Natural Medicine Journal Immune Health Special Issue 2021

Page 1



Immune Health

Is Hydrogen Water Worth the Hype?

Probiotics and Liver Cirrhosis

Bee Propolis for Upper Respiratory Tract Infections

Environmental Influences on the Microbiome

How to Strengthen Viral Immunity

Cancer Immunotherapy Insights

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Copyright © 2021 by the Natural Medicine Journal. All rights reserved.



Contents 4 Contributors 5

Message from the Publisher



Propolis for Upper Respiratory Tract Infections


Improved Natural Killer Cell Function with Seaweed Extract


Going Beyond the Hype of Hydrogen Water


Cancer Immunotherapy Dependent on Gut Biome


Probiotics and Their Immunological Impact on Liver Cirrhosis



Environmental Factors that Affect the Microbiome

An interview with Heather Zwickey, PhD



Strengthening Viral Immunity

An Interview with Russell Jaffe, MD, PhD



Contributors RAMNEEK BHOGAL, DC, DABCI, enjoys private practice at Wolfe Family Chiropractic in Metamora, MI. A graduate of Palmer College of Chiropractic, he is also a diplomate of the American Board of Chiropractic Internists and has trained with the Institute of Functional Medicine. Bhogal has been published in peer-­ reviewed journals and recently coauthored a chapter in a pediatric chiropractic textbook with his wife, Stephanie O’Neill Bhogal, DC, DICCP. Together, they also established Peak Potential Outreach, a nonprofit organization committed to bringing healthcare to the globally ­underprivileged.

TINA KACZOR, ND, FABNO, is editor-inchief 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 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 is the editor of the Textbook of Naturopathic Oncology. She has been published in several peer-reviewed journals. Kaczor is based in Portland, Oregon.

DANA G. COHEN, MD, has been practicing integrative medicine in private practice in the heart of Manhattan. Cohen earned her medical degree from St. George’s University School of Medicine, completed a 3-year internal medicine residency at Albany Medical Center, and was board-certified by the American Board of Internal Medicine in 1998. She is coauthor of the book, QUENCH: Beat Fatigue, Drop Weight, and Heal Your Body Through the New Science of Optimum Hydration (Hachette Books). For more information about Cohen visit her website at d ­

BERT MATHIESON, ND, RD, CDCES, is a naturopathic doctor, registered dietitian, and certified diabetes educator. He is the medical director at New Hampshire Natural Health Clinic in Bedford, New Hampshire. Mathieson is a general family practitioner and has special interests in diabetes, Lyme disease, and cancer. He is a member of the Oncology Association of Naturopathic Physicians (OncANP) and the International Lyme and Associated Diseases Society (ILADS). In his spare time he enjoys competing internationally in freestyle skateboarding and kayaking with his wife, Kitty.

KAROLYN A. GAZELLA has been writing and publishing integrative health information since 1992. She is the publisher of the Natural Medicine Journal and the author or coauthor of hundreds of articles and several booklets and books on the topic of integrative health. Gazella is the cocreator and chief executive officer of the iTHRIVE Plan, an innovative online wellness program specifically for cancer survivors. She also cohosts the popular podcast for patients, Five to Thrive Live, and hosts the Natural Medicine Journal podcast for integrative healthcare professionals.

JACOB SCHOR, ND, FABNO, is a graduate of National University of Naturopathic Medicine, Portland, Oregon, and recently retired from his practice in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is a past member of the board of directors of the Oncology Association of Naturopathic Physicians and American 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 past Abstracts & Commentary editor.


Copyright © 2021 by the Natural Medicine Journal. All rights reserved.

EDITOR-IN-CHIEF Tina Kaczor, ND, FABNO ABSTRACTS & ­COMMENTARY EDITOR Lise Alschuler, ND, FABNO PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry ASSOCIATE EDITOR Kristin Bjornsen PUBLISHED BY IMPACT Health Media, Inc. 223 N. Guadalupe #718 Santa Fe, NM 87501 Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2021 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.


An Integrative Approach to Enhancing Immunity This special issue of the Natural Medicine Journal explores a variety of topics related to immune function—an important and timely theme that is top of mind for most integrative health professionals these days. The sponsored podcast featuring integrative medical expert Russel Jaffe, MD, PhD, discusses ways to specifically enhance viral immunity. And another interview, this one featuring immunologist Heather Zwickey, PhD, explores how environmental factors affect the microbiome. In addition, our Abstracts & Commentary looks at a variety of recent research on i­mmunity-related topics, including upper respiratory tract infections, hydrogen water, Porphyra tenera, probiotics, and fecal microbiota transplant. It’s obvious from this diverse offering that integrative medicine continues to offer many valuable tools to help enhance immunity as integrative practitioners continue to play an important role in helping their patients. On behalf of the entire Natural Medicine Journal team, we thank you for your continued support and your ongoing efforts to keep your patients safe and healthy. As always, these publications would not be possible without the contributions of time and expertise from our writers, reviewers, and editorial board. We would also like to thank the advertisers who support our special issues. Please click on the ads to learn more about the quality products and companies featured in this issue. And finally, if you found this special issue interesting, please share it with a colleague. In health,

Karolyn A. Gazella Publisher, Natural Medicine Journal



Propolis for Upper Respiratory Tract Infections Could bees provide a solution to a prevalent and costly problem? REFERENCE

Esposito C, Garzarella EU, Bocchino B, et al. A standardized polyphenol mixture extracted from poplar-type propolis for remission of symptoms of uncomplicated upper respiratory tract infection (URTI): a monocentric, randomized, double-blind, placebo-controlled clinical trial. Phyto­medicine. 2021;(80):153368. STUDY OBJECTIVE

To evaluate the effects of a standardized oral spray of poplar-type propolis extract (M.E.D. Propolis) on the symptoms of mild upper respiratory tract infections (URTIs) DESIGN

A monocentric, placebo-controlled, double-blind clinical trial performed in an outpatient setting PARTICIPANTS

This study involved 122 subjects (58 in the propolis group and 64 in the placebo group). The age range was from 18 to 77 years; 54 subjects were male, and 68 were female. All subjects had signs and/or symptoms of a URTI. Subjects were examined by a physician and were eligible for inclusion in the study if they suffered from 1 or more of the following common URTI symptoms: sore throat, muffled dysphonia, and swelling and redness of the throat that began on the same day as the baseline visit (t=0). INTERVENTION

The subjects were randomly assigned to receive either a propolis oral spray or a placebo spray from t1 to t3 (5 days). Dose was 2 to 4 sprays 3 times daily. Researchers evaluated each participant at 4 time points: baseline=t0, after 3 days=t1, after 5 days=t2, and at 15 days=t3. The propolis spray was standardized to contain 15 mg/mL of polyphenols. The spray had a reproducible composition of the 6 major flavonoids found in this type of propolis (ie, galangin, chrysin, pinocembrin, apigenin, pinobanksin, quercetin). Each participant used 2 to 4 sprays 3 times daily for 5 days. The placebo spray had an identical appearance and flavor to the propolis spray. STUDY PARAMETERS ASSESSED

Apart from the primary outcome measure, the researchers evaluated the persistence of positive bacterial throat cultures at t3. They performed throat swabs on all subjects

By Bert Mathieson, ND, RD, CDCES at t0 and then again at t2 and t3 on those subjects who had an initially positive throat culture. At t0, 8 people in the treatment group and 7 people in the placebo group were positive for a bacterial URTI. At t3, none of the subjects in either the treatment or placebo group were found to have a positive bacterial throat culture. PRIMARY OUTCOME MEASURES

