The Microbiome and Integrative Medicine: Special Issue

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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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
authors; IMPACT Health Media, In good health,
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publication do not indicate
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Karolyn A. Gazella
the products or services by
the editors or authors of this Publisher, Natural Medicine Journal
publication. IMPACT Health
Media, Inc. is not liable for
any injury or harm to persons
or property resulting from
statements made or products
or services referred to in 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 Megan Chmelik
REFERENCE All participants were advised to main- PRACTICE IMPLICATIONS

Samimi M, Dadkhah A, Haddad tain their routine dietary and lifestyle
Kashani H, et al. The effects of synbi- habits throughout the study. A 3-day Polycystic ovary syndrome has become an
otic supplementation on metabolic food record and 3 physical activity increasingly prevalent endocrine disorder,
status in women with polycystic ovary records were completed during affecting up to 18% of reproductive-aged
syndrome: a randomized double- weeks 0, 3, 6, 9, and 12. women.1 Diagnosis, according to the
blind clinical trial [published online STUDY PARAMETERS ASSESSED Rotterdam Criteria, requires that 2 of the
ahead of print March 12, 2018]. Labs were obtained at weeks 0 and following criteria are met: chronic oligoovu-
Probiotics Antimicrob Proteins. 12 to assess markers of glycemic lation/anovulation; hyperandrogenism; and/
DESIGN control, including fasting plasma
or polycystic ovarian morphology. However,
A 12-week randomized double-blind glucose (FPG), serum insulin,
homeostatic model assessment for
symptom presentation and severity are highly
placebo-controlled clinical trial.
insulin resistance (HOMA-IR), and variable.2 Dysglycemia and dyslipidemia are
OBJECTIVE the quantitative insulin sensitivity common findings among many, though not
To determine the effect of synbi- check index (QUICKI), and measures all, women with PCOS. Because PCOS is asso-
otic supplementation on markers of of cardiometabolic risk, including ciated with an increased risk of type 2 diabetes
glycemic control and cardiometa- serum triglycerides, total cholesterol,
bolic risk in women with polycystic and cardiovascular disease, primary treatment
low-density lipoprotein cholesterol
ovary syndrome (PCOS). (LDL-C), high-density lipoprotein goals include improved insulin sensitivity and
cholesterol (HDL-C), very low-density normalization of lipid levels.3
PARTICIPANTS
lipoprotein cholesterol (VLDL-C), and
Sixty women, aged 18 to 40 years,
atherogenic index of plasma (AIP). Metformin, a first-line conventional inter-
with PCOS diagnosis based on
the Rotterdam criteria; women who PRIMARY OUTCOME MEASURES
vention for type 2 diabetes and PCOS, is
reported use of probiotic or synbi- Change in markers of glycemic control primarily used to regulate serum glucose and
otic supplementation within 3 months (FPG, serum insulin, HOMA-IR, and insulin levels. As a secondary effect, it may aid
of the trial were excluded. Further QUICKI) from baseline following 12 in weight loss by lowering serum lipid levels
exclusion criteria included smoking, weeks of synbiotic supplementation. and/or improving PCOS symptomology.4
pregnancy, and hyperandrogenism
KEY FINDINGS Metformin-induced alterations in gut micro-
and/or anovulation due to other
Of the 60 women enrolled, 2 from biota have been shown to contribute to its
causes (eg, Cushing syndrome,
each group withdrew for unspec- antidiabetic effects.5 A correlation between
androgen-secreting tumors, hyper- ified reasons. In keeping with the
prolactinemia, thyroid dysfunction). intention-to-treat principle, all partic-
gut dysbiosis and diabetes has been docu-
INTERVENTION ipants were included in the final mented in several papers.6,7 The same has been
Participants in the experimental analysis. reported in PCOS patients: Atypical findings
group (n=30) received capsules Significant improvements in serum of lower diversity and altered phylogenetic
containing Lactobacillus acidophilus insulin levels (P=0.002), HOMA-IR composition have been observed in women
strain T16, Lactobacillus casei strain (P=0.002), QUICKI (P<0.001), with PCOS when compared to controls.8,9
T2, and Bifidobacterium bifidum triglycerides (P=0.003), VLDL-C
strain T1 (2 x 109 CFU/g of each) (P=0.003), and AIP (P=0.03) were Two studies evaluating the effect of probiotics
plus 800 mg inulin. The control group observed in the experimental group on hormonal and metabolic markers in PCOS
(n=30) received capsules containing only. Neither group experienced have been conducted. The first, published by
inulin only. Dosing was 1 capsule significant changes in mean weight
taken orally once a day for 12 weeks. or BMI. When controlled for age and
Shoaei et al in 2015, reported improvements,
Compliance was determined upon baseline BMI, FPG levels became though mostly nonsignificant, in markers of
return of the medication container at significant (P=0.04) and AIP nonsig- glycemic control after 8 weeks of probiotic
the end of the trial. nificant (P=0.06). supplementation.10 A randomized controlled
“
trial published in January 2018 revealed beneficial effects of
supplementation on total testosterone, sex hormone–binding
globulin (SHBG), modified Ferriman-Gallwey (mFG) Atypical findings of
scores, high-sensitivity C-reactive protein (hs-CRP), total
antioxidant capacity (TAC), and malondialdehyde (MDA)
lower diversity and altered phylogenetic
after a 12-week intervention.11 composition have been observed in women
Use of synbiotic supplementation to modulate the micro- with PCOS when compared
”
biome has been of recent interest among researchers. Pairing
probiotics with prebiotics to create synbiotics is thought to to controls.
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 Several of this study’s investigators went on to conduct a
have on conditions such as metabolic syndrome,13 type 2 second study looking at the effect of synbiotic supplementa-
diabetes,14,15 gestational diabetes,16 rheumatoid arthritis,17 tion on hormonal status and biomarkers of inflammation and
and nonalcoholic fatty liver disease.18 oxidative stress. The study design was nearly identical to their
first. Following 12 weeks of supplementation, levels of SHBG
A total of 3 papers on synbiotics and PCOS have been and nitric oxide (NO) increased from baseline, while mFG
published, all within this year. The first was a randomized scores, hs-CRP, free androgen index (FAI), serum insulin,
controlled trial aiming to determine the effect of synbiotics and HOMA-IR fell significantly. There were no significant
on metabolic parameters and apelin-36, a potential marker changes in total testosterone, dehydroepiandrosterone sulfate
of insulin sensitivity.19 After 12 weeks of intervention, there (DHEA-S), total antioxidant capacity (TAC), glutathione
was a marked reduction in apelin levels, though no signifi- (GSH), or malondialdehyde (MDA).22
cant improvements in markers of dysglycemia (FBG, 2-hour
It is evident that dysbiosis is a common finding in PCOS, and
fasting plasma glucose, hemoglobin A1c [HbA1c], HOMA-IR, that interventions that alter gut microbiota composition have
QUICKI) or C-reactive protein (CRP) were observed.20 There the potential to positively impact metabolic, inflammatory,
are inconsistencies in the literature about whether PCOS and/or hormonal markers 8,9 Further research to determine
patients present with low or high apelin levels compared to the effects of different probiotic strains and dosing would be
controls, so the implications of these findings are unclear.21 helpful. Studies comparing probiotics to synbiotics would
also provide valuable information. Because the studies thus
The present study revealed significant beneficial changes to
far have involved women with elevated BMIs, it would be
markers of glycemic control, changes that could possibly
beneficial to conduct a study on women with lean PCOS. In
reduce overall risk of type 2 diabetes. Improvements were
the meantime, addressing gut health, with synbiotic supple-
seen in triglycerides, AIP, and VLDL-C; however, other lipid
mentation or other microbiota-modulating therapy, appears
parameters were not significantly impacted. Given that the
to be a worthwhile consideration for our patients with PCOS.
atherosclerotic cardiovascular disease (ASCVD) risk esti-
mator takes into consideration total cholesterol, LDL-C, While probiotics and supplements alike are generally consid-
and HDL-C, it is unlikely that a direct reduction in cardio- ered safe, they may not be safe for all individuals. According
vascular risk would be achieved from synbiotic supplemen- to a 2014 systematic review on probiotic safety, populations at
tation alone. risk for adverse effects include critically ill patients in intensive
11 Karamali M, Eghbalpour S, Rajabi S, et al. Effects of probiotic supplementation on

