown that a!!le extract *5%arenio et
al., 144C- and turmeric have beneficial effects toward treatin astric ulcers. Turmeric
*Curcuma longa- is a rhi/omatous herbaceous !erennial !lant of the iner family and
is a common )ndian s!ice that is used in traditional folk medicine for treatment of
various diseases. The turmeric extract has the ability to reduce astric ulcer incidences
in animal models by blockin histamine rece!tors *>im et al., 1440-. The im!ortant
bioactive com!ound in turmeric is curcumin which is not, however, readily
bioavailable when consumed as food.
D.B. I$'a..at!ry B!0( Dis(as(
)nflammatory conditions of the H)-tract are collectively termed as inflammatory
bowel disease *)B5-. The two !redominant forms of )B5 are ulcerative colitis *86-
and 6rohn%s disease *65-. 86 is confined to the lare intestine with inflammation
occurrin !rimarily in the mucosal linin, while 65 can affect any !art of the
alimentary tract with transmural inflammation. .lthouh there are some uni"ue
sym!toms distinuishin each disease, many of the sym!toms in86and65are shared.
)B5 affects all ae rou!s across the nations. . unimodel distribution with 20M94
years of ae for )B5 onset is the recent trend. But there could be a small second !eak
occurrin at 74M<4 ae rou!s for 86 *Sands and Hrabert, 1443-. The disease is more
!revalent in &orth .merica and ;estern Euro!e. There are about 2.7 million !atients
in &orth .merica with 94444 new cases re!orted annually. #revalence of 65 is
hiher in females, while 86 occurs more in males. .lso hiher incidence of both 65
and 86 are noted amon hiher socio-economic classes. (ecent studies indicated that
althouh the 6aucasians are more affected, the a! between !revalence amon
6aucasians and .fricanM.mericans is dimin-ishin *Sands and Hrabert, 1443-.
The !recise cause of )B5 is unknown but hy!otheses linkin the etioloy to envi-
ronmental chanes, dietary habits, immunoloic factors, smokin, and enetic
!redis!o-sition exist. Ex!osure to !ollution, industrial waste, smokin, and sunliht is
cited as maGor contributin factors for the develo!ment of )B5 *'anauer, 144D-.
Better sanita-tion and lesser ex!osure to infective aents are !ositively correlated to
hiher incidence rate. The intestinal microbiota may be altered in these cases
renderin these individuals susce!tible to )B5. 5ietary habits such as hiher fat and
refined suar consum!tion are also indicated as causative factors but remain
inconclusive. ?amilial dis!osition to the dis-ease ties )B5 to enetic factors *'anauer,
144DE Sands and Hrabert, 1443-.
Sym!toms of )B5 that ty!ically occur in alternate cycles of flare and remission
include mild-to-severe diarrhea, blood in stool, !ain associated with abdominal
cram!s, and se-vere urency to have a bowel movement. Loss of a!!etite and weiht
loss are also com-mon. )B5 is a risk factor for anal fissures, fistulas, and cancer. Skin
lesions, arthritis, and liver disorders could also occur as associated com!lications of
)B5. 6urrent treatments aim at reducin fre"uency, duration as well as intensity of
flares and !rolonin remission. $edications used in )B5 thera!y are anti-
inflammatory aents, antibiotics, immuno-modulators, and bioloics. $aGority of the
!atients will re"uire surery in ad-vanced staes. .lon with these conventional
thera!eutic aents, bioactive foods could yield additional su!!ort to alleviate the
condition.