The primary outcome measure was the resolution of URTI symptoms. Researchers assessed these symptoms at baseline (t0), 3 days (t1), after 5 days (t2), and at the final timepoint (t3) of the study, 15 days. At t1, 17% of the participants in the treatment group still had 1 symptom of an URTI. In contrast, about 72% of people in the placebo group still displayed 1 symptom (RR: 2.93, CI: 1.95–4.42). The results of a univariate analysis showed that only treatment with oral propolis spray was related to the disappearance of symptoms (resolution of all symptoms in the treatment group vs the placebo group: X2=35.57, df=1, P<0.001; resolution from sore throat in the propolis vs placebo group: X2=28.38, df=1, P<0.001; resolution of muffled dysphonia in the propolis vs placebo group: X2=4.38, df=1, P=0.036; and resolution of swelling and redness of the throat in the propolis vs placebo group: X2=16.85, df=1, P<0.001). All logistic models of the data were also significant, showing that the propolis spray was the only variable that correlated with the resolution of all symptoms and single symptoms (all symptoms: X2=46.51, df=7, P<0.001; sore throat: X2=34.21, df=6, P<0.001; swelling and redness of the throat: X2=23.19, df=6, P<0.001; muffled dysphonia: X2=7.87, df=3, P=0.048). There was no relationship noted between the resolution of symptoms after 3 days and the type of infection (bacterial or viral) or the age or gender of the subjects. KEY FINDINGS

The disappearance of all URTI symptoms occurred 2 days earlier in the propolis group vs the placebo group. Symptoms were gone within 5 days in the placebo group and within 3 days for the treatment group. This finding held true for both viral and bacterial URTIs. Since there were so few bacterial URTIs noted in this study, the authors were not able to make any conclusions related to the effects of propolis on antibiotic-resistant bacteria.


PRACTICE IMPLICATIONS Propolis has always interested me, and it has defied my attempts to categorize it. Is it an herbal medicine? Well, not exactly. It is certainly a “natural medicine.” Propolis is a very complex mixture consisting of polyphenols, wax, resins, pollen, essential oils, minerals, vitamins, and other components. It is created when bees collect plant exudates and mix them with their saliva.1 The bees use propolis to seal their hives, and it has an antimicrobial effect on the hive. The composition of propolis varies based on the type of bees, the time of the year, the plants the bees visit, and other variables.2 Dietrich Klinghardt, MD, recommends the incorporation of Brazilian green propolis into treatment plans for those with Lyme disease accompanied by bartonellosis. Bartonella is a gram-negative, intraerythrocytic bacteria that can be transmitted to humans by ticks and other vectors.3 In my experience, concomitant bartonellosis can make Lyme disease more complex to treat. People with chronic tick-borne diseases need treatment options, and it is nice to know that propolis can be on the menu. The bad thing about propolis, for the pharmaceutically minded, is that it is such a complex and variable mixture, making the “active compounds” difficult to identify. The good thing about propolis, for those who study and respect natural medicine, is that it is such a complex and variable mixture, with assumed synergies in medicinal compounds. A 2019 review by Przybylek and Karpinski notes that “this diversity of chemical composition gives propolis an additional advantage as an antibacterial agent. The combination of many active ingredients and their presence in various proportions prevents bacterial resistance from occurring.”4 Because of the concerning rise in nosocomial infections from antibiotic-resistant bacteria (especially of the gram-negative variety), there has been a recent focus on the development of “antibiotic hybrids.” These new drugs combine various classes of antibiotics in an attempt to overcome bacterial resistance.5 Perhaps the many constituents in propolis make it the ultimate “antibiotic hybrid?”

Clinicians using natural medicine should not be shy to incorporate propolis into treatment plans for many types of infections.

Clinicians using natural medicine should not be shy to incorporate propolis into treatment plans for many types of infections. As with many natural medications, propolis has nutrients that can enhance immunity and anti-inflammatory compounds to help deal with the inflammatory nature of infections.6 It has the multifaceted ability to be directly antimicrobial, nourishing, and immune-enhancing all at the same time.7 This is a high bar that would be quite hard for a synthetic drug to reach. As I continue to review studies on botanical/natural medicine, it appears less common to see a well-designed study on these topics conducted in the United States. This study is no exception. The current study was a collaboration between scientists in Italy and China. There are myriad variables that figure into the equation of the US medical system. One thing is certain though: We spend more on healthcare and have poorer outcomes than other developed nations.8 I can’t help but wonder how much it would benefit us if even a minute fraction of the money that we invest in pharmaceutical research were funneled into investigating natural medications and there were a serious attempt to integrate them into our primary healthcare system. This seems especially true in the age of growing microbial resistance to conventional antibiotics. I remember being impressed while on a trip to Japan that prescription “Kampo” herbal formulas were readily available at pharmacies. Every pharmacist whom we dropped in



on was familiar with Kampo herbal formulas and had a handy Kampo reference book to help them describe to us the composition and effects of these common prescriptions. In Japan, 90% of physicians prescribe Kampo herbal formulas, and the national insurance plan covers them.9 URTIs are the most common reason that people visit doctors worldwide. They result in a cost of $22 billion dollars and cause more than 20 million missed school/work days annually.10 Imagine the suffering that could be averted, and the money that could be saved, by incorporating propolis into the average primary-care URTI visit. This could help patients avoid more complicated URTIs and lessen the need for prescriptions such as steroids and codeine, which have significant side effects. Patients may also be better nourished to ward off the next immunologic assault.


1 Esposito C, Garzarella EU, Bocchino B, et al. A standardized polyphenol mixture extracted from poplar-type propolis for remission of symptoms of uncomplicated upper respiratory tract infection (URTI): a monocentric, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine. 2021;(80):153368. 2 Przybylek I, Karpinzki TM. Antibacterial properties of propolis. Molecules. 2019;24(11):2047. 3 Cheslock MA, Embers ME. Human bartonellosis: an underappreciated public health problem? Trop Med Infect Dis. 2019;4(2):69. 4 Przybylek I, Karpinzki TM. Antibacterial properties of propolis. Molecules. 2019; 24 (11):2047. 5 Domalaon R, Idowu T, Zhanel GG, Schweizer F. Antibiotic hybrids: the next generation of agents and adjuvants against gram-negative pathogens? Clin Microbiol Rev. 2018;31(2):e00077-17. 6 Sforcin JM. Propolis and the immune system: a review. J Ethnopharmacol. 2007;113(1):1-14. 7 Wolska K, Gorska A, Antosik K, Lugowska K. Immunomodulatory effects of propolis and its components on basic immune cell functions. Indian J Pharm Sci. 2019;81(4):575-588. 8 Tikkanen R, Abrams MK. U.S. health care from a global perspective, 2019: higher spending, worse outcomes? The Commonwealth Fund Web site. https://www.­globalperspective-2019. Accessed March 6, 2021. 9 Kobayashi Y. Kampo medicine in the new model core curriculum of pharmaceutical education. Yakugaku Zasshi. 2016;136(2):423-432. (Article in Japanese.) 10 Thomas M, Bomar PA. Upper respiratory tract infection. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.