care units, critically ill infants, postoperative and hospital- hormonal profiles, biomarkers of inflammation and oxidative stress in women with
ized patients, and those with immunodeficiency disorders. polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.
Arch Iran Med. 2018;21(1):1-7.
Probiotics are not necessarily contraindicated in these patients; 12 Pandey KR, Naik SR, Vakil BV. Probiotics, prebiotics and synbiotics- a review.
however, the risk-benefit ratio should be considered.23 In all J Food Sci Technol. 2015;52(12):7577-7587.
13 Rabiei S, Hedayati M, Rashidkhani B, et al. The effects of synbiotic supplemen-
cases, probiotic/synbiotic quality should be ensured. 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.
A paper written by Lise Alschuler, ND, FABNO, in 2011 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
outlines quality standards that may be helpful to consider No):1-5.
when selecting a probiotic supplement. 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.
REFERENCES 16 Nabhani Z, Hezaveh SJG, Razmpoosh E, Asghari-Jafarabadi M, Gargari BP. The
1 March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prev-
effects of synbiotic supplementation on insulin resistance/sensitivity, lipid profile
alence of polycystic ovary syndrome in a community sample assessed under
and total antioxidant capacity in women with gestational diabetes mellitus: a
contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-551.
randomized double blind placebo controlled clinical trial. Diabetes Res Clin Pract.
2 Moran LJ, Norman RJ, Teede HJ. Metabolic risk in PCOS: phenotype and adiposity 2018;138:149-157.
impact. Trends Endocrinol Metab. 2015;26(3):136-143.
17 Zamani B, Farshbaf S, Golkar HR, et al. Synbiotic supplementation and
3 Bajuk Studen K, Pfeifer M. Cardiometabolic risk in polycystic ovary syndrome the effects on clinical and metabolic responses in patients with rheumatoid arthritis:
[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 1102.
and pharmacodynamics. Pharmacogenet Genomics. 2012;22(11):820-827. 18 Mofidi F, Poustchi H, Yari Z, et al. Synbiotic supplementation in lean patients with
5 Rodriguez J, Hiel S, Delzenne NM. Metformin: old friend, new ways of action-impli- non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-con-
cation of the gut microbiome? Curr Opin Clin Nutr Metab Care. 2018;21(4):294-301. trolled, clinical trial. Br J Nutr. 2017;117(5):662-668.
6 Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women 19 Saedii AAF, Kamal AM, Naeem EA, et al. Apelin-36 and copeptin levels in polycystic
with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99- ovary syndrome. J Infec Dis Treat. 2017;3:1.
103. 20 Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic
7 Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in parameters and apelin in women with polycystic ovary syndrome: a randomised
type 2 diabetes. Nature. 2012;490(7418):55-60. double-blind placebo-controlled trial. Br J Nutr. 2018 Feb;119(4):398-406.
8 Lindheim L, Bashir M, J Münzker, et al. Alterations in gut microbiome composi- 21 Polak K, Czyzyk A, Simoncini T, et al. New markers of insulin resistance in polycystic
tion and barrier function are associated with reproductive and metabolic defects in ovary syndrome. J Endocrinol Invest. 2017;40(1):1-8.
women with polycystic ovary syndrome (PCOS): a pilot study. PLoS One. 2017;12(1). 22 Nasri K, Jamilian M, Rahmani E, et al. The effects of synbiotic supplementation on
9 Torres PJ, Siakowska M, Banaszewska B, et al. Gut microbial diversity in women hormonal status, biomarkers of inflammation and oxidative stress in subjects with
with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endo- polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.
crinol Metab. 2018;103(4):1502-1511. BMC Endocr Disord. 2018;18(1):21.
10 Shoaei T, Heidari-Beni M, Tehrani HG, et al. Effects of probiotic supplementation 23 Didari T, Solki S, Mozaffari S, et al. A systematic review of the safety of probiotics.
on pancreatic β-cell function and C-reactive protein in women with polycystic ovary Expert Opin Drug Saf. 2014;13(2):227-239.
syndrome: a randomized double-blind placebo-controlled clinical trial. Int J Prev
Med. 2015;6:27.
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Fiber Feeds Bacteria to Control

Mark Davis, ND,
Type 2 Diabetes Mellitus and Jacob Schor,
Investigators pit high-fiber diet against standard diet for glycemic control ND, FABNO
REFERENCE KEY FINDINGS

Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively Increasing fermentable fiber by blocking carbohydrate digestion
promoted by dietary fibers alleviate type 2 diabetes. Science. via the amylase inhibitor acarbose improved markers of type
2018;359(6380):1151-1156. 2 diabetes in both groups, but the high-fiber group did signifi-
cantly better. Hemoglobin A1c decreased in both groups but
OBJECTIVE
more so in the high-fiber group. Reduction in HbA1c was greater
To determine effects of a high-fiber diet on the gut micro-
in the high-fiber group from 4 weeks onward. A greater portion
biome and glucose regulation in individuals with established
of patients in the high-fiber group reached adequate glycemic
type 2 diabetes.
control (HbA1c<7%) compared to the standard-diet group (89%
DESIGN vs 50%). The high-fiber group lost more weight and had better
Randomized, open-label, parallel-group clinical trial lipid profiles. Improvements came faster and were greater
PARTICIPANTS
in patients who consumed a high-fiber diet in addition to the
Forty-three patients with clinically diagnosed type 2 diabetes enzyme inhibitor.
mellitus were randomized to either an intervention group Germ-free mice transplanted with post-intervention microbiota
(n=27) or the control group (n=16). derived from either patient group did better, showing better meta-
STUDY MEDICATION AND DOSAGE bolic health parameters than mice transplanted with pre-inter-
The experimental group received a high-fiber diet of fresh vention microbiota. Mice transplanted with microbiota obtained
vegetables, fruits, and nuts, supplemented with a gruel post-intervention from the high-fiber group did the best, having
(which included whole grains, beans, peanuts, lotus seed, the lowest fasting and postprandial blood glucose levels of all
and yam), bitter melon, and prebiotics. The control group mice, mirroring the results in the human patient group.
consumed an isocaloric diet based on Chinese Diabetes Metagenomic sequencing was performed on 172 fecal samples
Society guidelines. collected at 4 time points (days 0, 28, 56, and 84), which led
Both groups took the antidiabetic agent acarbose (an to a catalog of 4,893,833 nonredundant microbial genes. Both
amylase inhibitor) and discontinued any previously used patient groups had a reduction in gene richness (the number
glycemic control medications. Acarbose transforms starch of genes identified per sample) from day 0 to day 28, along
into fiber by reducing digestion and making it available as with significant clinical improvements, with no further changes
a fermentable carbohydrate to bacteria in the colon. The afterward.
experimental group had a much higher intake of dietary These last data challenge the current notion that greater overall
fiber but daily energy and macronutrient intake was similar diversity implies better health. However, gene richness tended
between groups. to be higher in the high-fiber group than in the normal diet group
To determine that interactions between the gut microbiota after day 28, and this trend was associated with better clinical
and the fiber were responsible for any observed changes in outcomes in the intervention group.
function, the gut microbiota from before and after the inter- The high-fiber diet favored the growth of bacteria that produce
ventions were transplanted into germ-free mice. These mice
SCFAs, especially bacteria that produce butyric acid. This increase
ended up with gut biomes that more resembled the trans-
in acid production significantly lowered gut pH in the high-fiber
planted biome of the donor than they resembled each other.
group. Fifteen bacterial strains were significantly promoted by
OUTCOME MEASURES the high-fiber diet, and 47 strains were significantly reduced. This
Hemoglobin A1c (HbA1c) was the primary outcome measure. response was clearly strain-specific; for example, of the 6 strains
Additional outcomes included proportion of participants of Faecalibacterium prausnitzii identified, only 1 strain was signifi-
who achieved glycemic control, fecal short chain fatty acid cantly promoted by the high-fiber diet. The 15 strains that were
(SCFA) levels, postprandial glucose, fasting blood glucose, promoted were all significantly associated with increased SCFA
lipid profiles, and other standard metabolic markers. production, which was inversely correlated with HbA1c.
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
8 Zhang X, Zhao Y, Xu J, et al. Modulation of gut microbiota by berberine and

a high-fiber diet, may have a significant effect on improving metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep.
glycemic control. Our only evidence using direct microbial 2015;5:14405.
9 Tiwari R, Gupta A, Joshi M, Tiwari G. Bilayer tablet formulation of metformin HCl
transplantation in humans is a study from 2012 that used and acarbose: a novel approach to control diabetes. PDA J Pharm Sci Technol.
fecal microbial transplant (FMT) from healthy, lean donors 2014;68(2):138-152.
10 Coe SA, Clegg M, Armengol M, Ryan L. The polyphenol-rich baobab fruit (Adan-
for men with metabolic syndrome. The men experienced sonia digitata L.) reduces starch digestion and glycemic response in humans. Nutr
Res. 2013;33(11):888-896.
temporary increases in peripheral insulin sensitivity, with 11 Li K, Yao F, Du J, Deng X, Li C. Persimmon tannin decreased the glycemic response
a trend toward improved hepatic insulin resistance.21 These 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.
changes were related to fecal microbial diversity and increases 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
in SCFAs.22 grower pigs. Food Funct. 2018;9(2):991-999.
13 Kerimi A, Nyambe-Silavwe, Gauer JS, Tomás-Barberán FA, Williamson G. Pome-
These data should also prompt us to rethink resistant starches 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
and how they affect diabetes. In the past we thought their Clin Nutr. 2017;106(6):1384-1393.
14 Homoki JR, Nemes A, Fazekas E, et al. Anthocyanin composition, antioxidant effi-
benefit was secondary to low glycemic index. Instead their ciency, and α-amylase inhibitor activity of different Hungarian sour cherry varieties
benefit may be in reaching the colon and increasing SCFA (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
production. 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.
REFERENCES 2014;4(11):e005497.
1 Anderson JW, Randles KM, Kendall CW, Jenkins DJ. Carbohydrate and fiber recom- 17 Xi B, Li S, Liu Z, et al. Intake of fruit juice and incidence of type 2 diabetes: a system-
mendations for individuals with diabetes: a quantitative assessment and meta-anal- atic review and meta-analysis. PLoS One. 2014;9(3):e93471.
ysis of the evidence. J Am Coll Nutr. 2004;23(1):5-17. 18 Ezeani C, Ezenyi I, Okoye T, Okoli C. Ocimum basilicum extract exhibits antidiabetic
2 He K, Shi JC, Mao XM. Safety and efficacy of acarbose in the treatment of diabetes effects via inhibition of hepatic glucose mobilization and carbohydrate metabolizing
in Chinese patients. Ther Clin Risk Manag. 2014;10:505-511. enzymes. J Intercult Ethnopharmacol. 2017;6(1):22-28.
3 Yang W, Liu J, Shan Z, et al. Acarbose compared with metformin as initial therapy 19 Gondi M, Prasada Rao UJ. Ethanol extract of mango (Mangifera indica L.) peel
in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority inhibits α-amylase and α-glucosidase activities, and ameliorates diabetes related
randomised trial. Lancet Diabetes Endocrinol. 2014;2(1):46-55. biochemical parameters in streptozotocin (STZ)-induced diabetic rats. J Food Sci
4 Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Technol. 2015;52(12):7883-7893.
Appl Environ Microbiol. 2014;80(19):5935-5943. 20 Schor J. Berries improve glycemic response to bread or sugar. Natural Medicine
5 Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population Journal. 2013;5(10).
induced by metformin treatment improves glucose homeostasis in diet-induced 21 Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from
obese mice. Gut. 2014;63(5):727-735. lean donors increases insulin sensitivity in individuals with metabolic syndrome.
6 Harsch IA, Konturek PC. The role of gut microbiota in obesity and type 2 and type 1 Gastroenterology. 2012;143(4):913-916.
diabetes mellitus: new insights into “old” diseases. Med Sci (Basel). 2018;6(2). pii: 22 Kootte RS, Levin E, Salojärvi J, et al. Improvement of insulin sensitivity after lean
E32. donor feces in metabolic syndrome is driven by baseline intestinal microbiota
7 Rodriguez J, Hiel S, Delzenne NM. Metformin: old friend, new ways of action-impli- composition. Cell Metab. 2017;26(4):611-619.
cation of the gut microbiome? Curr Opin Clin Nutr Metab Care. 2018;21(4):294-301.
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Breast Tissue Microbiota

