525210

research-article2014
PENXXX10.1177/0148607114525210Journal of Parenteral and Enteral NutritionTappenden

Invited Review
Journal of Parenteral and Enteral
Nutrition
Intestinal Adaptation Following Resection Volume 38 Supplement 1
May 2014 23S­–31S
© 2014 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607114525210
jpen.sagepub.com
Kelly A. Tappenden, PhD, RD, FASPEN1 hosted at
online.sagepub.com

Abstract
Intestinal adaptation is a natural compensatory process that occurs following extensive intestinal resection, whereby structural and functional
changes in the intestine improve nutrient and fluid absorption in the remnant bowel. In animal studies, postresection structural adaptations
include bowel lengthening and thickening and increases in villus height and crypt depth. Functional changes include increased nutrient
transporter expression, accelerated crypt cell differentiation, and slowed transit time. In adult humans, data regarding adaptive changes are
sparse, and the mechanisms underlying intestinal adaptation remain to be fully elucidated. Several factors influence the degree of intestinal
adaptation that occurs post resection, including site and extent of resection, luminal stimulation with enteral nutrients, and intestinotrophic
factors. Two intestinotrophic growth factors, the glucagon-like peptide 2 analog teduglutide and recombinant growth hormone (somatropin),
are now approved for clinical use in patients with short bowel syndrome (SBS). Both agents enhance fluid absorption and decrease requirements
for parenteral nutrition (PN) and/or intravenous fluid. Intestinal adaptation has been thought to be limited to the first 1–2 years following
resection in humans. However, recent data suggest that a significant proportion of adult patients with SBS can achieve enteral autonomy,
even after many years of PN dependence, particularly with trophic stimulation. (JPEN J Parenter Enteral Nutr. 2014;38(suppl 1):23S-31S)

Keywords
short bowel syndrome; intestinal resection; intestinal adaptation; malabsorption

Intestinal adaptation is a natural compensatory process that
occurs following extensive intestinal resection, whereby struc-
tural and functional changes in the intestine improve nutrient
and fluid absorption in the remnant bowel.1,2 The degree of
intestinal adaptation that can be achieved is related to both the
extent of the resection and the anatomy of the remnant bowel.
For example, adaptation is more pronounced in the ileum than
in the jejunum, which may account, in part, for the improved
outcomes observed in patients who retain some ileal tissue
compared with patients with end-jejunostomy, even after con-
trolling for the length of the remnant bowel.3,4 For adult
patients with short bowel syndrome (SBS), the degree of intes-
tinal adaptation by the remnant bowel is one of the factors that
determines whether permanent intestinal failure develops and
lifelong parenteral nutrition (PN) is necessary. This review
presents an overview of the structural and functional changes
that occur during intestinal adaptation following intestinal
resection, factors that play a role in mediating these changes,
and different approaches to measuring intestinal adaptation in
individual patients. This information is intended to provide cli-
nicians with a better understanding of the multifaceted process
of intestinal adaptation and its importance in the successful
management of adult patients with SBS.
differentiation into specialized mucosal cells (ie, enterocytes,
enteroendocrine cells, goblet cells, or Paneth cells).5 At the end
of their life cycles, the differentiated epithelial cells undergo
apoptosis.6 In animal studies, small bowel resection is fol-
lowed by a rapid acceleration of crypt cell proliferation
(Figure 1).7 As a result, crypt depth and villus height are
increased.3,8 In contrast, attenuation of apoptosis does not
appear to be a mechanism for intestinal adaptation; instead, the
rate may modestly increase as a consequence of enhanced
crypt cell proliferation and a greater total number of entero-
cytes.9 Intestinal resection is also associated with local angio-
genesis and resultant increases in tissue oxygenation and blood
flow (Figure 1).10-12 These changes support mucosal growth
and may also enhance absorptive function.
From the 1Department of Food Science and Human Nutrition, University
of Illinois at Urbana-Champaign, Urbana, Illinois.
Financial disclosure: The publication of the supplement in which
this article appears is supported by an educational grant from NPS
Pharmaceuticals, Inc (Bedminster, New Jersey). K.A.T. has served as a
consultant for NPS Pharmaceuticals, Inc. No financial compensation was
provided to K.A.T. for the preparation of this work. Funding for medical
writing assistance was provided by NPS Pharmaceuticals, Inc.

