AUGUST 2018 SUPPLEMENT

SPECIAL ISSUE

The Microbiome and

Integrative Medicine

The Gut-Skin Axis Lessons from Studying

Breast Microbiota 
Synbiotic Supplementation
for PCOS Ketogenic Diet Changes
Microbiome to Fight Seizures
Fiber Enhances Microbiome
to Control Glucose
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Copyright © 2018 by the Natural Medicine Journal. All rights reserved.

SPECIAL ISSUE
THE MICROBIOME AND INTEGRATIVE MEDICINE
AUGUST 2018 VOL. 10, NO. 81 (SUPPL)

Contents

ABSTRACTS & COMMENTARY

   6 Synbiotic Supplementation for Polycystic Ovary Syndrome

  10 Fiber Feeds Bacteria to Control Type 2 Diabetes Mellitus

  14 Breast Tissue Microbiota

  18 Ketogenic Diet Improves Seizures

PEER-REVIEWED ARTICLE

  22 The Gut-Skin Axis and Mechanisms for Communication

EXPERT INTERVIEW
  27 The Gut-Brain Axis
An interview with Steven Sandberg-Lewis, ND, DHANP

SPONSORED PODCAST
 28 A Deeper Exploration of Probiotics and the Gut Microbiome with Donald Brown, ND
Sponsored by Allergy Research Group

http://eepurl.com/d6zXb http://www.naturalmedicinejournal.com/blog
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Contributors

MEGAN CHMELIK is a third-year JACOB SCHOR, ND, FABNO,

naturopathic medical student at is a graduate of National College
National University of Natural Medi- of Naturopathic Medicine, Port-
cine in Portland, Oregon. Before land, Oregon, and now practices
moving to Portland, she worked for in Denver, Colorado. He served as
Rena Bloom, ND, and Jacob Schor, president to the Colorado Associa-
Megan Chmelik
ND, FABNO, at the Denver Naturo- Jacob Schor,
tion of Naturopathic Physicians and
pathic Clinic. As part of a tradition of ND, FABNO is on the board of directors
mentoring receptionists and preparing them for natu- of the Oncology Association of Natu-
ropathic school, Schor encouraged Chmelik to learn ropathic Physicians. He is recognized as a fellow by
how to use PubMed and write review articles. Now the American Board of Naturopathic Oncology. He
years later, it is clear that this passion of his has been serves on the editorial board for the International
passed down as she continues to write for NMJ during Journal of Naturopathic Medicine, Naturopathic
her spare time. Doctor News and Review (NDNR), and Integrative
Medicine: A Clinician’s Journal. In 2008, he was
MARK DAVIS, ND, is the medical awarded the Vis Award by the American Associa-
director of Good Life Medicine tion of Naturopathic Physicians. His writing appears
Center, Portland, Oregon, and his regularly in NDNR, the Townsend Letter, and Natural
naturopathic practice, Bright Medi- Medicine Journal, where he is the Abstracts &
cine Clinic, focuses on gastro­ Commentary editor.
enterological health. Davis is one
Mark Davis, ND of a handful of physicians in North RAJA SIVAMANI, MD, is a
America with clinical expertise in board-certified dermatologist, Ayur­
fecal microbiota transplantation. Davis is on the vedic practitioner, and serves as the
board of directors of the Fecal Transplant Founda- lead Scientific Advisor and Editor
tion, Carmel, Indiana, and chairs the Fecal Microbiota for Dermveda and LearnSkin. He is
Transplant Committee for the C diff Foundation, New currently an associate professor of
Port Richey, Florida. He received his naturopathic Raja Sivamani, clinical dermatology at the Univer-
degree with honors in research from the National MD, MS, AP sity of California, Davis and serves
College of Natural Medicine, Portland. He cohosts the as the director of clinical research and the Clinical
popular podcast The Naturocast. Trials Unit with a focus on engineering, nutrition,
and microbiome focused clinical studies. He is also
TINA KACZOR, ND, FABNO, is an adjunct assistant professor in the Department of
editor-in-chief of Natural Medicine Biological Sciences at the California State University,
Journal  and a naturopathic physi- Sacramento. He engages in clinical practice as well
cian, board certified in naturopathic as both clinical and translational research that inte-
oncology. She received her natu- grates bioengineering, nutrition, cosmetics, and skin
ropathic doctorate from National biology. With training in both allopathic and ayurvedic
Tina Kaczor, ND, University of Natural Medicine and medicine, he takes an integrative approach to his
FABNO completed her residency in natu- patients and in his research, with a focus on the gut
ropathic oncology at Cancer Treatment Centers of and skin microbiome and lipidome. He has published
America, Tulsa, Oklahoma. Kaczor received under- over 100 peer-reviewed research manuscripts, 10
graduate degrees from the State University of New textbook chapters, and a textbook titled Cosmeceu-
York at Buffalo. She is the past president and trea- ticals and Active Cosmetics, 3rd Edition. He has a
surer of the Oncology Association of Naturopathic passion for expanding the evidence and boundaries
Physicians and secretary of the American Board of of integrative medicine for skin care.
Naturopathic Oncology. She has been published
in several peer-reviewed journals. Kaczor is based
in Portland.

4 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
Copyright © 2017 by the Natural Medicine Journal. All rights reserved.