Analysis of postsurgical specimens Tina Kaczor, ND, FABNO
REFERENCE PRACTICE IMPLICATIONS

Hieken TJ, Chen J, Hoskin TL, et al. The microbiome of aseptically
collected human breast tissue in benign and malignant disease. The authors’ first assertion is that this study “confirms
Scientific Reports. 2016;6:30751. the existence of a distinct breast microbiome and differ-
OBJECTIVE
ences between the breast tissue microbiome in benign
To determine resident microbiome differences in breast tissue vs and malignant disease.” The first part of this may be
skin and in malignant vs nonmalignant breast tissue samples. little news to natural medicine practitioners, who have
DESIGN
been affecting the health of nursing babies by modifying
Observational cohort study mom’s flora, or recommending that a small dusting of
infant probiotic be placed on the nipple before feed-
PARTICIPANTS
Thirty-three women scheduled to undergo breast surgery at Mayo
ings. We’ve assumed organisms come from the breast
Clinic had their postsurgical specimens analyzed. Roughly half of for a long time. Perhaps we’ve based this knowledge
the women were found to have breast cancer (n=17), and half were on the 2 studies from the 1980s 1,2 that suggested the
diagnosed with benign breast disease (BBD; n=16). All of those with existence of a distinct breast flora, or perhaps we just
breast cancer were estrogen- and progesterone-receptor–positive, believed in the absence of evidence. According to the
and 29% were HER2/neu-receptor–positive (n=4). One participant current study’s authors, the 1980s studies that found
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%
distinct bacteria inhabiting the breast were widely
of all of those with breast cancer had lymph node involvement. dismissed, with detractors suggesting the bacteria were
Notably, there were some differences in the characteristics of the 2 likely contaminants from the skin.
groups (women with cancer and women with BBD). First, the median
age of each group and, correspondingly, menopausal status, was Interestingly, while the existence of endogenous
significantly different. The overall median age of the cohort was 60 bacteria in the breast appears to be news in medicine,
(range, 33-84); the median age was 75 (range, 44-84) for women it also seems to have been an “open secret” in plastic
with invasive cancer vs 49 (range, 33-70) for women with BBD surgery circles. These bacteria have been suspected to
(P=0.001). Of the women with cancer, 86.7% were peri/postmeno- be the cause of a subclinical infection responsible for
pausal and 13.3% were premenopausal, while 53.9% of the women
post-implant capsular contracture.3 Regardless, the
with BBD were peri/postmenopausal and 46.2% were premeno-
pausal (P=0.02). The time from incision to sample collection was study reviewed here confirms our long-held assump-
also statistically different between the 2 groups (median 82 min vs 52 tion that the breast has its own unique microbiome.
min in those with cancer and those without, respectively; P=0.0001). That much is crystal clear.
STUDY PARAMETERS ASSESSED
The more intriguing aspect of the study reviewed
Intraoperative tissue samples of the breast and overlying skin were
analyzed using 16S rDNA tag sequencing for microbial DNA signa- here is the presence of distinct microbes in cancerous
tures. Buccal swabs and breast skin swabs were also obtained and breast tissue vs BBD. The dominant taxonomy was
analyzed in the same manner. not different; Bacteroidetes and Firmicutes dominated
KEY FINDINGS
both samples. The differences were in the higher levels
Distinct microbial communities existed in the breast tissue vs samples of normally very low-abundance flora: Fusobacterium,
of overlying skin tissues, breast skin swabs, or buccal swabs. When Atopobium, Hydrogenophaga, Gluconacetobacter, and
comparing women with cancer to those with BBD, distinct microbial Lactobacillus (P<0.05). The last one may catch our
community differences were found. Specifically, several taxa that are attention, given Lactobacillus spp are assumed to be
less abundant overall are enriched in the cancer tissue vs the BBD
beneficial organisms. Lactobacilli, like all of these
tissue, including Fusobacterium, Atopobium, Gluconacetobacter,
Hydrogenophaga and Lactobacillus. Lastly, the nearby disease-free bacteria, are only associated with the cancer, not caus-
tissue in those with cancer versus the nearby normal tissue in those ative. The function of these bacteria and precisely
with BBD differed in taxa significantly (P=0.009). (continued on page 16)
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how they are interacting with the various components of the The second study, published by Urbaniak and colleagues,
stroma is not known yet. looked at the breast microbiome in 81 women from Canada
and Ireland, with and without breast cancer.5 The study
There were 2 prior studies using molecular (rather than was designed to definitively determine whether there were
culture) techniques to analyze breast cancer tissue. Xuan live bacteria (not just their DNA) present in what was has
and colleagues looked at breast cancer tissue versus normal been presumed to be sterile breast tissue. The group did find
tissue from the same donor and found that Methylobacterium bacteria, both through molecular and culture techniques,
radiotolerans was enriched in cancerous tissue while with Proteobacteria the dominant phylum. As an aside, this