Physiological Features of Intestinal Adaptation Received for publication December 11, 2013; accepted for publication
February 3, 2014.
Structural Changes Associated With Corresponding Author:
Intestinal Adaptation Kelly A. Tappenden, PhD, RD, FASPEN, Department of Food Science
and Human Nutrition, University of Illinois at Urbana-Champaign, 443
The epithelial mucosa of the intact small bowel undergoes con- Bevier Hall, 905 South Goodwin Avenue, Urbana, IL 61801, USA.
tinual self-renewal via crypt cell proliferation, migration, and Email: tappende@illinois.edu
Downloaded from pen.sagepub.com at RUTGERS UNIV on April 27, 2015
24S Journal of Parenteral and Enteral Nutrition 38(Suppl 1)
Figure 1.  Structural and functional changes that occur in the
intestine during postresection adaptation.
In humans, gross changes in intestinal morphological fea-
tures, including small bowel lengthening and dilation, have
been observed after resection or jejuno-ileal bypass.13,14
However, only limited evidence regarding modification of
intestinal microarchitecture post resection is available. Some
of the more frequently cited studies assessing structural intesti-
nal adaptation in humans have been conducted in pediatric
patients. McDuffie et al15 evaluated intestinal morphological
characteristics in 33 infants with neonatal necrotizing entero-
colitis both at the time of resection and also at ostomy reversal,
which occurred at a mean of 74 days post surgery. In these
patients, villus height and crypt depth increased by 32% and
22%, respectively, at ostomy reversal compared with baseline
(P < .01 for both measures). Furthermore, the magnitude of the
change in villus height was significantly correlated with the
length of small bowel removed (r = 0.36; P < .05).15
Few studies have been performed to date in adult patients,
and these studies have been limited by small sample sizes and
histological analyses performed at a single time point post
resection. Doldi14 reported enterocyte hyperplasia and a 70%–
75% increase in villus height in the small intestine of 13
patients at 2 years following jejuno-ileal bypass surgery com-
pared with controls; however, a statistical analysis was not per-
formed as part of this study. Joly et al16 documented a 35%
increase in crypt depth and a 22% increase in cell number/crypt
in the colon of 12 patients with jejuno-colonic anastomosis
compared with healthy controls (P < .005) at a mean of
9.8 years following resection, but the histological status of the
small intestine was not evaluated. Several other studies showed
no changes in epithelial proliferation or crypt depth and villus
height in the small intestine of patients with SBS compared
with healthy controls.17-19
Several reasons may account for the limited evidence for
structural adaptation in human adults following resection.
Studies performed to date have included relatively few
patients and have examined single time points. Furthermore,
most patients are maintained on PN for at least some time
following resection; however, enteral nutrition is required for
maximal intestinal adaptation (see below). In a longitudinal
study of 2 patients following small bowel resection, villus
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height was decreased for patients compared with control sub-
jects while they were maintained on PN but was increased
compared with control subjects 2 months after enteral feed-
ing resumed.20 Further, most animal studies involve resec-
tions of 75% or more of the intestinal tissue, but resections in
humans are rarely so extensive. In both human and animal
studies, the extent of resection correlates with the degree of
adaptation.15,18,21 Finally, mechanisms for adaptation may
differ between humans and other mammalian models.