EDITOR IN CHIEF MESSAGE FROM THE PUBLISHER

Tina Kaczor, ND, FABNO
ABSTRACTS &
­COMMENTARY EDITOR
Practical, Clinical Applications of the
Jacob Schor, ND, FABNO Human Microbiome Research
PUBLISHER
Karolyn A. Gazella The complex ecosystem of bacteria in and on the human body provides a vast play-
ground for researchers and clinicians alike. The practical applications of informa-
ASSOCIATE PUBLISHER tion gleaned from the human microbiome is not only fascinating, it’s rich with ways
Kathi Magee to increase treatment efficacy and enhance patient outcomes. And that’s what this
special issue of the Natural Medicine Journal is all about.
VP, CONTENT &
COMMUNICATIONS This subject is huge so there is only so much we can cover in one special issue. We
Deirdre Shevlin Bell hope you agree that this issue provides an array of microbiome information that you
can apply to your clinical practice. Our peer review paper on the skin/gut connec-
DESIGN tion is authored by one of our newest editorial board members, Raja Sivamani, MD,
a respected and widely published integrative dermatologist. We have two podcast
Karen Sperry
interviews featuring naturopathic experts: Donald Brown, ND, talks about probiotics
PUBLISHED BY and the microbiome and Steven Sandberg-Lewis, ND, discusses the gut-brain axis.
Our Abstracts and Commentary are diverse and feature a discussion about the keto-
IMPACT Health Media, Inc.
genic diet, synbiotic supplementation in women with PCOS, and type 2 diabetes.
Boulder, Colorado
Our Editor-in-Chief, Tina Kaczor, ND, FABNO, also reviews a fascinating study on the
Natural Medicine Journal (ISSN
microbiome differences in malignant versus non-malignant breast tissue.
2157-6769) is published 14
times per year by IMPACT
Health Media, Inc. Copyright Research into the human microbiome in health and illness is moving at a brisk pace.
© 2018 by IMPACT Health Staying on top of this research will become increasingly important to clinicians. We
Media, Inc. All rights reserved. hope we can help contribute to that knowledge base by doing special issues like
No part of this publication these. We appreciate the contributions of our authors, editors, and reviewers who
may be reproduced in whole contribute their time and expertise to help you help your patients.
or in part without written
permission from the publisher.
The statements and opinions in As always, if you like this issue, please share it with your colleagues so they can receive
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are the responsibility of the
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©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)  5
ABSTRACT & COMMENTARY
Synbiotic Supplementation for
Polycystic Ovary Syndrome
A randomized controlled trial
REFERENCE
Samimi M, Dadkhah A, Haddad
Kashani H, et al. The effects of synbi-
otic supplementation on metabolic
status in women with polycystic ovary
syndrome: a randomized double-
blind clinical trial [published online
ahead of print March 12, 2018].
Probiotics Antimicrob Proteins.  12 to assess markers of glycemic
DESIGN
A 12-week randomized double-blind
placebo-controlled clinical trial.
OBJECTIVE
To determine the effect of synbi-
otic supplementation on markers of
glycemic control and cardiometa-
bolic risk in women with polycystic
ovary syndrome (PCOS).
PARTICIPANTS
Sixty women, aged 18 to 40 years,
with PCOS diagnosis based on
the Rotterdam criteria; women who
reported use of probiotic or synbi-
otic supplementation within 3 months
of the trial were excluded. Further
exclusion criteria included smoking,
pregnancy, and hyperandrogenism
and/or anovulation due to other
causes (eg, Cushing syndrome,
androgen-secreting tumors, hyper-
prolactinemia, thyroid dysfunction).
INTERVENTION
Participants in the experimental
group (n=30) received capsules
containing Lactobacillus acidophilus
strain T16, Lactobacillus casei strain
T2, and Bifidobacterium bifidum
strain T1 (2 x 109 CFU/g of each)
plus 800 mg inulin. The control group
(n=30) received capsules containing
inulin only. Dosing was 1 capsule
taken orally once a day for 12 weeks.
Compliance was determined upon
return of the medication container at
the end of the trial.
6 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
All participants were advised to main-
tain their routine dietary and lifestyle
habits throughout the study. A 3-day
food record and 3 physical activity
records were completed during
weeks 0, 3, 6, 9, and 12.
STUDY PARAMETERS ASSESSED
Labs were obtained at weeks 0 and
control, including fasting plasma
glucose (FPG), serum insulin,
homeostatic model assessment for
insulin resistance (HOMA-IR), and
the quantitative insulin sensitivity
check index (QUICKI), and measures
of cardiometabolic risk, including
serum triglycerides, total cholesterol,
low-density lipoprotein cholesterol
(LDL-C), high-density lipoprotein
cholesterol (HDL-C), very low-density
lipoprotein cholesterol (VLDL-C), and
atherogenic index of plasma (AIP).
PRIMARY OUTCOME MEASURES
Change in markers of glycemic control
(FPG, serum insulin, HOMA-IR, and
QUICKI) from baseline following 12
weeks of synbiotic supplementation.
KEY FINDINGS
Of the 60 women enrolled, 2 from
each group withdrew for unspec-
ified reasons. In keeping with the
­intention-to-treat principle, all partic-
ipants were included in the final
­analysis.
Significant improvements in serum
insulin levels (P=0.002), HOMA-IR
(P=0.002), QUICKI (P<0.001),
triglycerides (P=0.003), VLDL-C
(P=0.003), and AIP (P=0.03) were
observed in the experimental group
only. Neither group experienced
significant changes in mean weight
or BMI. When controlled for age and
baseline BMI, FPG levels became
significant (P=0.04) and AIP nonsig-
nificant (P=0.06).
Megan Chmelik
PRACTICE IMPLICATIONS
Polycystic ovary syndrome has become an
increasingly prevalent endocrine disorder,
affecting up to 18% of reproductive-aged
women.1 Diagnosis, according to the
Rotterdam Criteria, requires that 2 of the
following criteria are met: chronic oligoovu-
lation/anovulation; hyperandrogenism; and/
or polycystic ovarian morphology. However,
symptom presentation and severity are highly
variable.2 Dysglycemia and dyslipidemia are
common findings among many, though not
all, women with PCOS. Because PCOS is asso-
ciated with an increased risk of type 2 diabetes
and cardiovascular disease, primary treatment
goals include improved insulin sensitivity and
normalization of lipid levels.3
Metformin, a first-line conventional inter-
vention for type 2 diabetes and PCOS, is
primarily used to regulate serum glucose and
insulin levels. As a secondary effect, it may aid
in weight loss by lowering serum lipid levels
and/or improving PCOS symptomology.4
Metformin-induced alterations in gut micro-
biota have been shown to contribute to its
antidiabetic effects.5 A correlation between
gut dysbiosis and diabetes has been docu-
mented in several papers.6,7 The same has been
reported in PCOS patients: Atypical findings
of lower diversity and altered phylogenetic
composition have been observed in women
with PCOS when compared to controls.8,9
Two studies evaluating the effect of probiotics
on hormonal and metabolic markers in PCOS
have been conducted. The first, published by
Shoaei et al in 2015, reported improvements,
though mostly nonsignificant, in markers of
glycemic control after 8 weeks of probiotic
supplementation.10 A randomized controlled
ABSTRACT & COMMENTARY
trial published in January 2018 revealed beneficial effects of
supplementation on total testosterone, sex hormone–binding
globulin (SHBG), modified Ferriman-Gallwey (mFG)
scores, high-sensitivity C-reactive protein (hs-CRP), total
antioxidant capacity (TAC), and malondialdehyde (MDA)
after a 12-week intervention.11
Use of synbiotic supplementation to modulate the micro-
biome has been of recent interest among researchers. Pairing
probiotics with prebiotics to create synbiotics is thought to
increase survivability of probiotics as they pass through the
upper intestinal tract, allowing for more effective delivery
into the colon.12 Since 2004, numerous papers have been
published with the hope to elucidate the role that synbiotics
have on conditions such as metabolic syndrome,13 type 2
diabetes,14,15 gestational diabetes,16 rheumatoid arthritis,17
and nonalcoholic fatty liver disease.18
A total of 3 papers on synbiotics and PCOS have been
published, all within this year. The first was a randomized
controlled trial aiming to determine the effect of synbiotics
on metabolic parameters and apelin-36, a potential marker
of insulin sensitivity.19 After 12 weeks of intervention, there
was a marked reduction in apelin levels, though no signifi-
cant improvements in markers of dysglycemia (FBG, 2-hour
fasting plasma glucose, hemoglobin A1c [HbA1c], HOMA-IR,
QUICKI) or C-reactive protein (CRP) were observed.20 There
are inconsistencies in the literature about whether PCOS
patients present with low or high apelin levels compared to
controls, so the implications of these findings are unclear.21
The present study revealed significant beneficial changes to
markers of glycemic control, changes that could possibly
reduce overall risk of type 2 diabetes. Improvements were
seen in triglycerides, AIP, and VLDL-C; however, other lipid
parameters were not significantly impacted. Given that the
atherosclerotic cardiovascular disease (ASCVD) risk esti-
mator takes into consideration total cholesterol, LDL-C,
and HDL-C, it is unlikely that a direct reduction in cardio-
vascular risk would be achieved from synbiotic supplemen-
tation alone.
©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)  7
“
Atypical findings of
lower diversity and altered phylogenetic
composition have been observed in women
with PCOS when compared
”
to controls.
Several of this study’s investigators went on to conduct a
second study looking at the effect of synbiotic supplementa-
tion on hormonal status and biomarkers of inflammation and
oxidative stress. The study design was nearly identical to their
first. Following 12 weeks of supplementation, levels of SHBG
and nitric oxide (NO) increased from baseline, while mFG
scores, hs-CRP, free androgen index (FAI), serum insulin,
and HOMA-IR fell significantly. There were no significant
changes in total testosterone, dehydroepiandrosterone sulfate
(DHEA-S), total antioxidant capacity (TAC), glutathione
(GSH), or malondialdehyde (MDA).22
It is evident that dysbiosis is a common finding in PCOS, and
that interventions that alter gut microbiota composition have
the potential to positively impact metabolic, inflammatory,
and/or hormonal markers 8,9 Further research to determine
the effects of different probiotic strains and dosing would be
helpful. Studies comparing probiotics to synbiotics would
also provide valuable information. Because the studies thus
far have involved women with elevated BMIs, it would be
beneficial to conduct a study on women with lean PCOS. In
the meantime, addressing gut health, with synbiotic supple-
mentation or other microbiota-modulating therapy, appears
to be a worthwhile consideration for our patients with PCOS.
While probiotics and supplements alike are generally consid-
ered safe, they may not be safe for all individuals. According
to a 2014 systematic review on probiotic safety, populations at
risk for adverse effects include critically ill patients in intensive
ABSTRACT & COMMENTARY
care units, critically ill infants, postoperative and hospital-
ized patients, and those with immunodeficiency disorders.
Probiotics are not necessarily contraindicated in these patients;
however, the risk-benefit ratio should be considered.23 In all
cases, probiotic/synbiotic quality should be ensured.
A paper written by Lise Alschuler, ND, FABNO, in 2011
outlines quality standards that may be helpful to consider
when selecting a probiotic supplement.
REFERENCES
1 March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prev-
alence of polycystic ovary syndrome in a community sample assessed under
contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-551.
2 Moran LJ, Norman RJ, Teede HJ. Metabolic risk in PCOS: phenotype and adiposity
impact. Trends Endocrinol Metab. 2015;26(3):136-143.
3 Bajuk Studen K, Pfeifer M. Cardiometabolic risk in polycystic ovary syndrome
[published online ahead of print May 29, 2018]. Endocr Connect.  a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2017;117(8):1095-
4 Gong L, Goswami S, Giacomini KM, et al. Metformin pathways: pharmacokinetics
and pharmacodynamics. Pharmacogenet Genomics. 2012;22(11):820-827.
5 Rodriguez J, Hiel S, Delzenne NM. Metformin: old friend, new ways of action-impli-
cation of the gut microbiome? Curr Opin Clin Nutr Metab Care. 2018;21(4):294-301.
6 Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women
with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99-
103.
7 Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in
type 2 diabetes. Nature. 2012;490(7418):55-60.
8 Lindheim L, Bashir M, J Münzker, et al. Alterations in gut microbiome composi-
tion and barrier function are associated with reproductive and metabolic defects in
women with polycystic ovary syndrome (PCOS): a pilot study. PLoS One. 2017;12(1).
9 Torres PJ, Siakowska M, Banaszewska B, et al. Gut microbial diversity in women
with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endo-
crinol Metab. 2018;103(4):1502-1511.
10 Shoaei T, Heidari-Beni M, Tehrani HG, et al. Effects of probiotic supplementation
on pancreatic β-cell function and C-reactive protein in women with polycystic ovary
syndrome: a randomized double-blind placebo-controlled clinical trial. Int J Prev
Med. 2015;6:27.
8 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
11 Karamali M, Eghbalpour S, Rajabi S, et al. Effects of probiotic supplementation on
hormonal profiles, biomarkers of inflammation and oxidative stress in women with
polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.
Arch Iran Med. 2018;21(1):1-7.
12 Pandey KR, Naik SR, Vakil BV. Probiotics, prebiotics and synbiotics- a review.
J Food Sci Technol. 2015;52(12):7577-7587.
13 Rabiei S, Hedayati M, Rashidkhani B, et al. The effects of synbiotic supplemen-
tation on body mass index, metabolic and inflammatory biomarkers, and appe-
tite in patients with metabolic syndrome: a triple-blind randomized controlled trial
[published online ahead of print April 19, 2018]. J Diet Suppl. 
14 Akram Kooshki A, Tofighiyan T, Rakhshani MH. Effects of synbiotics on inflammatory
markers in patients with type 2 diabetes mellitus. Glob J Health Sci. 2015;7(7 Spec
No):1-5.
15 Tajabadi-Ebrahimi M, Sharifi N, Farrokhian A, et al. A randomized controlled clinical
trial investigating the effect of synbiotic administration on markers of insulin metab-
olism and lipid profiles in overweight type 2 diabetic patients with coronary heart
disease. Exp Clin Endocrinol Diabetes. 2017;125(1):21-27.
16 Nabhani Z, Hezaveh SJG, Razmpoosh E, Asghari-Jafarabadi M, Gargari BP. The
effects of synbiotic supplementation on insulin resistance/sensitivity, lipid profile
and total antioxidant capacity in women with gestational diabetes mellitus: a
randomized double blind placebo controlled clinical trial. Diabetes Res Clin Pract.
2018;138:149-157.
17 Zamani B, Farshbaf S, Golkar HR, et al. Synbiotic supplementation and
the effects on clinical and metabolic responses in patients with rheumatoid arthritis:
1102.
18 Mofidi F, Poustchi H, Yari Z, et al. Synbiotic supplementation in lean patients with
non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-con-
trolled, clinical trial. Br J Nutr. 2017;117(5):662-668.
19 Saedii AAF, Kamal AM, Naeem EA, et al. Apelin-36 and copeptin levels in polycystic
ovary syndrome. J Infec Dis Treat. 2017;3:1.
20 Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic
parameters and apelin in women with polycystic ovary syndrome: a randomised
double-blind placebo-controlled trial. Br J Nutr. 2018 Feb;119(4):398-406.
21 Polak K, Czyzyk A, Simoncini T, et al. New markers of insulin resistance in polycystic
ovary syndrome. J Endocrinol Invest. 2017;40(1):1-8.
22 Nasri K, Jamilian M, Rahmani E, et al. The effects of synbiotic supplementation on
hormonal status, biomarkers of inflammation and oxidative stress in subjects with
polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.
BMC Endocr Disord. 2018;18(1):21.
23 Didari T, Solki S, Mozaffari S, et al. A systematic review of the safety of probiotics.
Expert Opin Drug Saf. 2014;13(2):227-239.
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ABSTRACT & COMMENTARY
Fiber Feeds Bacteria to Control
Type 2 Diabetes Mellitus
Investigators pit high-fiber diet against standard diet for glycemic control
REFERENCE
Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively
promoted by dietary fibers alleviate type 2 diabetes. Science.
2018;359(6380):1151-1156.
OBJECTIVE
To determine effects of a high-fiber diet on the gut micro-
biome and glucose regulation in individuals with established
type 2 diabetes.
DESIGN
Randomized, open-label, parallel-group clinical trial
PARTICIPANTS
Forty-three patients with clinically diagnosed type 2 diabetes
mellitus were randomized to either an intervention group
(n=27) or the control group (n=16).
STUDY MEDICATION AND DOSAGE
The experimental group received a high-fiber diet of fresh
vegetables, fruits, and nuts, supplemented with a gruel
(which included whole grains, beans, peanuts, lotus seed,
and yam), bitter melon, and prebiotics. The control group
consumed an isocaloric diet based on Chinese Diabetes
Society guidelines.
Both groups took the antidiabetic agent acarbose (an
amylase inhibitor) and discontinued any previously used
glycemic control medications. Acarbose transforms starch
into fiber by reducing digestion and making it available as
a fermentable carbohydrate to bacteria in the colon. The
experimental group had a much higher intake of dietary
fiber but daily energy and macronutrient intake was similar
between groups.
To determine that interactions between the gut microbiota
and the fiber were responsible for any observed changes in
function, the gut microbiota from before and after the inter-
ventions were transplanted into germ-free mice. These mice
ended up with gut biomes that more resembled the trans-
planted biome of the donor than they resembled each other.
OUTCOME MEASURES
Hemoglobin A1c (HbA1c) was the primary outcome measure.
Additional outcomes included proportion of participants
who achieved glycemic control, fecal short chain fatty acid
(SCFA) levels, postprandial glucose, fasting blood glucose,
lipid profiles, and other standard metabolic markers.
10 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
Mark Davis, ND,
and Jacob Schor,
ND, FABNO
KEY FINDINGS
Increasing fermentable fiber by blocking carbohydrate digestion
via the amylase inhibitor acarbose improved markers of type
2 diabetes in both groups, but the high-fiber group did signifi-
cantly better. Hemoglobin A1c decreased in both groups but
more so in the high-fiber group. Reduction in HbA1c was greater
in the high-fiber group from 4 weeks onward. A greater portion
of patients in the high-fiber group reached adequate glycemic
control (HbA1c<7%) compared to the standard-diet group (89%
vs 50%). The high-fiber group lost more weight and had better
lipid profiles. Improvements came faster and were greater
in patients who consumed a high-fiber diet in addition to the
enzyme inhibitor.
Germ-free mice transplanted with post-intervention microbiota
derived from either patient group did better, showing better meta-
bolic health parameters than mice transplanted with pre-inter-
vention microbiota. Mice transplanted with microbiota obtained
post-intervention from the high-fiber group did the best, having
the lowest fasting and postprandial blood glucose levels of all
mice, mirroring the results in the human patient group.
Metagenomic sequencing was performed on 172 fecal samples
collected at 4 time points (days 0, 28, 56, and 84), which led
to a catalog of 4,893,833 nonredundant microbial genes. Both
patient groups had a reduction in gene richness (the number
of genes identified per sample) from day 0 to day 28, along
with significant clinical improvements, with no further changes
afterward.
These last data challenge the current notion that greater overall
diversity implies better health. However, gene richness tended
to be higher in the high-fiber group than in the normal diet group
after day 28, and this trend was associated with better clinical
outcomes in the intervention group.
The high-fiber diet favored the growth of bacteria that produce
SCFAs, especially bacteria that produce butyric acid. This increase
in acid production significantly lowered gut pH in the high-fiber
group. Fifteen bacterial strains were significantly promoted by
the high-fiber diet, and 47 strains were significantly reduced. This
response was clearly strain-specific; for example, of the 6 strains
of Faecalibacterium prausnitzii identified, only 1 strain was signifi-
cantly promoted by the high-fiber diet. The 15 strains that were
promoted were all significantly associated with increased SCFA
production, which was inversely correlated with HbA1c.
ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS

“
This paper further demonstrates that human intestinal micro-
biota affect blood sugar control. This study suggests that we
can improve glycemic control by shifting bacterial populations
We already know that
in the intestinal microbiome. We already know that high-fiber high-fiber diets help control diabetes,
diets help control diabetes, but we have generally thought this
benefit was because higher fiber would lower the glycemic but we have generally thought this benefit
index of carbohydrates.1 We have repeated this idea for years
even as we began to appreciate that there is little difference in
was because higher fiber would
glycemic index between whole grain and white flour products. lower the glycemic index

”
We can now imagine that the difference in action was that
the whole-grain versions provided more fermentable carbohy- of carbohydrates.
drates and shifted gut microbiota.

Acarbose is available in the United States and Canada by

prescription only but rarely used. In China it is the most pomegranate,13 a range of anthocyanin-containing berries
common prescription employed for treating early type 2 such as cherries,14 and, in general, polyphenols.15
diabetes, the same indication used in the United States for
This study provides a mechanistic explanation for why a diet
which we might prescribe metformin.2 A 2014 Chinese study
high in vegetables, which provide fiber, and fruits, which may
that compared acarbose against metformin showed that both
have anti-amylase action, is useful in treating type 2 diabetes:
agents decreased HbA1c levels to similar degrees and were
the gut biome shifts to increase SCFA production. Diabetics
equally effective in controlling the disease.3 Metformin also are often cautioned against eating fruit, but this advice may
changes the gut microbiota,4 increasing levels of Akkermansia.5 actually be counterproductive; in fact, sugar-sweetened fruit
Diabetes is now considered a disease of the gut microbiota.6,7 juices are significantly associated with the risk of developing
The botanical extract berberine, which we have often used type 2 diabetes, but whole fruits16 and 100% fruit juices17
clinically to replace metformin, also shifts the gut biome in a are not. It may eventually prove useful to know the relative
similar manner as metformin.8 amylase inhibitory action and prebiotic content of various
types of fruit. A number of classic antidiabetes botanicals are
We should note that pharmaceutical companies are experi-
also amylase inhibitors, including Ocimum basilicum (basil)18
menting with combining metformin and acarbose together in
and mango.19
a single tablet.9
In 2013, Dr Schor reviewed a study in this journal20 that
The present study suggests a benefit from inhibiting amylase
suggested various berry jams lower glycemic impact of the
enzyme action. In this study acarbose was used to block
bread they are eaten with. In the light of this present study,
starch digestion. A number of fruits have a similar action.
that earlier information makes better sense. The berry concen-
If we were willing to anthropomorphize fruits, we could see trates may have acted as anti-amylose agents, similar to acar-
how they would prefer any of their consumers to get diar- bose, while providing fiber content. (Might we suggest toast,
rhea. Such digestive upset increases the odds of the fruit seeds’ jam, and berberine as a possible breakfast for diabetics?)
dispersal in the vicinity and provides an evolutionary advan-
tage. Thus many fruits contain chemicals that act as amylase This study’s results suggest that it may someday be possible to
inhibitors, including baobab fruit,10 persimmon,11 mango,12 create a probiotic supplement that, taken in combination with