D.D. Bi!a&ti+( F!!/s '!r Tr(at.($t !' IBD
6ruciferous veetables+ #henethyl isothiocyanate *#E)T6- is an oranosulfur
bioactive com!ound found in cruciferous !lants. #E)T6 can su!!ress the ex!ression
of inflamma-tory markers in mammalian cells and has the !otency com!arable to
as!irin in alleviatin in vivo inflammation *5ey et al., 144D-. The effectiveness of
#E)T6 essential oil *#EO- in the treatment of acute and chronic 86 as com!ared to a
current !rescri!tion dru *0-amino salicylic acid- was investiated in mouse models
*5ey et al., 1424-. The re-s!onse to treatment was ex!ressed as disease activity index
*?iure 94.1-, reflectin five clinical sins+ chane in body weiht, stool consistency,
fecal occult blood, visible rear-end bleedin and inflammation, and rectal !rotrusion.
#EO reduced inflammation, arrested intestinal bleedin, and hel!ed in remission of
the disease. .lso ex!ression of !roinflammatory cytokines was downreulated by
#EO in the mouse colon. The future direction of this study would be to follow u! with
effects of #EO in humans.
Tea+ Studies with chemically induced and enetically !redis!osed )B5 mouse
models have shown the efficacy of black and reen tea extracts to reduce the severity
of inflame-mation and weiht loss *)shihara et al., 1443E Iarilek et al., 1442-. But the
dosae used in these ex!eriments could be achieved only if an individual drinks 244M
144 cu!s of tea every day. 'ence, these results need validation in human beins and
also the a!!ro!riate thera!eutic dose needs to be established.
Hra!e+ Hra!e skin and seed contain 04M244 X
-2
of resveratrol, a !henolic com-
!ound. This com!ound is also !resent in ra!e wine, some berries, and nuts. (esver-
atrol has the ability to inhibit !roinflammatory cytokine tumor necrosis factor-c, and
inflammatory !athways involvin cyclo-oxyenase 2 *5as and 5as, 144<-. )n rats,
resveratrol reduced the damae due to trinitroben/ene-induced colitis. . sinificant
increase in the a!o!tosis of cells involved in colitis was also noted *$artin et al.,
144D-. But the low
Fi"#r( BR.? Effects of orally administered !hytocom!ound #EO and a common
!rescri!tion dru 0- .S. on the disease activity index *5.)- in 5SS-induced colitis in a
mouse model study. Sinificance of treatments in #EO and 0-.S. rou!s in res!ect to
diseased but untreated *5SS- rou! and are indicated by
l
!V4.40 and
ll
!V4.42 and
lll
!V4.442.
'ealthy control rou! from the study is also shown. 6linical sins included in the 5.) score
re!resent many of the human colitis sym!toms+ *a- acute colitis model. 5ata as meanSE$
*n=D- are shown at 0-day intervals. *b- 6hronic colitis model. 5ata as meanSE$ *n 24- are
shown at 9- and 1-day intervals durin induction and treatment !eriods res!ectively. .mino
salicylic acid, .S.E disease activity index, 5.)E standard error mean, SE$. .eproduced
from (ey$ M#$ Duhn$ P#$ .ibnic&y$ (#$ et al#$ 4595# (ietary phenethylisothiocyanate
attenuates bo*el inflammation in mice# MC Chemical iology$ 95$ H#
Bioavailability of resveratrol in body tissues and fast clearance rate from the body
remains a challene in usin it for treatment of )B5 in humans *8deniwe et al.,
144C-.
?ish oil and flax seed oil+ These oils are rich in omea-9 fatty acids that have
!roven anti-inflammatory and immunomodulatory !ro!erties. 'owever, animal
efficacy studies usin omea-9 fatty acids for treatment of )B5 yielded inconclusive
results *6alder, 144D-.
;hey culture+ The milk whey culture usin Propionibacterium freudenreichii ET-
9 con-tains bioactive substance called 2,7-dihydroxy-1-na!hthoic acid *5'&.-. This
com-!ound can stimulate the rowth of ifidobacteria in humans and animals. 5'&.
reduced the severity of trinitroben/ene-sulfonic-acid-induced colitis *8chida et al.,
144<-.
#omeranate+ . recently concluded study in rats with dextran sodium-sulfate-
induced colitis evaluated the use of !omeranate extract. )t was found that both !ome-
ranate extract and urolithin-., a microbiota-derived metabolite from !omeranate,
reduced the severity of colitis *Larrosa et al., 1424-.