Postresection adaptation clearly occurs in humans, as is dem-
onstrated by the majority of patients who progress from PN
dependence to enteral autonomy within the first several years
following surgery.22 Intestinal adaptation in humans may rely
more on functional rather than structural changes; however,
additional supporting clinical data are needed to draw defini-
tive conclusions.19
Functional Changes Associated With
Intestinal Adaptation
In addition to structural changes, functional adaptations that
increase absorptive capacity also occur following resection
(Figure 1). In animal studies, intestinal resection is associated
with increased expression of transporter proteins and
exchangers involved in nutrient, electrolyte, and water
absorption, including the sodium glucose cotransporter, Na+/
H+ exchangers, and Na+/K+ adenosine triphosphatases.23-26
Importantly, these studies have documented an elevation of
transporter or exchanger expression that is not wholly a result
of increased enterocyte mass. In addition, developing entero-
cytes express digestive enzymes and amino acid transporters
more rapidly following small bowel resection than in an
intact bowel, suggesting an accelerated maturation pro-
cess.27,28 The net result of these changes in protein expression
and activity is to increase the digestive and absorptive capac-
ity of the remnant bowel.23
Older studies in human adults documented enhanced
absorption of glucose per unit length of intestine following
resection.1,2 However, increased absorptive capacity observed
in these studies could be a result of localized hyperplasia, func-
tional adaptation, or both. Data regarding potential mecha-
nisms for functional postresection intestinal adaptation in
humans are sparse. In a study by Ziegler et al,19 expression of
PepT1, a transporter of dipeptides and tripeptides, was
increased in the colon, but not the small intestine, of patients
with SBS compared with controls.19 In contrast, a later pro-
spective case-control study failed to document a difference in
PepT1 mRNA or protein expression in the colon of 12 patients
with SBS compared with 14 healthy volunteers.16 However,
this later study was performed a mean of 9.8 ± 5.7 years after
resection, whereas in the earlier study, patients had been depen-
dent on PN for an average of 1.5–2.5 years. Thus, the rise in
colonic PepT1 expression may be an early event in the adapta-
tion process.
Tappenden 25S
Another mechanism for functional adaptation post resec-
tion is a deceleration of small bowel transit, which lengthens
the contact time between luminal nutrients and the absorptive
mucosa. In dogs, small intestinal transit time increased by 35%
and 29% following 50% and 75% resections, respectively,
between 4 weeks and 12 weeks after surgery (P < .05 for each
comparison).29 In patients who have undergone intestinal
resection, diarrhea decreases during the initial adaptive period
following surgery.30 Slowed gastrointestinal transit time, in
addition to other structural and functional changes, may con-
tribute to reduced diarrhea post resection. Indeed, compared
with healthy controls, patients with an ileal resection and
colon-in-continuity have higher plasma levels of peptide YY, a
hormone released by the distal intestine that acts to delay gas-
tric emptying and intestinal transit.31
Key Factors in Intestinal Adaptation
Multiple factors can influence the extent of intestinal adapta-
tion that occurs post resection, including anatomic features,
route of nutrition delivery, and hormones and growth factors.
Anatomic features.  The site of intestinal resection influences
the extent of subsequent adaptation, with the ileum displaying
greater adaptive potential than the jejunum.3,32,33 In humans,
proximal resections are associated with decreased diarrhea and
steatorrhea relative to distal resections.34 The increased adap-
tive capacity of the ileum relative to the jejunum may be attrib-
utable to the fact that under normal conditions, the distal
intestine is exposed to fewer luminal nutrients, which act as
potent stimuli for intestinal growth (see below). Indeed, in the
unresected intestine, villus height gradually decreases along
the proximal-distal axis.35 Furthermore, in transposition stud-
ies, an ileal segment that is moved proximally undergoes adap-
tation, as is evident by significant increases in mucosal growth
and glucose absorption, even in the absence of tissue loss.3,35 In
contrast, villus size decreases in jejunal segments that have
been transposed distally.35
In addition to the site of resection, the extent of resection
affects the adaptive outcome. In both humans and animals,
greater tissue loss is positively correlated with adaptation follow-
ing surgery.15,18,21 However, the ability of the gut to fully compen-
sate for tissue loss is limited. In a retrospective study of 268 adult
patients with SBS, remnant bowel length of <75 cm was signifi-
cantly associated with greater probability of permanent depen-
dence on PN in a multivariate analysis.36 The correlation between
remnant bowel length and anatomy with patient outcomes is dis-
cussed more fully in an accompanying article.37
Role of enteral nutrients. Enteral stimulation is required to