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)  11
ABSTRACT & COMMENTARY
a high-fiber diet, may have a significant effect on improving
glycemic control. Our only evidence using direct microbial
transplantation in humans is a study from 2012 that used
fecal microbial transplant (FMT) from healthy, lean donors
for men with metabolic syndrome. The men experienced
temporary increases in peripheral insulin sensitivity, with
a trend toward improved hepatic insulin resistance.21 These
changes were related to fecal microbial diversity and increases
in SCFAs.22
These data should also prompt us to rethink resistant starches
and how they affect diabetes. In the past we thought their
benefit was secondary to low glycemic index. Instead their
benefit may be in reaching the colon and increasing SCFA
production.
REFERENCES
1 Anderson JW, Randles KM, Kendall CW, Jenkins DJ. Carbohydrate and fiber recom-
mendations for individuals with diabetes: a quantitative assessment and meta-anal-
ysis of the evidence. J Am Coll Nutr. 2004;23(1):5-17.
2 He K, Shi JC, Mao XM. Safety and efficacy of acarbose in the treatment of diabetes
in Chinese patients. Ther Clin Risk Manag. 2014;10:505-511.
3 Yang W, Liu J, Shan Z, et al. Acarbose compared with metformin as initial therapy
in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority
randomised trial. Lancet Diabetes Endocrinol. 2014;2(1):46-55.
4 Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota.
Appl Environ Microbiol. 2014;80(19):5935-5943.
5 Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population
induced by metformin treatment improves glucose homeostasis in diet-induced
obese mice. Gut. 2014;63(5):727-735.
6 Harsch IA, Konturek PC. The role of gut microbiota in obesity and type 2 and type 1
diabetes mellitus: new insights into “old” diseases. Med Sci (Basel). 2018;6(2). pii:
E32.
7 Rodriguez J, Hiel S, Delzenne NM. Metformin: old friend, new ways of action-impli-
cation of the gut microbiome? Curr Opin Clin Nutr Metab Care. 2018;21(4):294-301.
12 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
8 Zhang X, Zhao Y, Xu J, et al. Modulation of gut microbiota by berberine and
metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep.
2015;5:14405.
9 Tiwari R, Gupta A, Joshi M, Tiwari G. Bilayer tablet formulation of metformin HCl
and acarbose: a novel approach to control diabetes. PDA J Pharm Sci Technol.
2014;68(2):138-152.
10 Coe SA, Clegg M, Armengol M, Ryan L. The polyphenol-rich baobab fruit (Adan-
sonia digitata L.) reduces starch digestion and glycemic response in humans. Nutr
Res. 2013;33(11):888-896.
11 Li K, Yao F, Du J, Deng X, Li C. Persimmon tannin decreased the glycemic response
through decreasing the digestibility of starch and inhibiting α-amylase, α-glucosi-
dase, and intestinal glucose uptake. J Agric Food Chem. 2018;66(7):1629-1637.
12 Pluschke AM, Williams BA, Zhang D, Gidley MJ. Dietary pectin and mango pulp
effects on small intestinal enzyme activity levels and macronutrient digestion in
grower pigs. Food Funct. 2018;9(2):991-999.
13 Kerimi A, Nyambe-Silavwe, Gauer JS, Tomás-Barberán FA, Williamson G. Pome-
granate juice, but not an extract, confers a lower glycemic response on a high-gly-
cemic index food: randomized, crossover, controlled trials in healthy subjects. Am J
Clin Nutr. 2017;106(6):1384-1393.
14 Homoki JR, Nemes A, Fazekas E, et al. Anthocyanin composition, antioxidant effi-
ciency, and α-amylase inhibitor activity of different Hungarian sour cherry varieties
(Prunus cerasus L.). Food Chem. 2016;194:222-229.
15 Xiao J, Ni X, Kai G, Chen X. A review on structure-activity relationship of dietary
polyphenols inhibiting α-amylase. Crit Rev Food Sci Nutr. 2013;53(5):497-506.
16 Li M, Fan Y, Zhang X, Hou W, Tang Z. Fruit and vegetable intake and risk of type
2 diabetes mellitus: meta-analysis of prospective cohort studies. BMJ Open.
2014;4(11):e005497.
17 Xi B, Li S, Liu Z, et al. Intake of fruit juice and incidence of type 2 diabetes: a system-
atic review and meta-analysis. PLoS One. 2014;9(3):e93471.
18 Ezeani C, Ezenyi I, Okoye T, Okoli C. Ocimum basilicum extract exhibits antidiabetic
effects via inhibition of hepatic glucose mobilization and carbohydrate metabolizing
enzymes. J Intercult Ethnopharmacol. 2017;6(1):22-28.
19 Gondi M, Prasada Rao UJ. Ethanol extract of mango (Mangifera indica L.) peel
inhibits α-amylase and α-glucosidase activities, and ameliorates diabetes related
biochemical parameters in streptozotocin (STZ)-induced diabetic rats. J Food Sci
Technol. 2015;52(12):7883-7893.
20 Schor J. Berries improve glycemic response to bread or sugar. Natural Medicine
Journal. 2013;5(10).
21 Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from
lean donors increases insulin sensitivity in individuals with metabolic syndrome.
­Gastroenterology. 2012;143(4):913-916.
22 Kootte RS, Levin E, Salojärvi J, et al. Improvement of insulin sensitivity after lean
donor feces in metabolic syndrome is driven by baseline intestinal microbiota
composition. Cell Metab. 2017;26(4):611-619.
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ABSTRACT & COMMENTARY
Breast Tissue Microbiota
Analysis of postsurgical specimens
REFERENCE
Hieken TJ, Chen J, Hoskin TL, et al. The microbiome of aseptically
collected human breast tissue in benign and malignant disease.
Scientific Reports. 2016;6:30751.
OBJECTIVE
To determine resident microbiome differences in breast tissue vs
skin and in malignant vs nonmalignant breast tissue samples.
DESIGN
Observational cohort study
PARTICIPANTS
Thirty-three women scheduled to undergo breast surgery at Mayo
Clinic had their postsurgical specimens analyzed. Roughly half of
the women were found to have breast cancer (n=17), and half were
diagnosed with benign breast disease (BBD; n=16). All of those with
breast cancer were estrogen- and progesterone-receptor–positive,
and 29% were HER2/neu-receptor–positive (n=4). One participant
with cancer dropped out of the analysis. Of the 15 participants with
breast cancer, 10 had stage I and 5 had stage II disease, and 13%
of all of those with breast cancer had lymph node involvement.
Notably, there were some differences in the characteristics of the 2
groups (women with cancer and women with BBD). First, the median
age of each group and, correspondingly, menopausal status, was
significantly different. The overall median age of the cohort was 60
(range, 33-84); the median age was 75 (range, 44-84) for women
with invasive cancer vs 49 (range, 33-70) for women with BBD
(P=0.001). Of the women with cancer, 86.7% were peri/postmeno-
pausal and 13.3% were premenopausal, while 53.9% of the women
with BBD were peri/postmenopausal and 46.2% were premeno-
pausal (P=0.02). The time from incision to sample collection was
also statistically different between the 2 groups (median 82 min vs 52
min in those with cancer and those without, respectively; P=0.0001).
STUDY PARAMETERS ASSESSED
Intraoperative tissue samples of the breast and overlying skin were
analyzed using 16S rDNA tag sequencing for microbial DNA signa-
tures. Buccal swabs and breast skin swabs were also obtained and
analyzed in the same manner.
KEY FINDINGS
Distinct microbial communities existed in the breast tissue vs samples
of overlying skin tissues, breast skin swabs, or buccal swabs. When
comparing women with cancer to those with BBD, distinct microbial
community differences were found. Specifically, several taxa that are
less abundant overall are enriched in the cancer tissue vs the BBD
tissue, including Fusobacterium, Atopobium, Gluconacetobacter,
Hydrogenophaga and Lactobacillus. Lastly, the nearby disease-free
tissue in those with cancer versus the nearby normal tissue in those
with BBD differed in taxa significantly (P=0.009).
14 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
Tina Kaczor, ND, FABNO
PRACTICE IMPLICATIONS
The authors’ first assertion is that this study “confirms
the existence of a distinct breast microbiome and differ-
ences between the breast tissue microbiome in benign
and malignant disease.” The first part of this may be
little news to natural medicine practitioners, who have
been affecting the health of nursing babies by modifying
mom’s flora, or recommending that a small dusting of
infant probiotic be placed on the nipple before feed-
ings. We’ve assumed organisms come from the breast
for a long time. Perhaps we’ve based this knowledge
on the 2 studies from the 1980s 1,2 that suggested the
existence of a distinct breast flora, or perhaps we just
believed in the absence of evidence. According to the
current study’s authors, the 1980s studies that found
distinct bacteria inhabiting the breast were widely
dismissed, with detractors suggesting the bacteria were
likely contaminants from the skin.
Interestingly, while the existence of endogenous
bacteria in the breast appears to be news in medicine,
it also seems to have been an “open secret” in plastic
surgery circles. These bacteria have been suspected to
be the cause of a subclinical infection responsible for
post-implant capsular contracture.3 Regardless, the
study reviewed here confirms our long-held assump-
tion that the breast has its own unique microbiome.
That much is crystal clear.
The more intriguing aspect of the study reviewed
here is the presence of distinct microbes in cancerous
breast tissue vs BBD. The dominant taxonomy was
not different; Bacteroidetes and Firmicutes dominated
both samples. The differences were in the higher levels
of normally very low-abundance flora: Fusobacterium,
Atopobium, Hydrogenophaga, Gluconacetobacter, and
Lactobacillus (P<0.05). The last one may catch our
attention, given Lactobacillus spp are assumed to be
beneficial organisms. Lactobacilli, like all of these
bacteria, are only associated with the cancer, not caus-
ative. The function of these bacteria and precisely
(continued on page 16)
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ABSTRACT & COMMENTARY
how they are interacting with the various components of the
stroma is not known yet.
There were 2 prior studies using molecular (rather than
culture) techniques to analyze breast cancer tissue. Xuan
and colleagues looked at breast cancer tissue versus normal
tissue from the same donor and found that Methylobacterium
radiotolerans was enriched in cancerous tissue while
Spingomonas yanoikuyae was enriched in the normal controls.4
Further, they found that the diversity of the flora was inversely
associated with the extent of disease, with advanced-disease
patients having less diversity in the breast biome. This was
a very small study, however, with only 20 participants, and
it was critiqued by the authors of the study reviewed here as
having high potential for contamination due to methodolog-
ical reasons.
16 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
The second study, published by Urbaniak and colleagues,
looked at the breast microbiome in 81 women from Canada
and Ireland, with and without breast cancer.5 The study
was designed to definitively determine whether there were
live bacteria (not just their DNA) present in what was has
been presumed to be sterile breast tissue. The group did find
bacteria, both through molecular and culture techniques,
with Proteobacteria the dominant phylum. As an aside, this
is also the dominant phylum found in human breast milk.6
The study was not designed to assess differences between
normal and cancerous tissue, nor between Canadian and
Irish women.
Since publication of the study reviewed here, Wang and
colleagues have confirmed that the breast microbiome in
women with breast cancer is distinct from the microbiome
ABSTRACT & COMMENTARY
in normal breast tissue. The microbiome of the mouth,
urinary tract, and breast tissue was determined in 57 women
with cancer and 21 women without cancer.7 The authors
found that the breast microbiome was significantly different
between the 2 groups (P=0.03), driven primarily by the pres-
ence of Methylobacterium in the cancerous tissue. In addition,
several gram-positive organisms including Corynebacterium
(P<0.01), Staphylococcus (P=0.02), Actinomyces (P<0.01), and
Propionibacteriaceae (P<0.01) were more abundant. Unlike
the current study, Lactobacillus spp were not enriched in the
breast cancer tissue. However, the presence of Lactobacillus in
the urine of postmenopausal women was lower than that of
premenopausal women. Oral microbiomes did not differ.
Note that while there are some consistencies in the above
molecular studies, much of the data thus far is not consis-
tent. This is due to several factors, including the immense
complexity of the microbiome, inherent differences in tech-
niques, expected ethnic variations in biomes, and the low
number of participants in each study. Put together, we can
confidently say that there is a unique microbial niche in the
breast itself, and breast cancer is distinctly different in its
microbiome signature vs normal breast tissue. The details of
these 2 findings will continue to be flushed out going forward.
A unique aspect of the study reviewed here is that the non-dis-
eased tissue near the malignancy also harbored a distinct flora
when compared with nearby tissue in those with BBD. This is