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Improved Natural Killer Cell Function with Seaweed Extract New findings on how nori seaweed may enhance the immune system REFERENCE

Jung SJ, Jang HY, Jung ES, et al. Effects of porphyra tenera supplementation on the immune system: A randomized, double-blind, and placebo-controlled clinical trial. Nutrients. 2020;12(6). DESIGN

Randomized, double-blind, placebocontrolled trial of 8-weeks duration OBJECTIVE

To determine if an extract of the seaweed Porphyra tenera (commonly known as nori or laver, and also referred to as Pyropia tenera) has measurable immune-enhancing effects and is safe in humans PARTICIPANTS

A total of 111 participants out of 120 (men=20, women=100) completed the trial. Researchers equally recruited intervention and placebo groups (60 each). All participants were over the age of 50 at the start of the study and all had white blood cell (WBC) counts in the normal range (3,000 to 8,000 cells/µL). Exclusion criteria was extensive and included the following: vaccination for influenza within the prior 3 months, body mass index (BMI) <18 kg/m2 or >35 kg/m2, presence of any acute disease process or chronic disease process, any supplementation with medications or functional foods associated with immune enhancement for the prior month, use of antipsychotic drugs in the prior 3 months, suspected alcoholism or drug abuse, participation in other human tests in the prior 3 months, those who are fertile and

not on contraceptives, and those with abnormal liver or kidney function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] more than 3 times the upper normal limit, serum creatinine >2.0 mg/dL). INTERVENTION

Participants in the intervention group consumed 2.5 g/d of Porphyra tenera extract (PTE) in capsule form. The extraction process began as 100 kg of dried Porphyra tenera in 10% ethanol at 80 ± 2.0 degrees Celsius. The ethanol-extracted fluid was then processed through a 1-µm filter, lyophilized, and concentrated to 10–20 degrees Brix at 65–70 degrees Celsius. The end product contained 68.45 (±20%) mg/g of a specific porphyran called porphyra334 (des­ignating the chemical structure of the porphyran from this species). The placebo was identical in weight, color, and flavor and contained 99.6% microcrystalline cellulose, 0.2% caramel coloring, and 0.2% silicon dioxide. PRIMARY OUTCOME MEASURES

Function of natural killer (NK) cells at week 0 versus week 8. Researchers measured this using CytoTox 96® Non-Radioactive Cytotoxicity Assay kit (Promega Corp, Madison, WI). Cytotoxicity was expressed as a percentage using both natural release and maximal release of lactate dehydrogenase (LDH), using K562 as target cells. K562 is a human leukemia cell line. Tests used effector/ target cell ratios of 50:1, 25:1, and 12.5:1.


By Tina Kaczor, ND, FABNO


Researchers compared laboratory markers of immune augmentation from baseline (week 0) and end of study (week 8). This included: cytokines (interleukin-2 [IL-2], IL6, IL-12, interferon-gamma, and tumor necrosis factor-alpha [TNF-alpha]). They assessed the incidence of upper respiratory infection (URI) at baseline (week 0), midway (week 4), and end of study (week 8) using the Wisconsin Upper Respiratory Symptom Survey. All participants had 3 visits total: baseline visit (week 0), midway (week 4), and end of study (week 8). RESULTS

NK-cell activity level in the PTE group increased at every dilution level ver­sus baseline (E:T=12.5:1 P=0.0004; E:T=25:1 P=0.0034; and E:T=50:1 P=0.0055). There was no increase in NK-cell activity in the placebo group. While there was a tendency for improved NK-cell activity in the intervention versus placebo group, this did not reach statistical significance. There were no differences in the secondary outcome measure of cytokine concentrations after 8 weeks between the 2 groups. Safety indicators showed there was no significant difference between the 2 groups in laboratory tests, electrocardiograms, or vital signs. Adverse reactions: abdominal dis­ comfort=1, heartburn=4, contact dermatitis=1, left knee pain=1, chronic dermatitis=1, trigger finger=1, increased liver enzyme function tests=1, burn on back of hand=1. Of all the

In a 2021 review of the compound porphyran, the authors summarize its effects as ‘antioxidation, anticancer, antiaging, antiallergic, immunomodulatory, hypoglycaemic, and hypolipidemic.’

adverse reactions reported, the researchers deemed 6 cases as possibly caused by the intervention. KEY FINDINGS

The primary outcome measure, NK-cell activity, showed there was improvement in the intervention group versus their baseline but no significant difference between the intervention and placebo groups. Of the evaluable 111 participants, the incidence of URI at week 8 was 10 cases. There was no difference in cases between the 2 groups. This 8-week study of Porphyra tenera extract showed overall safety of the preparation.

COMMENTARY In this short study, the effects of the Porphyra tenera extract (PTE) suggest that it increases NK-cell function activity. There was, however, no increase in cytokines and, thus, no systemic immune augmentation. This may be due to the short time course or due to a true lack of stimulation of cytokines from PTE. The low incidence of URIs over the 8-week study is not surprising given that the researchers recruited healthy volunteers who met stringent criteria. The seaweed Porphyra tenera is a red algae and 1 of 133 Porphyra species (Porphyra spp). Out of the 133 species, 6 of them are largely cultivated: Porphyra yezoensis, Porphyra tenera, Porphyra haitanensis, Porphyra pseudolinearis, Porphyra dentata, and Porphyra angusta. Referred to as “nori” in Japan, “gim” or “kim” in Korea, and “zicai” in China, Porphyra spp are commonly consumed across the Asia-Pacific region in various forms.1 In English-speaking countries around the world and in many research papers, Porphyra spp is referred to as “laver.” In the United States and Canada, any of these terms may be used depending on the regional derivation of a given recipe. Nori sheets and snacks dominate the seaweed market in the United States, encompassing one-third of all sales, and growing.2 Various seaweeds the world over have been used as food due to their macronutrients, micronutrients, and ease of obtaining them along shorelines.3 Porphyra spp have readily extractable pigments, lipids, minerals, vitamins, amino acids, and polysaccharides, making it an intriguing candidate for commercial production of these nutrients.4 There are so many nutrients densely packed into this foodstuff, that it has been proposed as a feasible and sustainable functional food.5 Porphyran, an indigestible polysaccharide unique to Porphyra spp, is thought to be responsible for its immunomodulatory effects. Chemically, porphyran is a sulfated polysaccharide whose structure varies slightly among species.6 Immune-modulating action of polysaccharides is not surprising. They are often a constituent that provides immune-modulatory properties in plants, fungi, and bacteria commonly used for immune support (eg, 1-3 beta glucan).7 In a 2021 review of the compound porphyran, the authors summarize its effects as “antioxidation, anticancer, antiaging, antiallergic, immunomodulatory, hypoglycaemic, and hypolipidemic.”6 How porphyran influences immune function is paradoxical and appears to be context dependent, with both immune-suppressive and immune-augmentative effects suggested in ©2021 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, MAY 2021 SUPPLEMENT—VOL. 13, NO. 51 (SUPPL)  11


rodent studies.8 The effects may depend on the physiological differences between acute and chronic inflammation and, more specifically, the immune requirements or aberrations involved in each.9 The net immune homeostatic effect of porphyran is suggested in animal studies showing benefits in conditions such as allergies and autoimmunity as well as infections and cancer.10-12 Another possible mechanism that can explain immune homeostasis is possible effects on the gut microbiota. The indigestible polysaccharide is a prebiotic and may alter the microbiota, thus affecting nearly every system in the body.13 In one study of mice with colitis induced by dextran sodium sulfate (DSS), Porphyra tenera extracts shifted the composition of the microbiome found in the mouse gut and ameliorated the colitis.14 In another rodent study, Porphyra yezoensis led to a 2-fold increase in secretory immunoglobulin A (IgA) in the cecum and synergized with another saccharide from the seaweed called glycerol galactoside, favorably shifting the microbiota and its metabolites.15 The study currently under review standardized the porphyran content to 68.45 (±20%) mg/g of porphyran334, the specific porphyrin found in this species of Porphyra. Whether this is ideal, whether the ethanol or 1-µm filter separated out other synergistic constituents, and how this extract compares to consuming the whole food are all lingering questions. While extraction may lead us to answer the question regarding which constituent is responsible for a given action, ethnobotanical use involves the whole seaweed prepared through roasting, boiling, frying, keeping raw, fermenting, etc. Arguably, when we are querying the action of a plant in its traditional use, we should also use traditional means of preparation to test physiological effects. There is 1 caveat to any sourcing of food from seawater, and that is contamination. Seaweed generally contains alginate or other absorptive compounds that can bind pollutants, including microplastics, in open waters. Integration of smaller molecules such as petroleum distillates and nanoplastics are also a concern. The uptake of heavy metals into

Porphyra spp is being studied as a means of bioremediation of contaminated waters, so the extent of their ability to take up pollutants should be top of mind. Fortunately, most of the nori snacks sold in the US are from cultivated sources, usually in Japan. It is important to make sure this detail is somewhere on the label. Red algae, or Porphyra spp, will continue to be studied for the precise constituents that can someday be used as drug-like compounds in medicine. The presence of diverse nutrients and complex polysaccharides makes this seaweed an appealing whole food to recommend for our patients. REFERENCES

1 Fleurence J. Seaweeds as Food. In: Seaweed in Health and Disease Prevention. Elsevier Inc.; 2016:149-167.

2 Global seaweed snacks market is expected to reach USD 2.8 billion by 2028. Fior Markets. Global-Seaweed-Snacks-Market-Is-Expected-to-Reach-USD-2-80-Billion-by-2028Fior-Markets.html. Accessed April 25, 2021. 3 Wells ML, Potin P, Craigie JS, et al. Algae as nutritional and functional food sources: revisiting our understanding. J Appl Phycol. 2017;29:949-982.