maintain the structure of the intestinal mucosa. The absence of
enteral nutrition induces mucosal atrophy and decreases diges-
tive enzyme and nutrient transporter activity in animals and
humans, even when adequate calories are provided via PN.38-40
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PN-induced mucosal atrophy reverses upon reintroduction of
enteral nutrition.38,39 In contrast, luminal nutrients enhance
postresection adaptation.41,42 Further, increased nutrient com-
plexity is associated with greater adaptation, likely because of
the greater digestive activity required for nutrient absorption.43
For example, rats and pigs fed a chow diet following intestinal
resection showed greater structural adaptation and digestive
enzyme activity than similar animals that received an elemen-
tal diet.42,44
Individual nutrients have been associated with intestinotro-
phic effects following resection. Fats, in particular, appear to
promote adaptation. Compared with standard chow, a high-fat
diet was associated with significantly increased bowel weight
and villus height at 14 days post resection in rats.45 In contrast,
a low-fat diet reduced markers of intestinal adaptation com-
pared with a higher fat diet containing the same number of
calories.46 Specific fats may vary in their ability to stimulate
adaptation. Long-chain triglycerides are superior to medium-
chain triglycerides in inducing hyperplasia of the intestinal epi-
thelium in the postresection setting.47,48 Among the long-chain
triglycerides, however, the relative benefit of saturated versus
polyunsaturated fatty acids has not been resolved. In a study by
Vanderhoof et al,49 resected rats receiving a diet high in men-
haden oil, a polyunsaturated fatty acid, showed greater
increases in mucosal weight and DNA and protein content
when compared with rats fed diets high in safflower oil, a less
highly unsaturated fatty acid, or beef tallow, a saturated fatty
acid. Similarly, diets high in docosahexaenoic acid and arachi-
donic acid, 2 polyunsaturated fatty acids, stimulated greater
increases in mucosal mass than diets high in safflower oil or
hydrogenated coconut oil.50 In contrast, a study by Keelan et
al51 demonstrated that resected rats receiving diets high in satu-
rated fatty acids had significantly increased jejunal glucose
transport compared with animals receiving diets high in poly-
unsaturated fatty acids. This study did not evaluate the micro-
architecture of the small bowel, but a more recent study by
Sukhotnik et al52 showed that villus height and crypt depth
increased significantly in resected rats receiving a diet high in
palmitic acid, a saturated fatty acid, compared with rats receiv-
ing a diet with low palmitic acid content. However, the results
of these animal studies may not directly translate to clinical
applications. Patients with SBS and colon-in-continuity are
generally not able to tolerate high-fat diets because of steator-
rhea and reduced nutrient absorption.53
Like long-chain triglycerides, short-chain fatty acids
(SCFAs) have been shown to enhance intestinal adaptation.
Most SCFAs in the human diet are derived from carbohydrates
that undergo bacterial fermentation in the colon.54 In unre-
sected rats maintained on PN, supplementation with SCFAs
significantly mitigated PN-induced declines in mucosal weight
and DNA and RNA content.55 Furthermore, SCFA supplemen-
tation of PN increases nutrient transporter expression and
nutrient absorption.56,57 Following experimental resection, PN
supplemented with SCFAs enhances intestinal adaptation in
26S Journal of Parenteral and Enteral Nutrition 38(Suppl 1)
mature rats and neonatal piglets.58,59 Although supporting data
are sparse, patients with SBS and colon-in-continuity may also
benefit from SCFAs. In a study of 6 patients with SBS, dietary
supplementation for 20 days with pectin, a starch that acts as a
substrate for bacterial SCFA production, increased colonic lev-
els of SCFAs and resulted in a nonsignificant trend for
increased fluid absorption.60
The amino acid glutamine, rather than glucose, is the pri-
mary energy source for enterocytes, a fact that has prompted
interest in exploring the role of glutamine in intestinal growth.61
In animal studies, the efficacy of glutamine depends on the
route of administration. When used as a supplement to PN, glu-
tamine counteracts PN-induced intestinal atrophy and improves
parameters of postresection adaptation.62-65 In contrast, gluta-
mine added to chow or an elemental diet has no effect on or
decreases measures of structural or functional intestinal adap-
tation.66-69 It is likely that any modest effects of glutamine are
masked by the greater trophic stimulation provided by luminal
nutrition in these studies. No studies assessing the effect of
glutamine alone on intestinal adaptation have been conducted
in humans with SBS, but glutamine in combination with
growth hormone (GH) has shown some efficacy (see below).
Hormones and growth factors. A variety of mediators have
been posited to act as intestinotrophic factors (Table 1). Two of
these, recombinant human GH (somatropin) and the glucagon-
like peptide 2 (GLP-2) analog teduglutide, are now approved
for clinical use in adult patients with SBS.