Spingomonas yanoikuyae was enriched in the normal controls.4 is also the dominant phylum found in human breast milk.6
Further, they found that the diversity of the flora was inversely The study was not designed to assess differences between
associated with the extent of disease, with advanced-disease normal and cancerous tissue, nor between Canadian and
patients having less diversity in the breast biome. This was Irish women.
a very small study, however, with only 20 participants, and
it was critiqued by the authors of the study reviewed here as Since publication of the study reviewed here, Wang and
having high potential for contamination due to methodolog- colleagues have confirmed that the breast microbiome in
ical reasons. women with breast cancer is distinct from the microbiome
in normal breast tissue. The microbiome of the mouth, of spreading a single plant seed, or a mere handful of plants,
urinary tract, and breast tissue was determined in 57 women and expecting a complex and healthy ecosystem to arise.
with cancer and 21 women without cancer.7 The authors While certain strains may eventually emerge in the research,
found that the breast microbiome was significantly different it will always be the entire environment of the body that must
between the 2 groups (P=0.03), driven primarily by the pres- be tended for proper establishment of the microenvironment
ence of Methylobacterium in the cancerous tissue. In addition, of the breast and its microbiota.
several gram-positive organisms including Corynebacterium
(P<0.01), Staphylococcus (P=0.02), Actinomyces (P<0.01), and This is not to say that application of particular bacterial
Propionibacteriaceae (P<0.01) were more abundant. Unlike strains is never indicated. Several strains of Lactobacillus
the current study, Lactobacillus spp were not enriched in the have been associated with increased immune recognition,
breast cancer tissue. However, the presence of Lactobacillus in decreased tumor growth, and increased survival in rodent
the urine of postmenopausal women was lower than that of models of breast cancer.9 Among these are specific strains of
premenopausal women. Oral microbiomes did not differ. L casei, L plantarum, and L reuteri. This is interesting given
that Lactobacillus spp were enriched only in the tissue with
Note that while there are some consistencies in the above
breast cancer in the current study. The role of the bacteria,
molecular studies, much of the data thus far is not consis-
again, has yet to be determined.
tent. This is due to several factors, including the immense
complexity of the microbiome, inherent differences in tech- For now, there is no outcome data in humans to suggest there
niques, expected ethnic variations in biomes, and the low are specific probiotics that will help prevent breast cancer or
number of participants in each study. Put together, we can its recurrence. In the absence of evidence, we often fall back
confidently say that there is a unique microbial niche in the to our philosophically based understanding of health and
breast itself, and breast cancer is distinctly different in its disease. In brief, this can be understood as optimizing the
microbiome signature vs normal breast tissue. The details of overall health of the organism, providing all necessary compo-
these 2 findings will continue to be flushed out going forward. nents of elements interwoven into the larger landscape of life
A unique aspect of the study reviewed here is that the non-dis- on the planet. In the context of the breast microbiome, this is
eased tissue near the malignancy also harbored a distinct flora certainly our best bet.
when compared with nearby tissue in those with BBD. This is
intriguing. The presence of a shift in flora before the disease is REFERENCES
1 Ransjö U, Asplund OA, Gylbert L, Jurell G. Bacteria in the female breast. Scand J
present means that someday we may be able to stratify risk of Plast Reconstr Surg. 1985;19(1):87-89.
developing breast cancer based on the microbiome present in 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.
the tissue. This would be a means of better determining risk 3 Bartsich S, Ascherman JA, Whittier S, Yao CA, Rohde C. The breast: a clean-con-
of sporadic breast cancer. 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.
In keeping with the popular metaphor of the body’s microbial 5 Urbaniak C, Cummins J, Brackstone M, et al. Microbiota of human breast tissue.
Appl Environ Microbiol. 2014;80(10):3007-3014.
niches as ecosystems, integrative practitioners are uniquely 6 Ward TL, Hosid S, Ioshikhes I, Altosaar I. Human milk metagenome: a functional
trained to improve the breast flora in the context of overall capacity analysis. BMC Microbiol. 2013;13(1):116.
7 Wang H, Altemus J, Niazi F, et al. Breast tissue, oral and urinary microbiomes in
health. In the modern reductionist medicine model, singular breast cancer. Oncotarget. 2017;8(50):88122-88138.
strains will be touted as specific for breast health. Indeed, 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.
there are numerous patented therapeutic probiotics available 9 Aragón F, Perdigón G, de Moreno de LeBlanc A. Modification in the diet can induce
following this line of thought.8 This would be the equivalent beneficial effects against breast cancer. World J Clin Oncol. 2014;5(3):455-464.
Ketogenic Diet Improves Seizures

Effect may be mediated through changes in gut biome Jacob Schor, ND, FABNO
REFERENCE journal of seizure occurrence was kept by a parent or guardian

