Natural Medicine Journal Microbiome Special Issue by Diversified Communications

AUGUST 2018 SUPPLEMENT

SPECIAL ISSUE

The Microbiome and Integrative Medicine

The Gut-Skin Axis Synbiotic Supplementation for PCOS Fiber Enhances Microbiome to Control Glucose

Lessons from Studying Breast MicrobiotaÂ Ketogenic Diet Changes Microbiome to Fight Seizures

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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 by Allergy Research Group

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Contributors MEGAN CHMELIK is a third-year naturopathic medical student at National University of Natural Medicine in Portland, Oregon. Before moving to Portland, she worked for Rena Bloom, ND, and Jacob Schor, ND, FABNO, at the Denver NaturoMegan Chmelik pathic Clinic. As part of a tradition of mentoring receptionists and preparing them for naturopathic school, Schor encouraged Chmelik to learn how to use PubMed and write review articles. Now years later, it is clear that this passion of his has been passed down as she continues to write for NMJ during her spare time. MARK DAVIS, ND, is the medical director of Good Life Medicine Center, Portland, Oregon, and his naturopathic practice, Bright Medicine Clinic, focuses on gastro enterological health. Davis is one of a handful of physicians in North Mark Davis, ND America with clinical expertise in fecal microbiota transplantation. Davis is on the board of directors of the Fecal Transplant Foundation, Carmel, Indiana, and chairs the Fecal Microbiota Transplant Committee for the C diff Foundation, New Port Richey, Florida. He received his naturopathic degree with honors in research from the National College of Natural Medicine, Portland. He cohosts the popular podcast The Naturocast. TINA KACZOR, ND, FABNO, is editor-in-chief of Natural Medicine Journal and a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National University of Natural Medicine and Tina Kaczor, ND, FABNO completed her residency in naturopathic oncology at Cancer Treatment Centers of America, Tulsa, Oklahoma. Kaczor received undergraduate degrees from the State University of New York at Buffalo. She is the past president and treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peer-reviewed journals. Kaczor is based in Portland.

JACOB SCHOR, ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and Jacob Schor, ND, FABNO is on the board of directors of the Oncology Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician’s Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary editor. RAJA SIVAMANI, MD, is a board-certified dermatologist, Ayur vedic practitioner, and serves as the lead Scientific Advisor and Editor for Dermveda and LearnSkin. He is currently an associate professor of clinical dermatology at the UniverRaja Sivamani, MD, MS, AP sity of California, Davis and serves as the director of clinical research and the Clinical Trials Unit with a focus on engineering, nutrition, and microbiome focused clinical studies. He is also an adjunct assistant professor in the Department of Biological Sciences at the California State University, Sacramento. He engages in clinical practice as well as both clinical and translational research that integrates bioengineering, nutrition, cosmetics, and skin biology. With training in both allopathic and ayurvedic medicine, he takes an integrative approach to his patients and in his research, with a focus on the gut and skin microbiome and lipidome. He has published over 100 peer-reviewed research manuscripts, 10 textbook chapters, and a textbook titled Cosmeceuticals and Active Cosmetics, 3rd Edition. He has a passion for expanding the evidence and boundaries of integrative medicine for skin care.

EDITOR IN CHIEF Tina Kaczor, ND, FABNO

MESSAGE FROM THE PUBLISHER

ABSTRACTS & COMMENTARY EDITOR Jacob Schor, ND, FABNO

Practical, Clinical Applications of the Human Microbiome Research

PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry PUBLISHED BY IMPACT Health Media, Inc. Boulder, Colorado Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2018 by IMPACT Health Media, Inc. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; IMPACT Health Media, Inc. assumes no liability for any information published herein. Advertisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this 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 articles or advertisements.

The complex ecosystem of bacteria in and on the human body provides a vast playground for researchers and clinicians alike. The practical applications of information gleaned from the human microbiome is not only fascinating, it’s rich with ways to increase treatment efficacy and enhance patient outcomes. And that’s what this special issue of the Natural Medicine Journal is all about. This subject is huge so there is only so much we can cover in one special issue. We 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 connection is authored by one of our newest editorial board members, Raja Sivamani, MD, a respected and widely published integrative dermatologist. We have two podcast interviews featuring naturopathic experts: Donald Brown, ND, talks about probiotics 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 ketogenic diet, synbiotic supplementation in women with PCOS, and type 2 diabetes. Our Editor-in-Chief, Tina Kaczor, ND, FABNO, also reviews a fascinating study on the microbiome differences in malignant versus non-malignant breast tissue. Research into the human microbiome in health and illness is moving at a brisk pace. Staying on top of this research will become increasingly important to clinicians. We hope we can help contribute to that knowledge base by doing special issues like these. We appreciate the contributions of our authors, editors, and reviewers who contribute their time and expertise to help you help your patients. As always, if you like this issue, please share it with your colleagues so they can receive Natural Medicine Journal each month—as well as our special issues—for free. In good health,

Karolyn A. Gazella Publisher, Natural Medicine Journal

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 synbiotic supplementation on metabolic status in women with polycystic ovary syndrome: a randomized doubleblind clinical trial [published online ahead of print March 12, 2018]. Probiotics Antimicrob Proteins. DESIGN

A 12-week randomized double-blind placebo-controlled clinical trial. OBJECTIVE

To determine the effect of synbiotic supplementation on markers of glycemic control and cardiometabolic 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 synbiotic 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, hyperprolactinemia, 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.