Growth hormone.  In the late 1970s, Taylor et al70 demon-
strated that hypophysectomy reduced measures of adaptation
in resected rats. GH, a pituitary hormone that induces systemic
proliferative and anabolic effects, was quickly identified as
a pituitary-derived factor with the potential to mediate intes-
tinal adaptation.71 However, subsequent preclinical studies
yielded mixed results. In some experiments, exogenous GH
significantly increased small bowel length, mucosal height,
jejunal villus height, and/or glutamine and leucine transport
in resected animals.72-74 In contrast, other experiments docu-
mented no effect of GH on postresection mucosal growth.74,75
Two small clinical studies have evaluated the effect of GH
alone on intestinal absorption in adult patients with SBS. The
first study included 10 patients and showed no improvement
in absorption of energy, nitrogen, or fluid following 8 weeks
of treatment with 0.024 mg/kg/d GH, although body weight
increased by a mean of 2.3 kg (P = .005).76 In contrast, the second
study evaluating 12 patients with SBS who received GH (0.05
mg/kg/d) for 3 weeks demonstrated significant enhancements
in absorption of energy (P < .002), nitrogen (P < .04), and car-
bohydrate (P < .04) as well as a mean increase in body weight
of 2.4 kg (P < .003).77 In a double-blind, placebo-controlled
study conducted in PN-dependent adult patients with SBS, 4
weeks of treatment with GH combined with an optimized diet
resulted in greater reductions in PN and/or intravenous (IV)
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volume requirements than diet modification alone. However, 3
months following treatment discontinuation, the GH-induced
PN/IV reductions were partially reversed and no longer signifi-
cantly different from baseline values.78
GH appears to be more effective as a part of a multimodal
therapy in combination with glutamine. Most, but not all, ani-
mal studies evaluating GH with glutamine document improve-
ments in measures of intestinal adaptation.65,79-81 In humans,
GH plus glutamine is associated with greater and longer lasting
reductions in PN/IV volume requirements and infusion fre-
quency than GH alone.78 Furthermore, in a subsequent study
by Guo et al,82 10 adult patients with SBS showed significant
increases in villus height, mucosal proliferation, and nitrogen
absorption following 4 weeks of treatment with GH, gluta-
mine, and enteral nutrition. A meta-analysis of 5 human studies
indicated that GH, with or without glutamine, improves energy
absorption in patients with SBS.83 However, a subanalysis of
data evaluating GH monotherapy showed no effect on energy
absorption. Furthermore, in most studies, any benefits of GH
were reversed upon treatment discontinuation. The authors of
the meta-analysis concluded that data regarding a potential
benefit of GH for patients with SBS are inconclusive.83
Somatropin, a recombinant form of human GH, was approved
for use as a 4-week treatment regimen in patients with SBS in
2003.84 However, cotreatment with glutamine is not a require-
ment for somatropin administration.
Further details regarding the pharmacological stimulation
of adaptation and the clinical effects of teduglutide and soma-
tropin are provided in a companion paper.85
GLP-2.  GLP-2 is synthesized by enteroendocrine L cells
of the distal small intestine and colon in response to nutrient
stimulation.86 In preclinical models, plasma GLP-2 concentra-
tions increase following resection, and postprandial GLP-2
levels correlate with the extent of intestinal adaptation.87,88 In
addition, PN supplemented with GLP-2 enhanced parameters
of postresection adaptation compared with PN alone, including
small bowel weight, small bowel surface area, villus height,
microvillus height, crypt cell proliferation, nutrient transporter
expression, and nutrient absorption.89,90 Even in the absence of
resection, exogenous GLP-2 augments small bowel weight and
length, villus height, crypt cell proliferation, and jejunal pro-
tein content.91 Expression of GLP-2 also increases in humans
following intestinal resection, particularly if the colon is in
continuity.92 Furthermore, in two phase 3 studies and a long-
term extension study, adult patients with SBS who were treated
with the GLP-2 analog teduglutide showed increases in villus
height and decreases in PN/IV fluid requirements.93-95 Tedu-
glutide is now approved for clinical use in adults with SBS
who are dependent on PN.96
Other factors.  A number of other proteins have shown intes-
tinotrophic effects in preclinical studies, including epidermal
growth factor (EGF),97-101 insulin-like growth factor-1,102-104
Tappenden 27S

Table 1.  Growth Factors Approved for Treatment of Short Bowel Syndrome in Adults.