Wu Q, Wang H, Fan YY, et al. Ketogenic diet effects on 52 chil- during the treatment phase. Seizure frequency was compared
dren with pharmacoresistant epileptic encephalopathy: a clin- at weeks 4, 12, and 24.
ical prospective study. Brain Behav. 2018;8(5):e00973.
Changes in the quality of seizures was determined using
DESIGN 4-hour–long EEGs at weeks 4 and 12. To compare effects, a
Prospective clinical trial 4-hour EEG was done before treatment and at 3 months after
treatment concluded. Gesell Development Scale was used to
OBJECTIVE
To measure the impact of a ketogenic diet on children suffering evaluate cognitive function after the 12 weeks of treatment.
from drug-resistant epileptic seizures Evaluating changes in seizure severity is complicated. Seizures
PARTICIPANTS
can change in type, frequency, and intensity. These researchers
Out of an initial group of 62 children, 52 children with pharma- used the Engel classification system that describes response to
coresistant epileptic encephalopathy completed 12 weeks of epilepsy treatments using the following grading system:
a ketogenic diet. Thirty of these 52 were male; ages ranged • Grade 1: complete remission after treatment
from 3 months to 7 years. All participants had been diagnosed • Grade II: rare epileptic episodes that affect function (90%-
with pharmacoresistant epileptic encephalopathy, had taken 100% remission)
2 or more kinds of antiepileptic drugs, and still had frequent • Grade III: seizures have improved (50% reduction in
seizures despite regular treatment (>4 seizures per month). All seizures)
of the participants were Chinese. • Grade IV: no significant improvement
DIETARY INTERVENTION PRIMARY OUTCOME MEASURE
Nutritionists prepared ketogenic diets for each participant in Treatment was considered effective if the patient had a 50% or
accordance with the modified Johns Hopkins program. The fat greater reduction in seizure activity.
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 KEY FINDINGS
circumstances of each patient. The ketogenic diet recipes were The treatment was considered effective in 29 of the 52
designed to fit Chinese eating habits. All participants received participants (56%) at the end of 12 weeks of treatment. In
the ketogenic diet intervention. responders, the effect of treatment was apparent in the first
2 weeks. Benefits were seen in 15 of the cases in the first
STUDY PARAMETERS ASSESSED
week of treatment. At the end of the study 14 participants
Participants underwent a full battery of lab testing, which
(27%) were seizure-free. A marked reduction in the number
included routine chemistries, urine, lipid, liver, and urinary
of seizures was seen in 9 cases (17%). A reduction by half or
profiles; ultrasound, electrocardiogram, and electroenceph-
more of the number of seizures was seen in 6 cases (11.5%).
alogram studies; and close monitoring of glucose, ketones,
The treatment was deemed not effective in 23 cases (44%).
seizures, and adverse reactions during the study period.
Keep in mind the bar for being effective was at least a 50%
Seizures were tracked starting a month before the dietary reduction in the number of seizures from baseline (Engel
intervention to get a baseline measure of seizure frequency. A classification Grade III or above).
PRACTICE IMPLICATIONS mice with populations of Akkermansia and Parabacteroides

Why is this study on ketogenic diets and epilepsy included bacteria conferred protection against seizures.
in this special issue that features articles on the human
Olson et al propose that the high-fat, low-carbohydrate
biome? At first glance you may think this article was inserted
ketogenic diet shifts the gut biome, decreasing diversity
inadvertently.
and increasing populations of Akkermansia muciniphila
The ketogenic diet was proven effective in treating childhood and Parabacteroides spp bacteria. This shift in populations
seizures nearly a hundred years ago.1 The ketogenic diet is far of bacteria then decreases gamma-glutamyltranspeptidase
from new even if this idea of employing it as a strategy in activity, decreasing gamma-glutamyl amino acids in the
drug-refractory cases is receiving recent attention.2 blood, which in turn increases gamma-aminobutyric acid
(GABA) levels in the brain. Increased GABA in the brain
What is new is that we have learned that the ketogenic diet’s offers the protection against seizures.
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 UCLA has already granted
their discussion, they were unsure why the diet works for licensing rights to a start-up company
nearly half of the participants. They suggested that shifting
the brain to using ketones as an energy source or perhaps the that is raising funds to develop a probiotic
”
caloric restriction itself might have something to do with the
benefits. treatment for epilepsy.
The newest hypothesis for the ketogenic antiseizure effect
is compelling enough to feature here, even if the data is
derived from mice experiments.
Hsiao’s lab has been producing a steady stream of interesting
Earlier mice experiments have demonstrated that ketogenic research related to the gut biome and its impact on the brains
diets prevent development of epilepsy,3 improve symptoms of mice and humans.
of autism,4 improve motor symptoms in Alzheimer’s disease,5
In 2013, Hsiao reported that in a mouse model of autism,
and reduce epileptic activity in the brain.6
alterations in microbiota and the gastrointestinal barrier
In the May 24, 2018 issue of Cell, Christine Olson and could be corrected using Bacteroides fragilis. Hsiao believes
colleagues at Elaine Hsiao’s lab at UCLA suggested that the modifying the gut biome in this way could reduce autism-
ketogenic diet quickly alters the gut biome in a specific way like symptoms.8 Hsiao’s work on autism continues. It is
so that it provides protection against both electrically induced now well-accepted that immune dysfunction and digestive
seizures and spontaneous tonic-clonic seizures in 2 mouse issues are common conditions among children on the autism
models of epilepsy.7 spectrum.9-10
In this mouse study, the authors demonstrated that the keto- UCLA has already granted licensing rights to a start-up
genic diet did not provide seizure protection to germ-free company that is raising funds to develop a probiotic treat-
mice, who were either raised in a germ-free environment or ment for epilepsy. The idea is that the right formulation of
were heavily treated with antibiotics. But transplanting the bacteria will modulate GABA, providing the neuroprotective
effects of a ketogenic diet in pill form. Swallowing a pill would REFERENCES

be easier than following a ketogenic diet and pose fewer risks of 1 Peterman MG. The ketogenic diet in epilepsy. JAMA. 1925;84(26):1979-1983.
2 Holtkamp M. Pharmacotherapy for refractory and super-refractory status
side effects.11 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.
There may be other strategies to increase gut populations of 2015;99:500-509.
these bacteria. Metformin, a drug used to treat type 2 diabetes, 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.
apparently increases populations of both these bacterial species in 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
mice.12 Yang et al reported in 2017 that chronic use of metformin Alzheimer’s pathology. PLoS One. 2013;8(9):e75713.
does have some antiseizure effect in mice.13 Consumption of 6 Forero-Quintero LS, Deitmer JW, Becker HM. Reduction of epileptiform
activity in ketogenic mice: the role of monocarboxylate transporters. Sci Rep.
certain “resistant starches” designed to reach the large intestine 2017;7(1):4900.
may also increase populations of these bacteria.14 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.
The relationships between various bacteria species and disease is 8 Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and
physiological abnormalities associated with neurodevelopmental disorders.
far from understood. Cell. 2013;155(7):1451-1463.
9 Hsiao EY. Gastrointestinal issues in autism spectrum disorder. Harv Rev
Psychiatry. 2014;22(2):104-111.
Both Akkermansia muciniphila and Acinetobacter calcoaceticus were 10 Vuong HE, Hsiao EY. Emerging roles for the gut microbiome in autism spec-
found to be 4 times more abundant in patients with multiple scle- trum disorder. Biol Psychiatry. 2017;81(5):411-423.
11 Taylor NP. Bloom bags cash, UCLA tech to treat epilepsy via the microbiome.
rosis (MS) than in healthy people, while Parabacteroides distasonis https://www.fiercebiotech.com/biotech/bloom-bags-cash-ucla-tech-to-treat-
epilepsy-via-microbiome. Published May 24, 2018. Accessed June 18, 2018.
is 4 times more abundant in healthy people than in patients with 12 Lee H, Lee Y, Kim J, et al. Modulation of the gut microbiota by metformin
MS. Akkermansia and Acinetobacter are associated with inflam- 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
matory responses in MS, while Parabacteroides appears to have termination. Biochem Biophys Res Commun. 2017;484(2):450-455.
an anti-inflammatory action.15 This makes determining how 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.
we approach the use of specific probiotics for any given patient v26.26164.
15 Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis
trickier than it may seem at first glance. patients modulate human T cells and exacerbate symptoms in mouse models.
Proc Natl Acad Sci. 2017;114 (40):10713-10718.
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.
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The Gut-Skin Axis and