4 Cao J, Wang J, Wang S, Xu X. Porphyra species: A mini-review of its pharmacological and nutritional properties. J Med Food. 2016;19(2):111-119. 5 Hentati F, Tounsi L, Djomdi D, et al. Bioactive polysaccharides from seaweeds. Molecules. 2020;25(14).

6 Qiu Y, Jiang H, Fu L, Ci F, Mao X. Porphyran and oligo-porphyran originating from red algae Porphyra: Preparation, biological activities, and potential applications. Food Chem. 2021;349. 7 Ramberg JE, Nelson ED, Sinnott RA. Immunomodulatory dietary polysaccharides: A systematic review of the literature. Nutr J. 2010;9(1):1-22.

8 Song J-H, Kang H-B, Park S-H, et al. Extracts of Porphyra tenera (Nori Seaweed) Activate the Immune Response in Mouse RAW264.7 Macrophages via NF- κ B Signaling. J Med Food. 2017;20(12):1152-1159. 9 Fu L, Qian Y, Wang C, Xie M, Huang J, Wang Y. Two polysaccharides from Porphyra modulate immune homeostasis by NF-κB-dependent immunocyte differentiation. Food Funct. 2019;10:2083.

10 Ishihara K, Oyamada C, Matsushima R, Murata M, Muraoka t. Inhibitory Effect of Porphyran, prepared from dried “nori”, on contact hypersensitivity in mice. Biosci Biotechnol Biochem. 2005;69(10):1824-1830. 11 Kazbowska K, Lin H-TV, Chang S-H, Tsai G-J. Anticancer Effects of Sterol Fraction from Red Algae Porphyra dentata. Evidence-Based Complement Altern Med. 2013;2013.

12 Bhatia S, Sharma A, Sharma K, et al. Review Article Novel Algal Polysaccharides from Marine Source: Porphyran. Vol 2.; 2008. Accessed April 25, 2021. 13 Cherry P, Yadav S, Strain CR, et al. Prebiotics from seaweeds: An ocean of opportunity? Mar Drugs. 2019;17(6).

14 Kim J, Choi JH, Ko G, et al. Anti-inflammatory properties and gut microbiota modulation of Porphyra tenera extracts in dextran sodium sulfate-induced colitis in mice. Antioxidants. 2020;9(998).

15 Ishihara K, Seko T, Oyamada C, Kunitake H, Muraoka T. Synergistic effect of dietary glycerol galactoside and porphyran from nori on cecal immunoglobulin A levels in mice. Food Sci Technol Res. 2021;27(1):95-101.




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Going Beyond the Hype of Hydrogen Water

New randomized, double-blind, controlled trial suggests hydrogen water can increase antioxidant capacity and reduce inflammation REFERENCE

Sim M, Kim CS, Shon WJ, Lee YK, Choi EY, Shin DM. Hydrogen-rich water reduces inflammatory responses and prevents apoptosis of peripheral blood cells in healthy adults: a randomized, double-blind, controlled trial. Sci Rep. 2020;10(1):12130. STUDY OBJECTIVE

To determine if hydrogen water versus plain water increases antioxidant capacity, reduces oxidative stress, and improves immune function in healthy adults PARTICIPANTS

A total of 38 healthy adults aged 20 to 59 years completed the trial and were randomly assigned to the plain water group (n=18) or the hydrogen water group (n=20). At baseline when the study began, there was no statistical difference in age, height, weight, body mass index (BMI), and daily water intake between the 2 groups (P>0.05). DESIGN

Randomized, double-blind, controlled trial INTERVENTION

For 4 weeks, each group drank 1.5 liters (approximately 51 ounces) of either plain or hydrogen water daily. The hydrogen water was regular water with hydrogen (H2) gas added. Researchers provided the water in 3 different bottles and directed all participants to drink the bottle of water within 1 hour of opening it to minimize the loss of dissolved hydrogen from those bottles containing it. MEASURED OUTCOMES

Researchers measured the following outcomes: • Antioxidant capacity as indicated by serum biological antioxidant potential (BAP) • Oxidative stress via the level of serum derivatives of reactive oxygen metabolites (d-ROMs) • Apoptosis via the number of apoptotic cells in the blood • Profiles of peripheral blood mononuclear cells (PBMCs) for cell-surface markers including CD4, CD8, CD14, CD20, and CD11b • Inflammation via toll-like receptor (TLR) NF-кB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling, as well as pro-inflammatory cytokine expression. 14 ©2021 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, MAY 2021 SUPPLEMENT—VOL. 13, NO. 51 (SUPPL)

By Dana G. Cohen, MD, and Karolyn A. Gazella

What is additionally interesting about this study is that the benefits of hydrogen water were more significant in individuals over age 30.


The following findings were observed:

• Participants in the hydrogen water group who were aged over 30 years showed a significant increase in BAP compared to the plain water group (P=0.028), but there was no significant effect on BAP in younger individuals in the hydrogen water group compared to plain water. • A marker for DNA damage due to oxidative stress (8-Oxo-2’-deoxyguanosine) significantly decreased in both groups (Δ=− 0.94 ± 1.44 ng/ mL, P<0.05 in the plain water group; Δ=−1.32 ± 1.05 ng/mL, P<0.001 in the hydrogen water group). • After the 4 weeks, the hydrogen water group showed a significantly lower percentage of PBMC apoptosis compared to the plain water group (P=0.036). • The frequency of CD14+ cells increased in the hydrogen water group and decreased in the plain water group, and this difference reached statistical significance (P=0.039). • The hydrogen water group had significantly lower expression levels of several cytokines: interleukin 1 beta (IL1B), interleukin 8 (IL8), interleukin 6 receptor (IL6R), and tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) compared to the plain water group. (continued on page 16)

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PRACTICE IMPLICATIONS Immune activation and inflammation go hand in hand as reactive oxygen species stimulate immune cells that cause the subsequent inflammatory response. Reducing underlying oxidative stress is an ongoing clinical objective with many patients, and finding safe, efficacious interventions that can do this on an ongoing basis is appealing. One such tool may be in the use of therapeutic hydrogen gas. In addition to hydrogen-rich water, hydrogen therapies include injecting hydrogen saline, inhaling hydrogen gas, using hydrogen eye drops, and taking hydrogen-rich water baths.1 The scientific community is just now uncovering hydrogen therapy’s mechanisms of action, which are diverse. They include:2 • Increasing antioxidant activity, • Inhibiting apoptosis and inflammation, • Modulating immune regulation, and • Regulating autophagy, circadian rhythm, and mitochondria. Hydrogen gas as a therapeutic tool is being investigated for a variety of conditions in the scientific literature because of these multiple mechanisms of action. But what does the research tell us specifically about hydrogen water?