intriguing. The presence of a shift in flora before the disease is
present means that someday we may be able to stratify risk of
developing breast cancer based on the microbiome present in
the tissue. This would be a means of better determining risk
of sporadic breast cancer.
In keeping with the popular metaphor of the body’s microbial
niches as ecosystems, integrative practitioners are uniquely
trained to improve the breast flora in the context of overall
health. In the modern reductionist medicine model, singular
strains will be touted as specific for breast health. Indeed,
there are numerous patented therapeutic probiotics available
following this line of thought.8 This would be the equivalent
©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)  17
of spreading a single plant seed, or a mere handful of plants,
and expecting a complex and healthy ecosystem to arise.
While certain strains may eventually emerge in the research,
it will always be the entire environment of the body that must
be tended for proper establishment of the microenvironment
of the breast and its microbiota.
This is not to say that application of particular bacterial
strains is never indicated. Several strains of Lactobacillus
have been associated with increased immune recognition,
decreased tumor growth, and increased survival in rodent
models of breast cancer.9 Among these are specific strains of
L casei, L plantarum, and L reuteri. This is interesting given
that Lactobacillus spp were enriched only in the tissue with
breast cancer in the current study. The role of the bacteria,
again, has yet to be determined.
For now, there is no outcome data in humans to suggest there
are specific probiotics that will help prevent breast cancer or
its recurrence. In the absence of evidence, we often fall back
to our philosophically based understanding of health and
disease. In brief, this can be understood as optimizing the
overall health of the organism, providing all necessary compo-
nents of elements interwoven into the larger landscape of life
on the planet. In the context of the breast microbiome, this is
certainly our best bet.
REFERENCES
1 Ransjö U, Asplund OA, Gylbert L, Jurell G. Bacteria in the female breast. Scand J
Plast Reconstr Surg. 1985;19(1):87-89.
2 Thornton JW, Argenta LC, McClatchey KD, Marks MW. Studies on the endogenous
flora of the human breast. Ann Plast Surg. 1988;20(1):39-42.
3 Bartsich S, Ascherman JA, Whittier S, Yao CA, Rohde C. The breast: a clean-con-
taminated surgical site. Aesthetic Surg J. 2011;31(7):802-806.
4 Xuan C, Shamonki JM, Chung A, et al. Microbial dysbiosis is associated with human
breast cancer. PLoS One. 2014;9(1):e83744.
5 Urbaniak C, Cummins J, Brackstone M, et al. Microbiota of human breast tissue.
Appl Environ Microbiol. 2014;80(10):3007-3014.
6 Ward TL, Hosid S, Ioshikhes I, Altosaar I. Human milk metagenome: a functional
capacity analysis. BMC Microbiol. 2013;13(1):116.
7 Wang H, Altemus J, Niazi F, et al. Breast tissue, oral and urinary microbiomes in
breast cancer. Oncotarget. 2017;8(50):88122-88138.
8 Dixit Y, Wagle A, Vakil B. Patents in the field of probiotics, prebiotics, synbiotics: a
review. J Food Microbiol Saf Hyg. 2016;01(02):1-13.
9 Aragón F, Perdigón G, de Moreno de LeBlanc A. Modification in the diet can induce
beneficial effects against breast cancer. World J Clin Oncol. 2014;5(3):455-464.
ABSTRACT & COMMENTARY
Ketogenic Diet Improves Seizures
Effect may be mediated through changes in gut biome
REFERENCE
Wu Q, Wang H, Fan YY, et al. Ketogenic diet effects on 52 chil-
dren with pharmacoresistant epileptic encephalopathy: a clin-
ical prospective study. Brain Behav. 2018;8(5):e00973.
DESIGN
Prospective clinical trial
OBJECTIVE
To measure the impact of a ketogenic diet on children suffering
from drug-resistant epileptic seizures
PARTICIPANTS
Out of an initial group of 62 children, 52 children with pharma-
coresistant epileptic encephalopathy completed 12 weeks of
a ketogenic diet. Thirty of these 52 were male; ages ranged
from 3 months to 7 years. All participants had been diagnosed
with pharmacoresistant epileptic encephalopathy, had taken
2 or more kinds of antiepileptic drugs, and still had frequent
seizures despite regular treatment (>4 seizures per month). All
of the participants were Chinese.
DIETARY INTERVENTION
Nutritionists prepared ketogenic diets for each participant in
accordance with the modified Johns Hopkins program. The fat
to nonfat ratio in each diet was incrementally increased from
0.5:1.0 to 4.0:1.0 within 1 to 2 months according to the specific
circumstances of each patient. The ketogenic diet recipes were
designed to fit Chinese eating habits. All participants received
the ketogenic diet intervention.
STUDY PARAMETERS ASSESSED
Participants underwent a full battery of lab testing, which
included routine chemistries, urine, lipid, liver, and urinary
profiles; ultrasound, electrocardiogram, and electroenceph-
alogram studies; and close monitoring of glucose, ketones,
seizures, and adverse reactions during the study period.
Seizures were tracked starting a month before the dietary
intervention to get a baseline measure of seizure frequency. A
18 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
Jacob Schor, ND, FABNO
journal of seizure occurrence was kept by a parent or guardian
during the treatment phase. Seizure frequency was compared
at weeks 4, 12, and 24.
Changes in the quality of seizures was determined using
4-hour–long EEGs at weeks 4 and 12. To compare effects, a
4-hour EEG was done before treatment and at 3 months after
treatment concluded. Gesell Development Scale was used to
evaluate cognitive function after the 12 weeks of treatment.
Evaluating changes in seizure severity is complicated. Seizures
can change in type, frequency, and intensity. These researchers
used the Engel classification system that describes response to
epilepsy treatments using the following grading system:
• Grade 1: complete remission after treatment
• Grade II: rare epileptic episodes that affect function (90%-
100% remission)
• Grade III: seizures have improved (50% reduction in
seizures)
• Grade IV: no significant improvement
PRIMARY OUTCOME MEASURE
Treatment was considered effective if the patient had a 50% or
greater reduction in seizure activity.
KEY FINDINGS
The treatment was considered effective in 29 of the 52
participants (56%) at the end of 12 weeks of treatment. In
responders, the effect of treatment was apparent in the first
2 weeks. Benefits were seen in 15 of the cases in the first
week of treatment. At the end of the study 14 participants
(27%) were seizure-free. A marked reduction in the number
of seizures was seen in 9 cases (17%). A reduction by half or
more of the number of seizures was seen in 6 cases (11.5%).
The treatment was deemed not effective in 23 cases (44%).
Keep in mind the bar for being effective was at least a 50%
reduction in the number of seizures from baseline (Engel
classification Grade III or above).
ABSTRACT & COMMENTARY
PRACTICE IMPLICATIONS
Why is this study on ketogenic diets and epilepsy included
in this special issue that features articles on the human
biome? At first glance you may think this article was inserted
inadvertently.
The ketogenic diet was proven effective in treating childhood
seizures nearly a hundred years ago.1 The ketogenic diet is far
from new even if this idea of employing it as a strategy in
drug-refractory cases is receiving recent attention.2
What is new is that we have learned that the ketogenic diet’s
impact on epilepsy may be related to its effect on the gut
biome.
The authors of the ketogenic diet study in children reviewed
here do not mention this in their discussion of results. In
their discussion, they were unsure why the diet works for
nearly half of the participants. They suggested that shifting
the brain to using ketones as an energy source or perhaps the
caloric restriction itself might have something to do with the
benefits.
The newest hypothesis for the ketogenic antiseizure effect
is compelling enough to feature here, even if the data is
derived from mice experiments.
Earlier mice experiments have demonstrated that ketogenic
diets prevent development of epilepsy,3 improve symptoms
of autism,4 improve motor symptoms in Alzheimer’s disease,5
and reduce epileptic activity in the brain.6
In the May 24, 2018 issue of Cell, Christine Olson and
colleagues at Elaine Hsiao’s lab at UCLA suggested that the
ketogenic diet quickly alters the gut biome in a specific way
so that it provides protection against both electrically induced
seizures and spontaneous tonic-clonic seizures in 2 mouse
models of epilepsy.7
In this mouse study, the authors demonstrated that the keto-
genic diet did not provide seizure protection to germ-free
mice, who were either raised in a germ-free environment or
were heavily treated with antibiotics. But transplanting the
©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)  19
mice with populations of Akkermansia and Parabacteroides
bacteria conferred protection against seizures.
Olson et al propose that the high-fat, low-carbohydrate
ketogenic diet shifts the gut biome, decreasing diversity
and increasing populations of Akkermansia muciniphila
and Parabacteroides spp bacteria. This shift in populations
of bacteria then decreases gamma-glutamyltranspeptidase
activity, decreasing gamma-glutamyl amino acids in the
blood, which in turn increases gamma-aminobutyric acid
(GABA) levels in the brain. Increased GABA in the brain
offers the protection against seizures.
“
UCLA has already granted
licensing rights to a start-up company
that is raising funds to develop a probiotic
”
treatment for epilepsy.
Hsiao’s lab has been producing a steady stream of interesting
research related to the gut biome and its impact on the brains
of mice and humans.
In 2013, Hsiao reported that in a mouse model of autism,
alterations in microbiota and the gastrointestinal barrier
could be corrected using Bacteroides fragilis. Hsiao believes
modifying the gut biome in this way could reduce autism-
like symptoms.8 Hsiao’s work on autism continues. It is
now well-accepted that immune dysfunction and digestive
issues are common conditions among children on the autism
spectrum.9-10
UCLA has already granted licensing rights to a start-up
company that is raising funds to develop a probiotic treat-
ment for epilepsy. The idea is that the right formulation of
bacteria will modulate GABA, providing the neuroprotective
ABSTRACT & COMMENTARY
effects of a ketogenic diet in pill form. Swallowing a pill would
be easier than following a ketogenic diet and pose fewer risks of
side effects.11
There may be other strategies to increase gut populations of
these bacteria. Metformin, a drug used to treat type 2 diabetes,
apparently increases populations of both these bacterial species in
mice.12 Yang et al reported in 2017 that chronic use of metformin
does have some antiseizure effect in mice.13 Consumption of
certain “resistant starches” designed to reach the large intestine
may also increase populations of these bacteria.14
The relationships between various bacteria species and disease is
far from understood.
Both Akkermansia muciniphila and Acinetobacter calcoaceticus were
found to be 4 times more abundant in patients with multiple scle-
rosis (MS) than in healthy people, while Parabacteroides distasonis
is 4 times more abundant in healthy people than in patients with
MS. Akkermansia and Acinetobacter are associated with inflam-
matory responses in MS, while Parabacteroides appears to have
an anti-inflammatory action.15 This makes determining how
we approach the use of specific probiotics for any given patient
trickier than it may seem at first glance.
Treatment of epilepsy may be on the verge of shifting to a focus
on altering the gut biome using a combination of probiotics, a
ketogenic diet, and supplementation with resistant starches. If
this strategy does indeed increase GABA levels in the brain, a
long list of other possible therapeutic targets is now in front of us.
20 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
REFERENCES
1 Peterman MG. The ketogenic diet in epilepsy. JAMA. 1925;84(26):1979-1983.
2 Holtkamp M. Pharmacotherapy for refractory and super-refractory status
epilepticus in adults. Drugs. 2018;78(3):307-326.
3 Lusardi TA, Akula KK, Coffman SQ, et al. Ketogenic diet prevents epilepto-
genesis and disease progression in adult mice and rats. Neuropharmacology.
2015;99:500-509.
4 Ruskin DN, Svedova J, Cote JL, et al. Ketogenic diet improves core symptoms
of autism in BTBR mice. PLoS One. 2013;8(6):e65021.
5 Brownlow ML, Benner L, D’Agostino D, Gordon MN, Morgan D. Ketogenic
diet improves motor performance but not cognition in two mouse models of
Alzheimer’s pathology. PLoS One. 2013;8(9):e75713.
6 Forero-Quintero LS, Deitmer JW, Becker HM. Reduction of epileptiform
activity in ketogenic mice: the role of monocarboxylate transporters. Sci Rep.
2017;7(1):4900.
7 Olson CA, Vuong HE, Yano JM, et al. The gut microbiota mediates the anti-sei-
zure effects of the ketogenic diet [published online ahead of print May 24,
2018]. Cell.