Licorice+ Ethanolic extract of licorice contains anti-inflammatory com!ound
labri-din. $ice with dextran sodium-sulfate-induced colitis were treated for < days
with the extract and this resulted in reduced weiht loss, decreased mortality, and
!revented short-enin of colon *>won et al., 144C-.
Turmeric+ 6urcumin, the bioactive com!ound in turmeric, has been used in animal
and human research for treatin )B5. Studies with chemically induced colitis animal
models suested that curcumin could alleviate the sym!toms of )B5. 6urcumin also
had beneficial effects at a concentration of 2444M2044 m !er day in a small human
study. 'owever, larer clinical trials are needed for conclusive efficacy and
bioavailability of curcumin in )B5 *'anai and Suimoto, 1443-.
#robiotics+ &umerous inde!endent studies have been conducted to evaluate the
efficacy of !robiotics in )B5 treatment and remission but the results are inconsistent.
. review on ex!eriments conducted suested that !robiotics used in combination
with standard thera!y yielded !ositive results. But this beneficial effect is not
obtained when !robiotics are used alone *6ary and Boullata, 1424-. .nother study
indicated that a combination of eiht strains of !robiotic bacteria was effective in the
maintenance of remission of )B5, while any sinle strain of bacteria did not yield
beneficial effects *'aller et al., 1424-.
#rebiotics+ 5ietary fibers that could be utili/ed by bacteria in the colon are termed as
!rebiotics. Bacteria ferment the fiber and !roduce metabolites. Short-chain fatty acids
such as acetate, !ro!ionate, and butyrate are the maGor metabolites of bacterial
fermen-tation in the colon. In vitro and in vivo studies indicate that butyrate has anti-
inflammatory and antitumor !ro!erties. The hy!othesis that dietary fiber is effective
in the attenuation of )B5 relies on these known !ro!erties of butyrate *(ose et al.,
144<-. 5ietary fibers from sources such as oat bran *'allert et al., 1449-, !syllium
seeds, inulin, and oliofructosaccharides *Leenen and 5ieleman, 144<- alleviated the
sym!toms of 86. Some ex!eriments yielded conflictin results on the efficacy of
dietary fiber for )B5 treat-ment. This could be due to the !resence of abnormal
microbiota in )B5 !atients. ?urther evaluation of the efficacy of combination thera!y
usin !rebiotics and !robiotics *toether termed as synbiotics- is needed. .lso the
strains of bacteria and ty!e of fiber that should be iven as combinations for o!timal
effects remains to be determined. Both these aents have excellent safety !rofile and
no known side effects.@ALIGNMENTA
E. GI CANCER
E.>. OraI Phary$"(aI a$/ Es!3ha"(a Ca$&(r
.!!roximately 94444 new cases of oral and !haryneal cancer and 29 444 new
cases of eso!haeal cancer are re!orted annually in the 8nited States *Hreenlee et al.,
1442-. .bout 34R of oral and !haryneal cancer is s"uamous cell carcinoma. Both
s"uamous cell carcinoma and adenocarcinoma occur in eso!haus. The common
etioloy of these tumors is smokin, alcohol consum!tion, tobacco and betel nut
chewin, as well as di-etary, enetic, and environmental. Iitamins, fruits, veetables,
tea, and coffee have been shown to have !rotective effect aainst oral cancer
*6hainani-;u, 1441-. 5iversified dets are hihly recommended to achieve !rotection
aainst these multifactorial diseases.
E.?. Gastri& Ca$&(r
;orldwide incidence of astric cancer has declined over last few decades
*Everhart, 144C-. This could be due to availability of efficient dianostic tools such as
endosco!y for !recancerous sins and surical removal o!tions of these !recancerous
cells and tis-sues. The two main sites for astric adenocarcinoma are !roximal and
distal stomach. The maGor risk factors are "# pylori infection, dietary factors, tobacco,
obesity, familial !redis-!osition, and radiation ex!osure *6rew and &euut, 144D-.