Effects on Intestinal Adaptation: Effects on Intestinal Adaptation:

Agent Preclinical Studies Clinical Studies Stage of Clinical Development
GH and somatropin •• GH increased small bowel •• Somatropin reduced mean PN/ •• One phase 3, placebo-controlled
length, mucosal height, jejunal IV volume requirements and randomized clinical trial
villus height, and glutamine and infusion frequency in patients completed; no long-term
leucine transport in some, but not with SBS; PN/IV effects extension studies available.78
all, studies.72-75 partially reversed after treatment •• Somatropin is approved for clinical
discontinuation.78 use as a 4-week treatment regimen
in adult patients with SBS.84
GH with glutamine •• GH plus glutamine increased •• Somatropin plus glutamine •• One phase 3, placebo-controlled
mucosal thickness, villus height, reduced PN/IV volume randomized clinical trial
crypt depth, cell proliferation, requirements and infusion completed; no long-term
DNA content, and nutrient frequency in patients with SBS extension studies available.78
absorption in some, but not all, (superior results to somatropin •• Somatropin is approved for
studies.65,79,80 alone).78 clinical use as a 4-week treatment
•• GH plus glutamine increased regimen in adult patients with
villus height, mucosal SBS.84
proliferation, and nitrogen
absorption in patients with SBS.82
•• GH plus glutamine increased
energy absorption.83
•• Some patients with SBS
achieved independence from
PN/IV following treatment with
GH, glutamine, and optimized
diet.124,125
GLP-2 and teduglutide •• GLP-2 increased small bowel •• Teduglutide increased villus •• Two phase 3, placebo-controlled
weight, small bowel surface area, height in patients with SBS.93,126 randomized clinical trials and
villus height, microvillus height, •• Teduglutide increased plasma 2 long-term extension studies
crypt cell proliferation, nutrient citrulline levels in patients with completed.94,95,126,127
transporter expression, and SBS.95,126 •• Teduglutide is approved for
nutrient absorption in resected •• Teduglutide reduced mean PN/IV clinical use in adults with
rats.89,90 volume requirements in patients short bowel syndrome who are
•• GLP-2 increased small bowel with SBS and decreased number dependent on PN.96
weight and length, villus height, of infusion days for a majority of
crypt cell proliferation, and patients; effects on PN/IV were
jejunal protein content.91 partially reversed after treatment
discontinuation.94,95,126
•• A small number of patients
treated with teduglutide achieved
independence from PN/IV.94,126,127
GH, growth hormone; GLP-2, glucagon-like peptide 2; PN/IV, parenteral nutrition and/or intravenous fluid; SBS, short bowel syndrome.

and hepatocyte growth factor.105,106 Of these, only EGF has
been tested clinically, in a single pilot study of 5 pediatric
patients.107 Following 6 weeks of treatment with 100 mcg/kg/d
EGF, patients demonstrated significant improvements in car-
bohydrate absorption and the percentage of calories obtained
from enteral feeds (P < .05 for each measure, compared with
baseline). Additional details regarding these and other poten-
tial mediators of intestinal adaptation are discussed in a review
by McMellen et al.71
Assessing Intestinal Adaptation
Compared with the wealth of animal studies investigating
postresection intestinal adaptation, the number of studies in
humans is relatively small. Reasons for this discrepancy
include the small size of the SBS population and the invasive
nature of many of the procedures required to assess structural
and functional adaptation. For example, histological analysis
of the small intestine requires biopsy, which can be a particular
hardship for patients who have already often endured multiple
abdominal surgeries. Magnifying endoscopy may provide a
means of evaluating the microarchitecture of the intestine in
the absence of biopsy, but further research on this method in
the SBS population is needed.82,108 For assessing functional
adaptation in patients with SBS, 72-hour metabolic balance
studies, with fecal and urinary analyses at baseline and after an
intervention, are the gold standard.109,110 However, this method
is complex, costly, and neither patient- nor clinician-friendly.