8 Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and
physiological abnormalities associated with neurodevelopmental disorders.
Cell. 2013;155(7):1451-1463.
9 Hsiao EY. Gastrointestinal issues in autism spectrum disorder. Harv Rev
Psychiatry. 2014;22(2):104-111.
10 Vuong HE, Hsiao EY. Emerging roles for the gut microbiome in autism spec-
trum disorder. Biol Psychiatry. 2017;81(5):411-423.
11 Taylor NP. Bloom bags cash, UCLA tech to treat epilepsy via the microbiome.
https://www.fiercebiotech.com/biotech/bloom-bags-cash-ucla-tech-to-treat-
epilepsy-via-microbiome. Published May 24, 2018. Accessed June 18, 2018.
12 Lee H, Lee Y, Kim J, et al. Modulation of the gut microbiota by metformin
improves metabolic profiles in aged obese mice. Gut Microbes. 2017:1-11.
13 Yang Y, Zhu B, Zheng F, et al. Chronic metformin treatment facilitates seizure
termination. Biochem Biophys Res Commun. 2017;484(2):450-455.
14 Graf D, Di Cagno R, Fåk F, et al. Contribution of diet to the composition of
the human gut microbiota. Microb Ecol Health Dis. 2015;26:10.3402/mehd.
v26.26164.
15 Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis
patients modulate human T cells and exacerbate symptoms in mouse models.
Proc Natl Acad Sci. 2017;114 (40):10713-10718. 
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PEER-REVIEWED ARTICLE
The Gut-Skin Axis and
Mechanisms for Communication
An emerging area of research in Western medicine
ABSTRACT
The association between gut health and general health
has been the focus of many medical approaches,
including traditional Chinese medicine, Ayurvedic medi-
cine, and naturopathic medicine. The discovery of the
gut microbiome has led to new areas of research that
focus on the possible biochemical mechanisms that can
relate gut health to local disease as well as the health of
distant organs. The relationship of the gut to the skin,
referred to as the gut-skin axis, is one emerging area of
research. Here we review several potential mechanisms
by which the gut may interact with the rest of the body
and the skin, along with several skin-related examples.
Further research is needed to delineate the biochemical
mechanisms in this emerging and exciting area.
INTRODUCTION
The gut and skin are both complex immune and neuro-
endocrine organs, and each has a community of microbes
that governs the physiology of their local surroundings.1
A 3-directional communication among the brain, skin,
and gut, along with influences from the immune and
endocrine systems, has been identified, although not fully
understood.1 Pathology of the gastrointestinal tract and
diet have been shown to influence skin health.2,3 Many
skin conditions have been linked to gastrointestinal
inflammation, including rosacea, psoriasis, and acne.2-4
Skin lesions can also occur in association with gastroin-
testinal conditions such as inflammatory bowel disease
(IBD) and celiac disease.5,6
The recognition that the gut and skin are connected is
not new; traditional forms of medicine that have been
around for thousands of years, such as Ayurvedic medi-
cine and traditional Chinese medicine, have a gut-cen-
tric approach to health and disease. As research continues
to expand in this area, the notion of a gut-skin axis has
started to emerge in Western research. In this review, we
aim to discuss emerging mechanisms for how the gut may
influence dermatologic health.
22 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
Raja Sivamani, MD, AP
(Ayurvedic Practitioner)
MODES OF COMMUNICATION FROM THE GUT
TO THE SKIN
The gut may communicate with the skin in several ways:
• Absorption of nutrients with a direct effect on the skin
• Absorption of nutrients that can stimulate hormonal changes
that affect the skin
• Influence of gut microbiota on the immune system
• Modulation of the local microbiome that releases metabolites
that may have distant effects on the skin
Absorption of nutrients with a direct effect
on the skin
The absorption of nutrients and their direct effects on the skin
has been a focus of several studies. For example, the intake of
carotenoids has been correlated to yellowing of the skin,7,8 and
beta-carotene supplementation has been studied in the preven-
tion of sunburns.9 In addition, oral vitamin E can be delivered
to the skin, especially through sebaceous glands.10
Absorption of nutrients that stimulate
a change in hormones
Absorbed nutrients frequently shift hormones in the body.
Examples include the influence of carbohydrates and whey
protein on insulin levels, which can have an impact on the skin.
As an example, whey protein may be associated with increased
insulin secretion11 and has been reported as a potential culprit
in acne flares.12-14 Insulin-like growth factor 1 (IGF-1) activates
the sebaceous glands to produce more inflammatory mediators
and more sebum,15 which may trigger a worsening of acne.
Moreover, consuming more high-glycemic, refined carbohy-
drates may increase the concentration of IGF-1 and increase
the risk of developing acne.16
The influence of gut microbiota
on the immune system
The gut microbiota interact with the immune system and
appear to interact with and educate the regulatory T cells that
can drive inflammation elsewhere in the body.17,18 Regulatory
(continued on page 24)
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PEER-REVIEWED ARTICLE
T cells seem to play an important role in autoimmune and
inflammatory skin diseases19-21 although the role of the gut
microbiome remains under study in these areas.
Modulation of the local microbiome and influence
on the local immune system
The microbiota and the gut epithelial lining interact and
release secondary metabolites that can have distant effects
on the skin. Previous studies have suggested that changes in
gut microbiota and the microbiota-derived inflammatory
mediators may impact chronic inflammation and the risk for
cardiovascular disease, obesity, kidney disease, and diabetes.22
There is growing evidence that gut-derived mediators may
communicate with the skin as well. Examples of mediators
include lipopolysaccharide (LPS) and short chain fatty acids.
It has been hypothesized that gut-derived LPS may play a role
in acne inflammation,23 though definitive mechanistic studies
are still lacking. Short-chain fatty acids have long been postu-
lated to affect general inflammation in the body and modu-
late obesity, diabetes, and colon cancer risk.24,25 Short-chain
fatty acids may modulate inflammation,25 and patients with
acne have lower blood levels of these fatty acids than healthy
controls (Sivamani, unpublished data, 2018).
While these mechanisms may not serve as a comprehen-
sive examination of the gut-skin axis, they bring to light the
“
The recognition that
the gut and skin are connected is not new;
traditional forms of medicine that have
been around for thousands of years, such as
Ayurvedic medicine and traditional Chinese
medicine, have a gut-centric approach to
health and disease.
24 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
gut’s ability to communicate with the skin through multiple
modalities. As research continues to grow, we will gain a
better understanding of which of these mechanisms, and
likely other mechanisms, may serve as important mediators
and thus a target for both pharmacological and nutritional
intervention.
Apart from possible mechanisms, there are several lines of
evidence that suggest that gut dysbiosis is involved in skin
disease. We review a few of them below.
DISEASE-BASED EXAMPLES OF GUT
DYSBIOSIS IN SKIN DISEASE
Small intestinal bacterial overgrowth and
papulopustular rosacea
Often mistaken for acne, papulopustular rosacea can occur
with erythematotelangiectatic rosacea, and is characterized by
erythema, papules, and pustules.26 Papulopustular rosacea is
not only associated with a dysbiosis of the cutaneous micro-
biome, but also with small intestinal bacterial overgrowth
(SIBO), a dysbiosis of the intestinal tract.3,27 Oral antibiotic
treatment of SIBO has been shown to induce remission in
rosacea symptoms.3,28,29
Dysbiosis and psoriasis
One recent study comparing the gut microbial compo-
sition of patients with psoriasis to that of healthy patients
found that psoriasis patients had an increased presence of
Faecalibacterium and decreased Bacteroides compared to the
healthy controls.4 A similar study found that, compared to
healthy controls, psoriasis patients had an increased ratio
of Faecalibacterium to Bacteroides in the intestinal micro-
biome and an increase in Streptococcus and decrease in both
Propionibacterium and Actinobacteria on the skin’s surface.4
High-glycemic diet and acne vulgaris
The Standard American Diet (SAD) is a high-glycemic diet
rich in processed fast foods, refined carbohydrates, animal
proteins, and omega-6 polyunsaturated fatty acids.30 Seventy-
five percent of Americans consume a Standard American
PEER-REVIEWED ARTICLE
Diet.31 Studies have shown that consuming a Standard American
Diet increases pro-inflammatory mediators.31 Leucine, an amino
acid found in animal protein and dairy products, stimulates
the mammalian target of rapamycin complex 1 (mTORC1);32
mTORC1 then activates SREBP,33 which is a transcription
factor that drives lipogenesis in the sebocytes. Sebocytes convert
leucine into fatty acids and sterols to synthesize sebaceous
lipids.33 Overaction of mTORC1 through the consumption of
a SAD increases the secretion of androgen hormones such as
testosterone, which activates mTORC1 to stimulate the seba-
ceous follicles to produce more sebum.33 Acne is recognized to
be an mTORC1-driven disease of civilization and diet.32,33 Areas
where high-glycemic diets are not consumed, such as in isolated
hunter-gatherer communities, have extremely low rates of acne.34
Inflammatory bowel disease and
various skin lesions
Crohn’s disease and ulcerative colitis are the 2 main categories
of IBD.6 Their pathophysiology is not limited to the gastrointes-
tinal tract; IBD is associated with extraintestinal manifestations
in 6% to 47% of patients.6 In 25% of patients with IBD, the
extraintestinal manifestations precede the diagnosis of Crohn’s or
ulcerative colitis.6 The cutaneous extraintestinal manifestations
of IBD include erythema nodosum, pyoderma gangrenosum,
Sweet’s syndrome, and oral lesions.6 Erythema nodosum is the
most commonly reported skin lesion associated with IBD, and
pyoderma gangrenosum reflects IBD in its most severe state.6
Although the mechanism is not well-­understood, information
collected from a clinical trial suggested that blockade of tumor
necrosis factor (TNF) may play a role in the pathogenesis of these
skin conditions in IBD.6
Celiac disease and dermatitis herpetiformis
Dermatitis herpetiformis is an extremely pruritic eruption seen
on the buttocks and the extensor surfaces of the extremities.
It affects approximately 17% of patients with celiac disease,5
though it may not be detected until up to 10 years after the
celiac disease diagnosis.5 In most cases, dermatitis herpetiformis
in patients with celiac disease indicates poor adherence to a
gluten-free diet.5
©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)  25
THE ROLE OF PROBIOTICS
Oral probiotics act locally when ingested, but can have
effects on distant organ systems through the immune
system.35 Through interactions with lymphoid tissue,
probiotics may regulate the release of inflammatory cyto-
kines that are often increased in various skin conditions.36
Indeed, there are several lines of evidence supporting the
use of probiotics for skin conditions.
A systematic review and meta-analysis of randomized
controlled trials concluded that, although Lactobacillus
plantarum and Lactobacillus rhamnosus did not have a
significant effect on SCORAD (scoring atopic dermatitis)
scores in children with atopic dermatitis, Lactobacillus
fermentum, Lactobacillus salivarius, and a mixture of 4
different strains (Lactobacillus rhamnosus GG, L rham-
nosus LC705, Bifidobacterium breve, and Propionibacterium
freudenreichii ssp Shermanii) did.37,38 In acne patients,
oral supplementation of Lactobacillus decreased the levels
of IGF-1 fourfold compared to no probiotic supplemen-
tation.39 In another study, patients with acne who were
supplementing with Lactobacillus acidophilus, Lactobacillus
delbrueckii, and Bifidobacterium bifidum along with
conventional antibiotic treatment experienced increased
resolution of their acne and better tolerance of the antibi-
otic treatment.40
Despite these promising results, there remain many ques-
tions. Further research is needed to better understand how
specific strains should be chosen and dosed. Most of the
research has focused on bacteria, and it is not known if
fungal microbiota and probiotics that are inclusive of fungi
are important.
While questions still remain, there is no doubt that further
research into the gut microbiome and how it contributes
more widely to general health is exciting. As our knowledge
grows regarding how food, probiotics, and the gut micro-
biome modulate health, it is our hope that our dietary and
lifestyle patterns will shift toward both healthier skin and a
healthier metabolic state.
PEER-REVIEWED ARTICLE