)ntake of antioxidants such as vitamin 6 and E !rovides !rotection aainst astric
cancer. .nnual endosco!ic screenin in hih risk rou!s may hel! to detect the
tumors in early stae and mortality could be reduced *6rew and &euut, 144D-.
BE.B. C!!r(&ta Ca$&(r
.lthouh incidences of colorectal cancer are declinin in the recent years, still it
ranks second in causin death amon all cancers in the 8nited States *Everhart,
144C-. The averae lifetime risk of develo!in colorectal cancer for a !erson is
0.21R. Henetic, environmental, and dietary factors contribute to the develo!ment of
the disease. The normal colon mucosa is lined by columnar cells and forms
invainations or cry!ts. ;hen ex!osed to carcinoenic factors, !roliferative cells in
the cry!ts lose the ability to control cell division and leads to the formation of
aberrant cry!t foci *.6?- or !oly!s. These !oly!s are the early markers of cancer risk
and have the !otential to develo! into adenoma and adenocarcinoma if left untreated.
#eriodic screenin for .6? is an effective tool for early dianosis. )f detected early,
surical intervention is !ossible.
E.D. Bi!a&ti+( F!!/ C!.3!$($ts i$ Pr(+($ti!$ !' GI Ca$&(r
Black (as!berry+ .ddition of black ras!berry in diet for 1 weeks reduced
dimethylsulfoxide-induced oral tumor incidence in hamsters *6asto et al., 1441-.
Black ras!berry contains various anticarcinoenic aents such as ellaic acid, vitamin
E and 6, ferulic acid, and folic acid.
Tomato+ Lyco!ene is the maGor bioactive com!ound in tomatoes. 'uman case
con-trol studies conducted in 21 countries includin in the 8nited States re!orted an
inverse relationshi! between tomato or lyco!ene intake and astric cancer occurrence
*Hiovannucci, 2333-. . study in :a!an that examined the !lasma level of lyco!ene in
blood indicated that reions where !eo!le have hih !lasma lyco!ene concentration
had lesser incidences of astric cancer and vice versa. Tomato consum!tion exhibits
the most consistent neative association to astric cancer amon all veetable and
fruit consum!tion data *Hiovannucci, 2333-.
Tea and coffee extracts+ Bioactive com!ounds in tea leaf extracts include allic
acid kaem!ferol, "uercetin, catechin, e!icatechin, oleic acid, !almitic acid, linoleic
acid, and linolenic acid. ;hen the oral s"uamous carcinoma cells were treated with
tea leaf extract, it induced a!o!tosis or cell death *6hia et al., 1424-. The !roa!o!totic
enes were u!reulated and anti-a!o!totic enes were downreulated, likely due to
the !resence of !oly!henols.
#rebiotics+ 5ietary fibers include inulin, resistant starch, cellulose, hemicelluloses,
and !ectins. (ich sources of dietary fiber include bran, fruits, veetables, nuts,
leumes, seeds, and berries. 5ietary fibers are fermented by colon bacteria to !roduce
short-chain fatty acids such as butyrate with known anticarcinoenic !ro!erty. The
suested mechanism of the action of butyrate is iven in ?iure 94.9 *.ndoh et al.,
1449-. ?iber also increases the fecal bulk and decrease transit time. This will reduce
the ex!osure time of intestinal mucosa to mutaens that lead to the develo!ment of
cancer.
#robiotics and synbiotics@ ifidobacterium lactis$ Lactobacillus bulgaricus$
!treptococcus ther-mophilus$ L# casie$ L# acidophilus$ L# gassrei$ # breve$
!treptococcus cremoris$ and !# lactis are shown to reduce colon cancer risk.
6ombination of L# rhamnosus and # lactis with inulin iven for 99 weeks reduced the
number of a/oxymethane-induced colon carcinomas in rats *;ollowski et al., 1442-.