Mechanisms for Communication Raja Sivamani, MD, AP
An emerging area of research in Western medicine (Ayurvedic Practitioner)
ABSTRACT MODES OF COMMUNICATION FROM THE GUT

The association between gut health and general health TO THE SKIN
has been the focus of many medical approaches, The gut may communicate with the skin in several ways:
including traditional Chinese medicine, Ayurvedic medi-
• Absorption of nutrients with a direct effect on the skin
cine, and naturopathic medicine. The discovery of the
gut microbiome has led to new areas of research that • Absorption of nutrients that can stimulate hormonal changes
focus on the possible biochemical mechanisms that can that affect the skin
relate gut health to local disease as well as the health of • Influence of gut microbiota on the immune system
distant organs. The relationship of the gut to the skin, • Modulation of the local microbiome that releases metabolites
referred to as the gut-skin axis, is one emerging area of that may have distant effects on the skin
research. Here we review several potential mechanisms
Absorption of nutrients with a direct effect
by which the gut may interact with the rest of the body
on the skin
and the skin, along with several skin-related examples.
The absorption of nutrients and their direct effects on the skin
Further research is needed to delineate the biochemical
has been a focus of several studies. For example, the intake of
mechanisms in this emerging and exciting area.
carotenoids has been correlated to yellowing of the skin,7,8 and
INTRODUCTION beta-carotene supplementation has been studied in the preven-
tion of sunburns.9 In addition, oral vitamin E can be delivered
The gut and skin are both complex immune and neuro-
to the skin, especially through sebaceous glands.10
endocrine organs, and each has a community of microbes
that governs the physiology of their local surroundings.1
Absorption of nutrients that stimulate
A 3-directional communication among the brain, skin, a change in hormones
and gut, along with influences from the immune and
endocrine systems, has been identified, although not fully Absorbed nutrients frequently shift hormones in the body.
understood.1 Pathology of the gastrointestinal tract and Examples include the influence of carbohydrates and whey
diet have been shown to influence skin health.2,3 Many protein on insulin levels, which can have an impact on the skin.
skin conditions have been linked to gastrointestinal As an example, whey protein may be associated with increased
inflammation, including rosacea, psoriasis, and acne.2-4 insulin secretion11 and has been reported as a potential culprit
Skin lesions can also occur in association with gastroin- in acne flares.12-14 Insulin-like growth factor 1 (IGF-1) activates
testinal conditions such as inflammatory bowel disease the sebaceous glands to produce more inflammatory mediators
(IBD) and celiac disease.5,6 and more sebum,15 which may trigger a worsening of acne.
Moreover, consuming more high-glycemic, refined carbohy-
The recognition that the gut and skin are connected is drates may increase the concentration of IGF-1 and increase
not new; traditional forms of medicine that have been the risk of developing acne.16
around for thousands of years, such as Ayurvedic medi-
cine and traditional Chinese medicine, have a gut-cen- The influence of gut microbiota
tric approach to health and disease. As research continues on the immune system
to expand in this area, the notion of a gut-skin axis has The gut microbiota interact with the immune system and
started to emerge in Western research. In this review, we appear to interact with and educate the regulatory T cells that
aim to discuss emerging mechanisms for how the gut may can drive inflammation elsewhere in the body.17,18 Regulatory
influence dermatologic health. (continued on page 24)
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T cells seem to play an important role in autoimmune and gut’s ability to communicate with the skin through multiple
inflammatory skin diseases19-21 although the role of the gut modalities. As research continues to grow, we will gain a
microbiome remains under study in these areas. better understanding of which of these mechanisms, and
likely other mechanisms, may serve as important mediators
Modulation of the local microbiome and influence and thus a target for both pharmacological and nutritional
on the local immune system intervention.
The microbiota and the gut epithelial lining interact and
release secondary metabolites that can have distant effects Apart from possible mechanisms, there are several lines of
on the skin. Previous studies have suggested that changes in evidence that suggest that gut dysbiosis is involved in skin
gut microbiota and the microbiota-derived inflammatory disease. We review a few of them below.
mediators may impact chronic inflammation and the risk for
cardiovascular disease, obesity, kidney disease, and diabetes.22 DISEASE-BASED EXAMPLES OF GUT
DYSBIOSIS IN SKIN DISEASE
There is growing evidence that gut-derived mediators may
communicate with the skin as well. Examples of mediators Small intestinal bacterial overgrowth and
include lipopolysaccharide (LPS) and short chain fatty acids. papulopustular rosacea
It has been hypothesized that gut-derived LPS may play a role Often mistaken for acne, papulopustular rosacea can occur
in acne inflammation,23 though definitive mechanistic studies with erythematotelangiectatic rosacea, and is characterized by
are still lacking. Short-chain fatty acids have long been postu- erythema, papules, and pustules.26 Papulopustular rosacea is
lated to affect general inflammation in the body and modu- not only associated with a dysbiosis of the cutaneous micro-
late obesity, diabetes, and colon cancer risk.24,25 Short-chain biome, but also with small intestinal bacterial overgrowth
fatty acids may modulate inflammation,25 and patients with (SIBO), a dysbiosis of the intestinal tract.3,27 Oral antibiotic
acne have lower blood levels of these fatty acids than healthy treatment of SIBO has been shown to induce remission in
controls (Sivamani, unpublished data, 2018). rosacea symptoms.3,28,29
While these mechanisms may not serve as a comprehen-
Dysbiosis and psoriasis
sive examination of the gut-skin axis, they bring to light the
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
The recognition that Faecalibacterium and decreased Bacteroides compared to the
healthy controls.4 A similar study found that, compared to
the gut and skin are connected is not new; healthy controls, psoriasis patients had an increased ratio