Similar to therapeutic hydrogen gas, hydrogen water has been studied in diverse patient populations and has shown positive effects on antioxidant status, immunity, and inflammation. For example, a 2017 randomized, placebo-controlled trial involving colon cancer patients undergoing chemotherapy treatment showed that hydrogen water helped protect against chemotherapy-induced liver damage compared to placebo.3 This is consistent with a 2011 randomized, placebo-controlled trial involving liver cancer patients that showed hydrogen water reduced radiation-induced oxidative stress without compromising the antitumor effects compared to placebo.4 In that study, quality-of-life scores were also significantly better in the hydrogen water group compared to placebo. Metabolic syndrome is another area where there is growing research regarding the benefits of hydrogen water. In a 2010 pilot study involving individuals at risk of developing metabolic syndrome, the group drinking the hydrogen water had a 39% increase in the antioxidant enzyme superoxide dismutase (SOD), an 8% increase in high-density lipoprotein cholesterol, and a 13% decrease in total cholesterol.5 Similarly, a 2020 randomized, double-blind, placebo-controlled trial showed that the group drinking the hydrogen water had significantly reduced blood cholesterol, glucose, and hemoglobin A1c, and improved inflammatory markers and redox homeostasis compared to placebo.6 In a 2012 pilot study involving patients with rheumatoid arthritis (RA), hydrogen water not only reduced markers of oxidative stress, but it also improved RA symptoms.7 A 2013 randomized, controlled trial involving patients with hepatitis B showed that hydrogen water improved markers of oxidative stress and liver function compared to placebo.8



A 2017 double-blind, placebo-controlled study discovered that the anti-inflammatory and antioxidant activity of hydrogen water can also impact the central nervous system. In that study, the group drinking the hydrogen water had improvements in mood, anxiety, and overall quality of life compared to placebo.9 (continued on page 18)


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Preliminary research also demonstrates that hydrogen water may positively influence the gut microbiome. In a trial involving female juvenile soccer players, 2 months of drinking hydrogen water reduced IL1, IL2, and tumor necrosis factor; increased SOD, total antioxidant capacity, and whole blood hemoglobin; and improved the diversity and abundance of gut flora.10 As this paper points out, the US Food and Drug Administration has recognized hydrogen gas as a food additive with generally recognized as safe (GRAS) status. The research confirms that hydrogen water is safe when consumed at the recommended doses. One argument often made regarding the hydrogen water studies is that merely increasing consumption of water will confer significant health benefits and that even mild dehydration can contribute to a variety of illnesses.11 However, that argument is not valid in studies comparing hydrogen water to the same amount of plain water consumed. This latest clinical trial adds credence to the therapeutic efficacy of hydrogen water, which has come under fire as being all hype and no substance. What is additionally interesting about this study is that the benefits of hydrogen water were more significant in individuals over age 30. Because aging is often accompanied by increased systemic oxidative stress and damage, it makes sense that as one ages, the need for enhanced antioxidant defenses would also increase and, therefore, those individuals would get more benefit from hydrogen water. This is also true for individuals dealing with dysregulated redox balance and systemic inflammation due to illness. From a clinical perspective, the research appears to support the use of hydrogen water for a variety of conditions that require immune regulation, increased antioxidant activity, and reduced inflammation. The biggest clinical issue with hydrogen water is the cost. Individual cans or bottles range from $2.50 to $3.00 each versus about $0.60/bottle of spring water. In this particular study, the participants drank 51 ounces a day, which is more than 6 8-ounce bottles, adding

up to about $15/day. Hydrogen water tablets and machines are also available, which may cut down on the cost somewhat. Hydrogen water packaging can also be an issue. The authors of this study did not identify the type of packaging; however, they did direct participants to drink the water within an hour to reduce hydrogen loss. Hydrogen dissipates quickly, and if hydrogen water is packaged in plastic or glass, it likely will not contain much hydrogen. Special packaging is required to maintain optimal hydrogen levels. As with any intervention, there are pros and cons. While cost may be a con, patient compliance may be a pro. After all, asking patients to drink more water is something integrative practitioners do all the time in clinical practice. Asking them to drink a certain type of water may be an easy solution for some patients who are not as compliant with dietary supplement recommendations. Assessing the individual patient to choose the proper intervention is something that integrative practitioners excel at. In some cases, hydrogen water may be worth considering. REFERENCES

1 Shi J, Duncan B, Kuang X. Hydrogen treatment: a novel option in liver disease. Clin Med. 2021;21(2):e223-e227. 2 Yang M, Dong Y, He Q, et al. Hydrogen: a novel option in human disease treatment. Oxid Med Cell Longev. 2020;2020. 3 Yang Q, Ji G, Ran R, et al. Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy. Mol Clin Oncol. 2017;7(5):891-896. 4 Kang K, Kang Y, Choi I, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res. 2011;1:11. 5 Nakao A, Toyoda Y, Sharma P, et al. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome—an open label pilot study. J Clin Biochem Nutr. 2010;46(2):140-149. 6 LeBaron TW, Singh RB, Fatima G, et al. Effects of 24-week, high-concentration hydrogen-rich water on body composition, blood lipid profiles, and inflammation biomarkers in men and women with metabolic syndrome: a randomized controlled trial. Diabetes, Metab Syndr Obes. 2020;13:889-896. 7 Ishibashi T, Sato B, Rikitake M, et al. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res. 2012;2(27). 8 Xia C, Liu W, Zeng D, et al. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Transl Sci. 2013;6(5):372-375. 9 Mizuno K, Sasaki AT, Ebisu K, et al. Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life. Med Gas Res. 2017;7(4):247-255. 10 Sha J, Zhang S, Lu Y, et al. Effects of the long-term consumption of hydrogen-rich water on antioxidant activity and the gut flora in female juvenile soccer players from Suzhou, China. Med Gas Res. 2018;8(4):135-143. 11 El-Sharkawy AM, Shota O, Lobo DN. Acute and chronic effects of hydration status on health. Nutr Rev. 2015;73(S2):97-109.




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Cancer Immunotherapy Dependent on Gut Biome Results from a proof-of-concept trial REFERENCE

Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371(6529):595-602. DESIGN

Proof of concept; open-label trial PARTICIPANTS

Between June 2018 and January 2020, researchers enrolled 16 melanoma patients who had not responded to anti–PD-1 (anti–programmed cell death protein 1) immunotherapy and continued to have progressive disease. STUDY MEDICATION AND DOSAGE

Participants received fecal microbiota transplant (FMT) from patients who had responded to treatment. Seven donors, including 4 who had experienced a complete response and 3 with partial response to treatment with anti–PD-1 therapy, supplied fecal materials to treat the 16 patients. Each study participant received a single donor–derived FMT followed by additional pembrolizumab therapy every 3 weeks until disease progression or intolerable toxicity. OUTCOME MEASURES

Progression-free survival (PFS) and overall survival (OS). In addition, researchers conducted and compared detailed analyses of fecal biome in patients and donors. They analyzed a total of 223 fecal samples from 15 of the recipients and from 7 donors. KEY FINDINGS

Fifteen of the enrolled patients received FMT and had at least 1 restaging scan via computed tomography (CT) and were evaluable for response. One patient declined so rapidly as their disease progressed that their response was not included. Researchers noted objective responses (ORs) in 3 out of the 15 patients, a 20% response rate. In addition, 3 of the 15 patients, an additional 20%, had durable sustained disease (SD) that lasted longer than 12 months. PFS and OS of all patients were 3.0 and 7.0 months, respectively, at a median follow-up of 7 months. In the 6 patients with disease control (ie, OR and SD), median PFS and OS were both 14.0 months, respectively. Among these patients, 1 patient exhibited ongoing partial response after >2 years and is currently on surveillance, and 4 patients still remain on treatment. One patient who had a complete response to treatment died from a complication of an elective surgery unrelated to their cancer or to treatment. FMT together with pembrolizumab treatment overcame resistance to anti– PD-1 treatment in a subset of refractory melanoma patients. 20 ©2021 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, MAY 2021 SUPPLEMENT—VOL. 13, NO. 51 (SUPPL)