6ruciferous veetables+ This includes cabbae, broccoli, cauliflower, kale,
Brussels s!routs, and watercress. These veetables contain bioactive com!ounds such
as folate, vitamin 6, toco!herols, carotenoids, lucosinolates, isothiocyanates, and
!oly!henols. Hlucosinolates metaboli/e to !roduce isothiocyanates and indoles,
which !ossess !otent
Fi"#r( BR.B Scheme showin !ro!osed anti-inflammatory mechanisms of butyrate, a by-
!roduct of dietary fibers and !rebiotics. Modified from 'igures 0 and : in ,ndoh$ ,#$
TsuCi&a*a$ T#$ 'uCiyama$ M#$ 4550# .ole of dietary fiber and short-chain fatty acids in the
colon# Current Pharmaceutical (esign$ <$ 0HG;:8$ published by entham !cience Publishers
Ltd.@ALIGNMENTA
anticarcinoenic !ro!erty. )sothiocyanates such as sulfora!hane are cytotoxic and
indoles are cytostatic *#a!!a et al., 144<-.
G. CONCL*SION
6onsum!tion of fruits, nuts, and veetables offer !rotective benefits aainst H)
diseases *:edrychowski et al., 1424-. But intake of whole food that contains bioactive
com!ounds does not always uarantee H) health !rotection. 6oncentration of these
health-benefitin com!ounds in food miht vary and can be lower than that re"uired
to elicit a thera!eutic effect. .dditionally, bioavailability !arameters may vary
de!endin on the form con-sumed, such as cooked versus raw, and other factors.
Scientifically established standard-i/ed !rocessin of these bioactive aents into
su!!lements may hel! to overcome some of these hurdles. Henetic makeu! of an
individual may determine how much benefit can !otentially be derived from the
intake of fruits and veetables or even !rocessed su!!le-ments. This conce!t has
iven birth to the newer research field of nutritional enomics, which !rovides the
tools and framework to study dietMene interactions *5ebusk, 1424-. .dvancement in
this direction could ultimately !rovide uidelines for individuali/ed diet !lans to
deliver healthy dosae of bioactive com!ounds and the "uantity of whole food
containin bioactive com!ounds.
)t is enerally acce!ted that bioactive com!ounds could !rovide a safer alternative
to !revailin chemothera!eutic aents that are known to have side effects. ;hile this
is !ar-tially true iven the existin history of human use and folklore in many cases,
toxic con-centration and !harmacoloical dose must be established before the !urified
bioactive substances are marketed. .n extensive body of research has demonstrated
the ability of bioactive aents to modulate !atho!hysioloical !rocesses !roducin H)
health ben-efits. 'owever, many of these investiations relied on in vitro or
!reclinical observations. 6ontrolled human trials must be conducted in future to
validate these observations and scientifically establish the !otential health-!romotin
benefits.
ACKNOWLEDGMENTS
This work was made !ossible by funds from &ational )nstitutes of 'ealth vrant }
(44 .T447170w, 8nited States 5e!artment of .riculture v}91C244w, and South
5akota .riculture Ex!eriment Station v} 92C444w. The authors are also thankful to
numerous authors who have contributed to the research in the field of astric diseases
and effects of bioactive com!ounds in astrointestinal disorders. Owin to word
limitation, the au-thors were unable to cite many excellent research contributions.
Therefore, they ure the readers to cross reference from within the cited articles.
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RELEVANT WEBSITES
htt!+,,www.ccfa.or, M 6rohn%s A 6olitis ?oundation of .merica 5isease
)nformation. *accessed 4<.42.1422-.
htt!+,,www.ccfa.or M 6rohn%s A 6olitis ?oundation of .merica. E!idemioloy.
*accessed 4<.42.1422-.
htt!+,,seer.cancer.ov,statfacts, M Lifetime risk for colorectal cancer information.
*accessed 4<.42.1422-.