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23 Bowe WP, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin axis - back to
3 Agnoletti AF, DE Cole E, Parodi A, et al. Etiopathogenesis of rosacea: a prospective
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study with a three-year follow-up. G Ital Dermatol Venereol. 2017;152(5):418-423.
24 Schwarz A, Bruhs A, Schwarz T. The short-chain fatty acid sodium butyrate func-
4 Codoner FM, Ramirez-Bosca A, Climent E, et al. Gut microbial composition in
tions as a regulator of the skin immune system. J Invest Dermatol. 2017;137(4):855-
patients with psoriasis. Sci Rep. 2018;8(1):3812.
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5 Salmi TT, Hervonen K, Kurppa K, Collin P, Kaukinen K, Reunala T. Celiac disease
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diet. Scand J Gastroenterol. 2015;50(4):387-392.
2017;9(12).
6 Greuter T, Navarini A, Vavricka SR. Skin manifestations of inflammatory bowel
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Reports. 2016;8(1):6387.
7 Pezdirc K, Hutchesson MJ, Williams RL, et al. Consuming high-carotenoid fruit and
27 Gallo RL, Nakatsuji T. Microbial symbiosis with the innate immune defense system
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of the skin. J Invest Dermatol. 2011;131(10):1974-1980.
single-blind randomized crossover trial. J Acad Nutr Diet. 2016;116(8):1257-1265.
28 Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in rosacea:
8 Pezdirc K, Hutchesson MJ, Whitehead R, Ozakinci G, Perrett D, Collins CE. Fruit,
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29 Drago F, De Col E, Agnoletti AF, et al. The role of small intestinal bacterial over-
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30 Totsch SK, Quinn TL, Strath LJ, et al. The impact of the Standard American Diet in
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31 United States Department of Agriculture. Dietary Guidelines for Americans 2015-
11 Salehi A, Gunnerud U, Muhammed SJ, et al. The insulinogenic effect of whey protein
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35 Kober MM, Bowe WP. The effect of probiotics on immune regulation, acne, and
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20 Melnik BC, John SM, Chen W, Plewig G. T helper 17 cell/regulatory T-cell imbalance
40 Jung GW, Tse JE, Guiha I, Rao J. Prospective, randomized, open-label trial
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moderate acne. J Cutan Med Surg. 2013;17(2):114-122.