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28S Journal of Parenteral and Enteral Nutrition 38(Suppl 1)
Plasma citrulline, a nonessential amino acid produced by
enterocytes, is considered to be a surrogate biomarker for
enterocyte mass.111 In several studies, plasma citrulline levels
were strongly correlated with remnant small bowel length.112-116
In patients with SBS, a postabsorptive plasma citrulline level
of <20 µmol/L (ie, half the normal level in adult controls) was
significantly associated with permanent PN dependence when
measured >2 years following the last abdominal surgery.112
However, whether citrulline levels accurately reflect the func-
tional absorptive capacity of the small intestine remains unre-
solved. Some studies have reported a correlation between
plasma citrulline levels and nutrient absorption, whereas others
have not.112,114-117 Additional studies are required to determine
whether plasma citrulline provides an accurate assessment of
postresection functional adaptation.
Other parameters have been used as surrogates for postre-
section adaptation in human studies, including weaning off
PN, fluid composite effect (ie, increase in urine production,
plus decrease in PN and/or IV fluids, plus reduction in oral
fluid intake),95 oral intake and stool weight/oral intake ratio,109
and absorption of inert sugars.118
Timing of Intestinal Adaptation in Human
Adults
Data related to the timing and duration of intestinal adaptation
in human adults are sparse. According to general consensus,
the majority of intestinal adaptation in adults occurs within the
first 2 years following resection.119 In a study of 50 patients
with extensive bowel resection, there was no improvement in
fecal weight or fecal excretion of fat, potassium, or nitrogen at
≥1 year (mean, 81 months) after surgery compared with
<6 months after surgery.30 In the oft-cited report by Messing
et al,22 95% of 64 patients with transient intestinal failure
obtained enteral autonomy within the first 2 years post resec-
tion. In contrast, other studies suggest that significant adapta-
tion can occur beyond the 2-year mark in adults. Gouttebel et
al120 evaluated calcium absorption in 30 patients with SBS
between 1.5 and 120 months after intestinal resection. Patients
who were tested more than 2 years post surgery (mean,
52 months) absorbed significantly more calcium than patients
who were evaluated within 24 months of resection (mean,
9 months).120 Furthermore, in a recent study that followed
268 patients with SBS at a single institution for a median of
4 years (range, 0.3–24 years), 26% were weaned off PN more
than 2 years after the restoration of digestive continuity.36
Similarly, among 72 patients with SBS who achieved enteral
autonomy during a long-term follow-up study, 47% had been
PN dependent for 2–5 years and 18% had been PN dependent
for >5 years.121 Trophic stimulation may enhance this latent
adaptive response. In a 52-week study of patients with SBS, 3
of 25 patients receiving 0.05 mg/kg/d teduglutide were weaned
off PN after 2–25 years of PN therapy.94 Taken together, these
data suggest that although most intestinal adaptation in adults
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occurs early in the postoperative course, continued improve-
ments in intestinal absorptive capacity are possible and do
occur for many years following resection. The timing of intes-
tinal adaptation following resection may differ in pediatric
patients, who experience growth of their remnant intestines as
they age122,123; however, a full exploration of the topic is
beyond the scope of this paper.
Conclusions
A wealth of preclinical data has highlighted many of the mech-
anisms responsible for adaptation in nonhuman animals,
including mucosal hyperplasia, angiogenesis, accelerated
enterocyte differentiation, increased expression and activity of
nutrient transporters, and slowed intestinal transit. However,
whether some or all of those processes contribute to intestinal
adaptation in humans as well remains to be fully resolved.
Newer, less invasive techniques for assessing intestinal micro-
architecture and improved methods of evaluating intestinal
absorptive function may provide additional insights into the
natural history of postresection adaptation in human patients.
Many, but not all, patients with SBS achieve enteral auton-
omy in the postresection period. Maximizing adaptation in the
intestinal remnant by application of newer intestinotrophic
therapies may enhance outcomes for these patients. Recent
studies suggest that some patients can achieve PN indepen-
dence even many years following the initial resection. These
data argue against the long-held dogmatic assertion that adap-
tation occurs only in the first 12–24 months following resec-
tion and provide additional hope for patients with SBS.
Acknowledgments
Medical writing assistance was provided by Heather Heerssen,
PhD, of Complete Healthcare Communications, Inc (Chadds Ford,
Pennsylvania) under the direction of the author. K.A.T. is respon-
sible for the content of the manuscript and had final approval of all
revisions.
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