By Jacob Schor, ND, FABNO PRACTICE IMPLICATIONS Note: A similar study by Baruch et al was published in the same issue of Science as this study by Davar et al under discussion. In the Baruch study, 10 patients with refractory metastatic melanoma were treated with FMT from 2 donors who had complete responses to prior immunotherapy treatment. The combination of FMT and, in the Baruch study, nivolumab rather than pembrolizumab resulted in 3 responses, including 1 complete response.1 Both of these drugs, pembrolizumab and nivolumab, are monoclonal antibodies that bind to and block PD-1. The US Food and Drug Administration approved them at about the same time; pembrolizumab was approved in September 2014 and nivolumab that December, for treating advanced melanoma. They are now both approved to treat a range of cancers. PD-1 is a negative regulator of T-cell immune function; that is, it suppresses the immune system’s response. This suppression guards against autoimmune disease, but it also weakens the immune system’s ability to kill cancer cells. Anti–PD-1 drugs, such as these, halt this suppression, allowing the immune system to recognize and kill cancer cells.2 These drugs provide long-term clinical benefit to nearly 40% of patients with advanced melanoma, though only 10% to 20% of patients will have durable complete responses.3 Researchers are directing their efforts toward increasing this response rate. Aware that antibiotic use with these drugs is associated with poorer response rates, and knowing the microbiota influence on the development and function of the immune (continued on page 22)

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system,4 investigators have focused on how altering the gut microbiota might improve outcome. Researchers have attempted to identify specific bacteria associated with better treatment outcomes. For naturopathic doctors, anti–PD-1 drugs are outside our scope of practice, but we should understand the implications for our patients who are undergoing treatment with these or similar drugs. The term “microbiome” refers to the collective genomes of all the microorganisms in a particular environment, and microbiota are the community of microorganisms themselves. There are about 100 trillion microorganisms, mostly bacteria but also viruses, fungi, and protozoa, living in the human digestive tract. Conceptually we should view the microbiome as a virtual organ, a part of the body. The human genome consists of about 23,000 genes, while the microbiome contains more than 3 million genes, producing thousands of metabolites that augment or replace many of the functions of the host and strongly influence the health of the host. For several years, we’ve watched this idea develop—that the gut biome affects immunotherapy drugs. In January 2018, Gopalakrishnan et al reported that after analyzing oral and gut microbiomes of human melanoma patients (N=112), significant differences were seen in diversity and composition in responders versus nonresponders to anti– PD-1 treatment. Fecal samples from the responders showed significantly higher alpha diversity.5 Alpha and beta diversity are 2 terms commonly used in biome studies. They are both higher-level measures used to describe the microbiome in a sample. They do not provide information on changes in abundance of specific taxa. Alpha diversity is a composite of different measurements that estimate the diversity within a single sample. These measures reflect the richness (number) or distribution (evenness) of a microbial sample or aim to communicate a combination of both properties. Beta diversity is a measure of the similarity or dissimilarity of 2 communities.6

In 2018, Bertrand Routy profiled stool samples from patients with lung and kidney cancers and reported that nonresponding patients had low levels of Akkermansia muciniphila. Oral supplementation of these bacteria to antibiotic-treated mice restored their response to immunotherapy.7 Researchers have now created lists of bacteria associated with positive clinical response and which seem to be lacking in nonresponding patients, yet the results have not been definitive enough to yield a recipe for a bacterial combination to give all patients. Instead, both of these 2 new studies used fecal transplants from responders as a way to transfer the entire gut microbiota from 1 patient to another. Earlier studies had already reported that FMT in mice would transfer benefit from responders to nonresponders, but the question as to whether this could translate into humans persisted. Mice and humans have dissimilar gut microbiota; they share only about 4% of their bacterial metagenome.8 The results from both Davar and Baruch tell us that FMT does work in humans as well as in mice. This is a big deal. The anti–PD-1 drugs have had a large impact in treating melanoma over the last few years. Nivolumab and pembrolizumab have achieved an overall response rate (ORR) of 40% to 50% and a 5-year OS rate of 30% to 40% in patients with metastatic melanoma.9 These treatments are expensive. In 2016 treatment with either drug was priced at about $150,000 per year. Combination therapy with both pembrolizumab and nivolumab was a deal at $256,000 per year.10 Let’s pause to do the math on a napkin. Sixty out of 100 patients treated with immunotherapy do not respond. Let’s say that patients in the Davar study were recruited from those 60 nonresponders, and 20% of those 60—that is, another 12 people—responded to additional drug treatment, increasing the number who respond to treatment from 40 to 52. If this proves true, it is remarkable. Even with all the caveats that this was a small study, etc., this still deserves attention as FMT is something that patients might even do on their own, perhaps before they even begin treatment. It’s (continued on page 24)


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also something that the drug companies should support, as nonresponders may be justified to attempt further treatment with these drugs after receiving FMT. As anti–PD-1 drugs are now approved for so many cancers, chances are increasing that any cancer patient you see will eventually be treated with 1 of them. Proactive efforts to improve their response rate by modifying their gut biome may be useful. At this point it is unknown whether similar shifts in the biome that increase response rate to anti– PD-1 drugs affect the natural course of cancer in those not exposed to these drugs. As the general characteristics of a healthy gut biome appear to be shared across a broad range of conditions, it is possible that such measures may prove useful. We could/should start applying knowledge of how diet and supplements change the gut biome and use that knowledge to inform interventions against a broader range of diseases than just cancer. The basic goal should be to increase alpha diversity. Low diversity is associated with a range of diseases including inflammatory bowel disease, psoriatic arthritis, diabetes, atopic eczema, obesity, and arterial stiffness. Diversity is the “good indicator” being used to define a healthy gut. Cancer patients, specifically those scheduled for anti– PD-1 treatment, should avoid antibiotics and take steps to encourage alpha diversity.11 They should consider FMT, though at this point, whether this should be done prior to initial treatment is uncertain. We do not yet know of an authorized source for obtaining stool “infusates” from “anti–PD-1 responders.” Certainly, nonresponders to treatment should have FMT before resuming treatment. Davar reports that gut microbiota can change significantly after a single FMT. In general fiber is considered good for increasing diversity, but recent interventional studies indicate that major increases in a single type of dietary fiber can temporarily reduce diversity, as the microbes that digest the specific type of fiber being supplemented are specifically enriched.12

The results from both Davar and Baruch tell us that FMT does work in humans as well as in mice. This is a big deal.

The obvious work-around is not to rely on 1 specific type of fiber but to consume a range of them and eat a wide variety of foods. High-intensity sweeteners, the sugar substitutes, are now suspected of reducing alpha diversity. These sweeteners, such as sucralose, aspartame, and saccharin, have been shown to disrupt the balance and diversity of gut microbiota.13,14 Food additives—in particular, emulsifiers found in most processed foods—should be avoided as they are associated with reduced diversity, at least in animals.15 Promoting consumption of less-processed foods and avoiding ultra-processed foods should remain central. While the focus of our patient advice should be to promote consumption of a healthy diet, many patients are attracted to 1 or more of the popular restrictive diets that limit consumption of specific foods. We need to view these diets with caution in light of how they impact the gut biome and balance that with any symptom relief provided by avoidance. The low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diets used to treat irritable bowel syndrome may be the most problematic for obvious reasons. The complex saccharides that this diet hopes to eliminate are food sources for intestinal bacteria, and eliminating these foods will literally starve some of the biome. Data comparing vegans with omnivores have shown only slight differences in gut bacterial communities between