26 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)
EXPERT INTERVIEW

The Gut-Brain Axis

An interview with Steven Sandberg-Lewis, ND, DHANP

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Approximate listening time: 30 minutes

In this interview Natural Medicine Journal’s editor-in-chief, Tina Kaczor, ND, FABNO, and Steven
Sandberg-Lewis, ND, DHANP, discuss the integral role of the gut microbiota in mood and cogni-
tion. A review of how the gut and brain communicate through both the nerves and gut microbial
metabolites is discussed. They also talk about how intestinal permeability and brain permeability are
associated and what you can do about it. As a naturopathic clinician with over 40 years’ experience,
Sandberg-Lewis shares some clinically useful pearls along the way.

ABOUT THE EXPERT

STEVEN SANDBERG-LEWIS, ND, DHANP, has
been practicing since 1978, teaches gastroenter-
ology at National University of Natural Medicine and SUBSCRIBE TO THE
has a private practice at 8Hearts Health and Wellness NMJ PODCAST
in Portland, Oregon. He lectures, presents webinars IN iTunes
and interviews on issues of digestive health. He is the
author of the medical textbook Functional Gastroenter-
ology: Assessing and Addressing the Causes of Func-
tional Digestive Disorders, Second Edition, 2017. His column Functional
Gastroenterology Bolus appears regularly in the Townsend Letter.

Within gastroenterology, he has special interest and expertise in inflam-

matory bowel disease, irritable bowel syndrome, small intestine bacterial
overgrowth (SIBO), hiatal hernia, gastroesophageal and bile reflux (GERD),
biliary dyskinesia, and chronic states of nausea and vomiting.

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In this interview, naturopathic physician and probiotic expert Donald Brown, ND, discusses the role
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Research Consultants (NPRC) in Seattle. He is a member
of the Advisory Board of the American Botanical Council
(ABC) and the Editorial Board of The Integrative Medicine
Alert. He was a member of the Board of Directors for the
International Probiotics Association (2008-2010) and its
Scientific Advisory Board (2006-2008). He has also previ-
ously served as an advisor to the Office of Dietary Supple-
ments at the National Institutes of Health.
Brown is the author of Herbal Prescriptions for Health
and Healing (Lotus Press, 2002) and was a contrib-
utor to The Natural Pharmacy (Prima Publishing, 2006),
the A-Z Guide to Drug-Herb-Vitamin Interactions (Prima
Publishing, 2006), and The Textbook of Natural Medicine
(Churchill Livingstone, 2006).
Founded in 1979 by molecular geneticist Stephen Levine,
PhD, Allergy Research Group® is one of the very first truly hypo-
allergenic nutritional supplement companies. For nearly 40
years Allergy Research Group® has been a leading innovator
and educator in the natural products industry. Our dedication to
the latest research about cutting-edge nutritional supplements
continues to this day.
Our purpose is to provide customers with products they can use to
improve their patients’ quality of life, through scientific-based inno-
vation, purity of ingredients, education, and outstanding service.
ARG is proud to be a sponsor of the Clinical Education LinkedIn
Forum, a closed peer-to-peer group on LinkedIn where healthcare
professionals can ask clinical questions and receive evidence-
based and clinical-based responses by experts in their field.
Visit  www.clinicaleducation.org/linkedin for more information
and to sign up for free!
Visit  www.allergyresearchgroup.com for more information on
ARG and our products.

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28 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, AUGUST 2018 SUPPLEMENT—VOL. 10, NO. 81 (SUPPL)