Megan Chmelik All participants were advised to maintain 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 12 to assess markers of glycemic 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 unspecified reasons. In keeping with the intention-to-treat principle, all participants 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 nonsignificant (P=0.06).

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 oligoovulation/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 associated 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 intervention 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 microbiota have been shown to contribute to its antidiabetic effects.5 A correlation between gut dysbiosis and diabetes has been documented 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 microbiome 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 significant 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 estimator takes into consideration total cholesterol, LDL-C, and HDL-C, it is unlikely that a direct reduction in cardiovascular risk would be achieved from synbiotic supplementation alone.

“

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 supplementation 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 supplementation or other microbiota-modulating therapy, appears to be a worthwhile consideration for our patients with PCOS. While probiotics and supplements alike are generally considered 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 hospitalized 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 prevalence 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. 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-implication 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):99103. 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 composition 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 Endocrinol 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.

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 supplementation on body mass index, metabolic and inflammatory biomarkers, and appetite 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 metabolism 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: a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2017;117(8):10951102. 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-controlled, 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 microbiome 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 interventions were transplanted into germ-free mice. These mice ended up with gut biomes that more resembled the transplanted 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.

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 significantly 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 metabolic health parameters than mice transplanted with pre-intervention 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 significantly 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 microbiota affect blood sugar control. This study suggests that we can improve glycemic control by shifting bacterial populations in the intestinal microbiome. We already know that high-fiber diets help control diabetes, but we have generally thought this benefit was because higher fiber would lower the glycemic index of carbohydrates.1 We have repeated this idea for years even as we began to appreciate that there is little difference in glycemic index between whole grain and white flour products. We can now imagine that the difference in action was that the whole-grain versions provided more fermentable carbohydrates 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 common prescription employed for treating early type 2 diabetes, the same indication used in the United States for which we might prescribe metformin.2 A 2014 Chinese study that compared acarbose against metformin showed that both agents decreased HbA1c levels to similar degrees and were equally effective in controlling the disease.3 Metformin also changes the gut microbiota,4 increasing levels of Akkermansia.5 Diabetes is now considered a disease of the gut microbiota.6,7 The botanical extract berberine, which we have often used clinically to replace metformin, also shifts the gut biome in a similar manner as metformin.8

“

We already know that high-fiber diets help control diabetes, but we have generally thought this benefit was because higher fiber would lower the glycemic index of carbohydrates.

”

pomegranate,13 a range of anthocyanin-containing berries such as cherries,14 and, in general, polyphenols.15

This study provides a mechanistic explanation for why a diet high in vegetables, which provide fiber, and fruits, which may have anti-amylase action, is useful in treating type 2 diabetes: the gut biome shifts to increase SCFA production. Diabetics are often cautioned against eating fruit, but this advice may actually be counterproductive; in fact, sugar-sweetened fruit juices are significantly associated with the risk of developing type 2 diabetes, but whole fruits16 and 100% fruit juices17 are not. It may eventually prove useful to know the relative 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 experialso 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 concenIf we were willing to anthropomorphize fruits, we could see trates may have acted as anti-amylose agents, similar to acarhow 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 advantage. 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 recommendations for individuals with diabetes: a quantitative assessment and meta-analysis 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-implication of the gut microbiome? Curr Opin Clin Nutr Metab Care. 2018;21(4):294-301.

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 (Adansonia 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-glucosidase, 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. Pomegranate juice, but not an extract, confers a lower glycemic response on a high-glycemic 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 efficiency, 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 systematic 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/postmenopausal and 13.3% were premenopausal, while 53.9% of the women with BBD were peri/postmenopausal and 46.2% were premenopausal (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 signatures. 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).

Tina Kaczor, ND, FABNO PRACTICE IMPLICATIONS The authors’ first assertion is that this study “confirms the existence of a distinct breast microbiome and differences 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 feedings. 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 assumption 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 causative. 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 methodological reasons.

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 presence 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 consistent. This is due to several factors, including the immense complexity of the microbiome, inherent differences in techniques, 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-diseased 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

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 components 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-contaminated 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 children with pharmacoresistant epileptic encephalopathy: a clinical 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 pharmacoresistant 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 electroencephalogram 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

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

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 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 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 autismlike 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

In this mouse study, the authors demonstrated that the ketogenic 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

UCLA has already granted licensing rights to a start-up company that is raising funds to develop a probiotic treatment 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 sclerosis (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 inflammatory 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.