groups. There are significant differences, though, in the metabolomes (the metabolites produced by the bacteria and found in the blood) between the 2 groups.16 Whether these differences affect anti–PD-1 therapy is not yet clear. Consuming gluten-free bread probably reduces microbiota dysbiosis in people with celiac disease because it appears to do so in monkeys.17 Still, most people who are avoiding gluten these days do not have celiac disease. A large 2017 observational study reported an increased risk of heart disease in gluten avoiders, probably because they avoid most whole grains, which reduces their intake of the fiber required to support bacteria.18 A small clinical trial reported that the gut microbiota changed significantly—and not for the better—in 21 healthy people on gluten-free diets in just 4 weeks, their microbiota showing lower abundance in several key species.19 How this might affect anti–PD-1 therapy also remains unknown. We naturopaths can’t help ourselves and are always diet-focused, but we should remember that drugs are the largest influence on gut microbiota, not diet, accounting

for 10% of the variations seen.20 Antibiotics, proton pump inhibitors, and osmotic laxatives are the major players and are used regularly by large numbers of people.21,22 The gut microbiota can change remarkably fast. A past study reports that major shifts in bacterial population occur within days to weeks of dietary changes.23 In a trial that shifted participants from a plant-based diet to an animal-protein diet, extreme changes occurred in less than a week.24 While the public now assumes probiotics are something of a panacea, they may spell trouble with anti–PD-1 therapy. Many of us recall work done at MD Anderson Cancer Center and reported at a conference in 2018 by Christine Spencer. Spencer and colleagues had gathered data about diet and supplements from 113 melanoma patients, along with stool samples from each. Spencer reported that patients eating high-fiber diets were 5 times more likely to respond to anti–PD-1 therapy than those on a low-fiber diet. (Although these findings are still unpublished, the authors assure me we will see results in print soon.) We might have predicted benefit, as fiber encourages biome diversity, though few would have guessed this much. Surprisingly, taking probiotic supplements was associated with a 70%


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lower chance of responding to therapy.25 Probiotics do not necessarily increase diversity; rather they discourage growth of competing bacteria. Utility in treating disease varies by species and strain.26 A study published in March 2021 suggests probiotics may still be useful in anti–PD-1 therapy for lung cancer. Kuzuki Takada reported that in patients with non–small cell lung cancer (NSCLC), using probiotics was associated with a significant difference in outcome for the better. In patients (N=294) treated with either pembrolizumab or nivolumab, progression-free survival was significantly longer (HR[95% CI]=1.73[1.42–2.11]) in those who took probiotics. Although overall survival trended longer, it did not reach significance. Those who did not use probiotics were half as likely to experience disease control (OR[95% CI]=0.51[0.35–0.74], P=0.0004). The idea that probiotics are helpful in NSCLC and harmful in melanoma when combined with anti–PD-1 treatments is disturbing. We prefer data that reveal a consistent response across cancer types.27 It may be that probiotics play a distinct role in lung cancer. We’ve seen hints of this before. A large, pooled analysis (N= 627,988 men and 817,862 women) from 2019 linked both yogurt and fiber consumption with significantly lower risk of lung cancer. High versus no yogurt consumption was associated with a 19% reduction in risk (HR[95% CI]=0.81[0.76–0.87]). The combination of high fiber and yogurt consumption was associated with a 30% decrease in risk (HR=0.67[0.61–0.73]).28 Coming back to the Davar and Baruch studies, we see that the utility of FMT as an adjunctive therapy with cancer immunotherapy is certainly of interest. The medical world will want to study this further prior to adoption, but our patients will be impatient to move forward and incorporate FMT into their treatment regimes. REFERENCES

1 Baruch EN, Youngster I, Ben-Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371(6529):602-609. 2 Faghfuri E, Faramarzi MA, Nikfar S, Abdollahi M. Nivolumab and pembrolizumab as immune-modulating monoclonal antibodies targeting the PD-1 receptor to treat melanoma. Expert Rev Anticancer Ther. 2015;15(9):981-93..

3 Ascierto PA, Long GV, Robert C, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 2019;5(2):187-194. 4 Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121-141. 5 Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97103. 6 Key terms in microbiome projects. Biomcare Web site. key-terms-in-microbiome-projects/. Accessed March 5, 2021. 7 Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97. 8 Hugenholtz F, de Vos WM. Mouse models for human intestinal microbiota research: a critical evaluation. Cell Mol Life Sci. 2018;75:149-160. 9 Gellrich FF, Schmitz M, Beissert S, Meier F. Anti-PD-1 and novel combinations in the treatment of melanoma-an update. J Clin Med. 2020;9(1):223. 10 Latner AW, Rosania K. Immunotherapies for melanoma: worth the cost? First Report Managed Care Web site. article/immunotherapies-melanoma-worth-cost. Accessed March 5, 2021. 11 Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018;361:k2179. 12 Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018;359:1151-1156. 13 Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: impact of low calorie sweeteners and the link to insulin resistance? Physiol Behav. 2016;164(Pt B):488-493. 14 Fowler SPG. Low-calorie sweetener use and energy balance: results from experimental studies in animals, and large-scale prospective studies in humans. Physiol Behav. 2016;164(Pt B):517-523. 15 Chassaing B, Koren O, Goodrich JK, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015;519:92-96. 16 Wu GD, Compher C, Chen EZ, et al. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut. 2016;65:63-72. 17 Mohan M, Chow CT, Ryan CN, et al. Dietary gluten-induced gut dysbiosis is accompanied by selective upregulation of microRNAs with intestinal tight junction and bacteria-binding motifs in rhesus macaque model of celiac disease. Nutrients. 2016;8:8. 18 Lebwohl B, Cao Y, Zong G, et al. Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study. BMJ. 2017;357:j1892. 19 Bonder MJ, Tigchelaar EF, Cai X, et al. The influence of a short-term gluten-free diet on the human gut microbiome. Genome Med. 2016;8:45. 20 Falony G, Joossens M, Vieira-Silva S, et al. Population level analysis of gut microbiome variation. Science. 2016;352:560-564. 21 Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65:749-756. 22 Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science. 2016;352:544-545. 23 O’Keefe SJ, Li JV, Lahti L. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015;6:6342. 24 David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559-563. 25 AACR 2019: Diet may influence gut microbiome and response to immunotherapy. The ASCO Post Web site. Accessed March 5, 2021. 26 Compare D, Sgamato C, Nardone OM, et al. Probiotics in gastrointestinal diseases: all that glitters is not gold. Dig Dis. 2021. doi: 10.1159/000516023. Online ahead of print. 27 Takada K, Shimokawa M, Takamori S, et al. Clinical impact of probiotics on the efficacy of anti-PD-1 monotherapy in patients with nonsmall cell lung cancer: a multicenter retrospective survival analysis study with inverse probability of treatment weighting. Int J Cancer. 2021. doi: 10.1002/ijc.33557. Online ahead of print. 28 Yang JJ, Yu D, Xiang YB, et al. Association of dietary fiber and yogurt consumption with lung cancer risk: a pooled analysis. JAMA Oncol. 2020;6(2):e194107.