traditional forms of medicine that have of Faecalibacterium to Bacteroides in the intestinal micro-
biome and an increase in Streptococcus and decrease in both
been around for thousands of years, such as Propionibacterium and Actinobacteria on the skin’s surface.4
Ayurvedic medicine and traditional Chinese High-glycemic diet and acne vulgaris
medicine, have a gut-centric approach to The Standard American Diet (SAD) is a high-glycemic diet
rich in processed fast foods, refined carbohydrates, animal
health and disease. proteins, and omega-6 polyunsaturated fatty acids.30 Seventy-
five percent of Americans consume a Standard American
Diet.31 Studies have shown that consuming a Standard American THE ROLE OF PROBIOTICS
Diet increases pro-inflammatory mediators.31 Leucine, an amino Oral probiotics act locally when ingested, but can have
acid found in animal protein and dairy products, stimulates effects on distant organ systems through the immune
the mammalian target of rapamycin complex 1 (mTORC1);32 system.35 Through interactions with lymphoid tissue,
mTORC1 then activates SREBP,33 which is a transcription probiotics may regulate the release of inflammatory cyto-
factor that drives lipogenesis in the sebocytes. Sebocytes convert kines that are often increased in various skin conditions.36
leucine into fatty acids and sterols to synthesize sebaceous Indeed, there are several lines of evidence supporting the
lipids.33 Overaction of mTORC1 through the consumption of use of probiotics for skin conditions.
a SAD increases the secretion of androgen hormones such as
testosterone, which activates mTORC1 to stimulate the seba- A systematic review and meta-analysis of randomized
ceous follicles to produce more sebum.33 Acne is recognized to controlled trials concluded that, although Lactobacillus
be an mTORC1-driven disease of civilization and diet.32,33 Areas plantarum and Lactobacillus rhamnosus did not have a
where high-glycemic diets are not consumed, such as in isolated significant effect on SCORAD (scoring atopic dermatitis)
hunter-gatherer communities, have extremely low rates of acne.34 scores in children with atopic dermatitis, Lactobacillus
fermentum, Lactobacillus salivarius, and a mixture of 4
Inflammatory bowel disease and different strains (Lactobacillus rhamnosus GG, L rham-
various skin lesions nosus LC705, Bifidobacterium breve, and Propionibacterium
Crohn’s disease and ulcerative colitis are the 2 main categories freudenreichii ssp Shermanii) did.37,38 In acne patients,
of IBD.6 Their pathophysiology is not limited to the gastrointes- oral supplementation of Lactobacillus decreased the levels
tinal tract; IBD is associated with extraintestinal manifestations of IGF-1 fourfold compared to no probiotic supplemen-
in 6% to 47% of patients.6 In 25% of patients with IBD, the tation.39 In another study, patients with acne who were
extraintestinal manifestations precede the diagnosis of Crohn’s or supplementing with Lactobacillus acidophilus, Lactobacillus
ulcerative colitis.6 The cutaneous extraintestinal manifestations delbrueckii, and Bifidobacterium bifidum along with
of IBD include erythema nodosum, pyoderma gangrenosum, conventional antibiotic treatment experienced increased
Sweet’s syndrome, and oral lesions.6 Erythema nodosum is the resolution of their acne and better tolerance of the antibi-
most commonly reported skin lesion associated with IBD, and otic treatment.40
pyoderma gangrenosum reflects IBD in its most severe state.6
Despite these promising results, there remain many ques-
Although the mechanism is not well-understood, information
tions. Further research is needed to better understand how
collected from a clinical trial suggested that blockade of tumor
specific strains should be chosen and dosed. Most of the
necrosis factor (TNF) may play a role in the pathogenesis of these
research has focused on bacteria, and it is not known if
skin conditions in IBD.6
fungal microbiota and probiotics that are inclusive of fungi
are important.
Celiac disease and dermatitis herpetiformis
Dermatitis herpetiformis is an extremely pruritic eruption seen While questions still remain, there is no doubt that further
on the buttocks and the extensor surfaces of the extremities. research into the gut microbiome and how it contributes
It affects approximately 17% of patients with celiac disease,5 more widely to general health is exciting. As our knowledge
though it may not be detected until up to 10 years after the grows regarding how food, probiotics, and the gut micro-
celiac disease diagnosis.5 In most cases, dermatitis herpetiformis biome modulate health, it is our hope that our dietary and
in patients with celiac disease indicates poor adherence to a lifestyle patterns will shift toward both healthier skin and a
gluten-free diet.5 healthier metabolic state.
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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-
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5 Salmi TT, Hervonen K, Kurppa K, Collin P, Kaukinen K, Reunala T. Celiac disease
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evolving into dermatitis herpetiformis in patients adhering to normal or gluten-free
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disease. Clin Rev Allergy Immunol. 2017;53(3):413-427.
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
vegetables influences skin yellowness and plasma carotenoids in young women: a
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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9 Kopcke W, Krutmann J. Protection from sunburn with beta-carotene—a meta-
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34 Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris:
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AUGUST 2018 SUPPLEMENT

The Microbiome and

The Gut-Skin Axis Lessons from Studying

Stable at room Delayed-release Gluten-free Non-dairy

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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

22 The Gut-Skin Axis and Mechanisms for Communication

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

EDITOR IN CHIEF MESSAGE FROM THE PUBLISHER

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The Gut-Skin Axis and

ABSTRACT MODES OF COMMUNICATION FROM THE GUT

REFERENCES 21 Owczarczyk-Saczonek A, Czerwinska J, Placek W. The role of regulatory T cells

The Gut-Brain Axis

ABOUT THE EXPERT

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

A Deeper Exploration of Probiotics and

ABOUT THE EXPERT ABOUT THE SPONSOR

SUBSCRIBE TO THE NMJ PODCAST IN iTunes

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