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 epileptogenesis 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-seizure 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 spectrum 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-treatepilepsy-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 medicine, 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 neuroendocrine 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 gastrointestinal 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 medicine and traditional Chinese medicine, have a gut-centric 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.

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 prevention 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 carbohydrates 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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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 postulated to affect general inflammation in the body and modulate 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 comprehensive 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.

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 microbiome, 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 composition 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 microbiome 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 Seventyfive percent of Americans consume a Standard American

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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 sebaceous 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 gastrointestinal 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

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 cytokines 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 rhamnosus 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 supplementation.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 antibiotic treatment.40 Despite these promising results, there remain many questions. 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 microbiome modulate health, it is our hope that our dietary and lifestyle patterns will shift toward both healthier skin and a healthier metabolic state.

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REFERENCES

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21 Owczarczyk-Saczonek A, Czerwinska J, Placek W. The role of regulatory T cells and anti-inflammatory cytokines in psoriasis. Acta Dermatovenerol Alp Pannonica Adriat. 2018;27(1):17-23. 22 Al-Obaide MAI, Singh R, Datta P, et al. Gut microbiota-dependent trimethylamine-n-oxide and serum biomarkers in patients with T2DM and advanced CKD. J Clin Med. 2017;6(9). 23 Bowe WP, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future? Gut Pathog. 2011;3(1):1. 24 Schwarz A, Bruhs A, Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system. J Invest Dermatol. 2017;137(4):855864. 25 McNabney SM, Henagan TM. Short chain fatty acids in the colon and peripheral tissues: a focus on butyrate, colon cancer, obesity and insulin resistance. Nutrients. 2017;9(12). 26 Mikkelsen CS, Holmgren HR, Kjellman P, et al. Rosacea: a clinical review. Dermatol Reports. 2016;8(1):6387. 27 Gallo RL, Nakatsuji T. Microbial symbiosis with the innate immune defense system of the skin. J Invest Dermatol. 2011;131(10):1974-1980. 28 Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6(7):759764. 29 Drago F, De Col E, Agnoletti AF, et al. The role of small intestinal bacterial overgrowth in rosacea: A 3-year follow-up. J Am Acad Dermatol. 2016;75(3):e113-e115. 30 Totsch SK, Quinn TL, Strath LJ, et al. The impact of the Standard American Diet in rats: Effects on behavior, physiology and recovery from inflammatory injury. Scand J Pain. 2017;17:316-324. 31 United States Department of Agriculture. Dietary Guidelines for Americans 20152020. Current eating patterns in the United States. https://health.gov/dietaryguidelines/2015/guidelines/chapter-2/current-eating-patterns-in-the-united-states/ . Accessed July 30, 2018. 32 Melnik B. Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol. 2012;4(1):20-32. 33 Melnik BC. Acne vulgaris: The metabolic syndrome of the pilosebaceous follicle. Clin Dermatol. 2018;36(1):29-40. 34 Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590. 35 Kober MM, Bowe WP. The effect of probiotics on immune regulation, acne, and photoaging. Int J Womens Dermatol. 2015;1(2):85-89. 36 Hacini-Rachinel F, Gheit H, Le Luduec JB, Dif F, Nancey S, Kaiserlian D. Oral probiotic control skin inflammation by acting on both effector and regulatory T cells. PLoS One. 2009;4(3):e4903. 37 Huang R, Ning H, Shen M, Li J, Zhang J, Chen X. Probiotics for the treatment of atopic dermatitis in children: a systematic review and meta-analysis of randomized controlled trials. Front Cell Infect Microbiol. 2017;7:392. 38 Viljanen M, Savilahti E, Haahtela T, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy. 2005;60(4):494-500. 39 Quadros E, Landzert NM, LeRoy S, Gasparini F, Worosila G. Colonic absorption of insulin-like growth factor I in vitro. Pharm Res. 1994;11(2):226-230. 40 Jung GW, Tse JE, Guiha I, Rao J. Prospective, randomized, open-label trial comparing the safety, efficacy, and tolerability of an acne treatment regimen with and without a probiotic supplement and minocycline in subjects with mild to moderate acne. J Cutan Med Surg. 2013;17(2):114-122.

EXPERT INTERVIEW

The Gut-Brain Axis

An interview with Steven Sandberg-Lewis, ND, DHANP Play Now

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 cognition. 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 gastroenterology at National University of Natural Medicine and has a private practice at 8Hearts Health and Wellness in Portland, Oregon. He lectures, presents webinars and interviews on issues of digestive health. He is the author of the medical textbook Functional Gastroenterology: Assessing and Addressing the Causes of Functional Digestive Disorders, Second Edition, 2017. His column Functional Gastroenterology Bolus appears regularly in the Townsend Letter.

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Within gastroenterology, he has special interest and expertise in inflammatory 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.