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Probiotics and Their Immunological Impact on Liver Cirrhosis Findings from a double-blind, randomized, placebo-controlled trial REFERENCE

Macnaughtan J, Figorilli F, García-López E, et al. A double-blind, randomized placebo-controlled trial of probiotic Lactobacillus casei Shirota in stable cirrhotic patients. Nutrients. 2020;12(6):1651. STUDY OBJECTIVE

To ascertain if probiotic Lactobacillus casei Shirota (LcS) positively impacts neutrophil function and rates of infection in patients with liver cirrhosis versus a placebo. DESIGN

A double-blind, randomized and placebocontrolled trial at 2 hospitals in the United Kingdom PARTICIPANTS

Investigators screened 110 patients and included 92 with cirrhosis of any etiology at 2 hospitals. These patients presented with relevant clinical findings consistent with a cirrhosis diagnosis as well as a Child-Pugh score less than 10. Patients were between ages 18 and 78 years and had abstained from alcohol consumption for 2 weeks preceding screening. They were randomly assigned (1:1) to either the intervention or placebo group being stratified for alcoholic and nonalcoholic cirrhosis etiology. Exclusion criteria included: • Child-Pugh score >10 • Active infection • Antibiotic treatment 7 days prior to enrollment • Gastrointestinal hemorrhage • Use of immunomodulating agents • Use of proton pump inhibitors • Use of pre-, pro-, or synbiotics • Creatinine >150 mmol/L • Hepatic encephalopathy II-IV • Pancreatitis • Organ failure • Hepatic malignancy • Pregnancy


Patients in the intervention group received a 65-mL bottle of a LcS drink that yielded a 6.5 billion colony-forming-unit (CFU) bacteria (Yakult Europe) content, to be taken 3 times per day for 6 months. The placebo group was given a similar-looking and similar-tasting drink yielding no bacteria. Patients received 45 bottles every 2 weeks, with the empty, consumed bottles being a measure of compliance. Investigators recorded clinical benchmarks inclusive of blood and biochemical testing at screening, days 0 and 14, and months 1, 3, and 6. They gathered analytes relevant to intestinal hyperpermeability at months 0, 1, and 6. PRIMARY OUTCOME MEASURES

One of the primary endpoints in this study was the change in neutrophil function. Investigators evaluated this using isolation and coincubation methods to measure reactive oxygen species (ROS) production and prevalence of phagocytosis. The additional primary endpoint included incidence of infection, evaluated through routine clinical blood chemistry. Secondary outcomes included plasma cytokine profile concentration at various intervals, concluding at 6 months. Investigators evaluated intestinal hyperpermeability using urinary lactulose rhamnose ratio, venous endotoxin concentrations, and bacterial DNA identification with polymerase chain reaction (PCR) testing. The final secondary outcome was the quality-of-life assessment, which was accomplished with the use of the standardized SF-36 tool.



Overall, no significant differences in neutrophil function were observed between the intervention and placebo groups. For patients with atypical neutrophil function at the study’s onset, the 6-month LcS treatment yielded a significantly higher ROS production outcome compared to the placebo arm [1403(1214– 1821) versus 1168.00(1014–1266), P=0.02]. This is suggestive of improved neutrophil function in that subset. No significant changes in infection episodes were noted between randomized groups at the end of the study. Intestinal hyperpermeability was also observed to be in a normal range in both groups, with bacterial DNA positivity being 10.1% (placebo group) and 8.1% (LcS group). Outcomes with plasma cytokine concentrations were not significantly different in the vast majority of specific cytokines evaluated in the study. It was observed that LcS lowered median plasma interleukin 1 beta (IL1B; P=0.04) and monocyte chemotactic protein-1(MCP-1; P=0.04) concentration in the alcoholic subset. Further observation revealed a lowered interleukin 17A (IL17A) concentration in the nonalcoholic cohort (P=0.02). Macrophage inflammatory protein-1 beta (MIP-1β) concentrations were lowered in the LcS as a whole at the 6-month interval (P=0.04). The 36-Item Short Form Health Survey (SF-36) scores assessing quality of life showed no significant differences between either arm of the study.

PRACTICE IMPLICATIONS In the ever-evolving landscape of understanding the role of the human gut microbiome, a significant portion of the clinical and scientific dialogue has turned to the role played between the gut and the immune system.1 This dialogue extends into the physiological mechanisms of chronic alcohol consumption and the impact it has on the gut microbiome. This, in turn, brings forth a body of evidence elucidating mechanisms of how altered flora contribute to alcohol-associated liver disease.2 Given that, in cases of liver cirrhosis, an imbalance in the gut microbiome has been observed, the progression of inquiry in this study is logical and intriguing. This logic is now juxtaposed in another body of thought that postulates that gut dysbiosis can be implicated in alcoholic liver diseases. The health of the gut microbiome is crucial as dysbiosis results in intestinal inflammation and liver injury, and the subsequent restoration of microbiota, using approaches such as promoting commensal bacterial abundance, could be beneficial in alleviating disease progression.3 The investigators in this study aspire to further establish if LcS can impact immune function to ultimately translate to therapeutic benefit from probiotic use in patients with cirrhosis, both alcoholic and nonalcoholic. This was motivated by previous evidence of LcS, in a smaller study, suggesting a positive correlation.4 While the trial concludes that 1 specific mechanism of action, neutrophil activation, is not notably impacted, it is important to note that a subset of the participants was positively impacted. Those who presented with a lower-than-normal baseline function of neutrophil activity saw this activity improve to more normal and expected levels. This is consistent with the aforementioned open-label pilot study.4 No adverse effects were observed, and there was no increase in infections in all 92 participants, which speaks to the safety of LcS in this patient demographic. The most important outcome is that of a positive change in cytokine profile in all participants in the LcS group of the study. This suggests that a restoration of gut health creates a downregulation of inflammatory cytokines; however, the

mechanism of action appears to be independent of factors related to intestinal hyperpermeability. This raises more questions for potential studies in the future. Areas of further inquiry, both in the realm of clinical practice as well as study design, bring a number of additional issues to the forefront. Are all probiotics created equal in quality, and does this impact outcomes? Clinical practitioners will suggest that their patient outcomes are proof of this concept and that reputable sources of therapeutic probiotics need to be given consideration. Secondly, the singularity or diversity of probiotic species should be given deliberation as a growing body of evidence suggests diversity of the gut microbiome is correlated with improved health outcomes.5 To this end, consideration should be given to methodologies for gastrointestinal (GI) biome mapping, stool culturing, and other objective evaluations of gut microbiome. Lastly, the dose-dependent effect must be taken into account when selecting therapeutic probiotics and their ability to yield desired CFUs. Clinical observations and case studies suggest that higher-CFU interventions correlate with improved outcomes; however, clear cautions and contraindications exist, and the “more is better” approach has its risks and limitations.6 GI mapping becomes a critical tool in this consideration as well. Clinicians have several emerging bodies of scholarly evidence and clinical outcomes to reconcile in the implementation of probiotics and the restoration of gut microbiota. Clearly the benefits of doing so are inclusive of, but not limited to, improved hepatic health and immune function. REFERENCES

1 Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. 2016;535(7610):65-74. 2 Mendes BG, Schnabl B. From intestinal dysbiosis to alcohol-associated liver disease. Clin Mol Hepatol. 2020;26(4):595-605. 3 Gupta H, Suk KT, Kim DJ. Gut microbiota at the intersection of alcohol, brain, and the liver. J Clin Med. 2021;10(3):541. 4 Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol. 2008;48(6):945-951. 5 Lloyd-Price J, Abu-Ali G, Huttenhower C. The healthy human microbiome. Genome Med. 2016;8(1):51. 6 Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105(7):1636-1641.



Environmental Factors that Affect the Microbiome An interview with Heather Zwickey, PhD

The gut microbiome has a tremendous impact on immunity. In a recent interview, Editor-in-Chief Tina Kaczor, ND, FABNO, had the opportunity to talk with immunologist and Natural Medicine Journal Editorial Board Member Heather Zwickey, PhD, about environmental factors that affect the gut microbiome. They discussed pesticides, herbicides, and petroleum chemicals and the impacts they can have on the 100 trillion–plus microorganisms that reside in the human gut.

Tina Kaczor, ND, FABNO: What do you think is the most pressing topic that people need to know about as far as environmental factors that influence the gut?

Many microbes can

use tryptophan and other ring-based amino acids without needing the shikimate pathway, which is what glyphosate blocks. But Lactobacillus and Bifidobacterium, 2 of the big ones, require the shikimate pathway, and glyphosate can kill them.

Heather Zwickey, PhD: I think that as we start to discuss gut microbiota, it has such a profound impact on the immune system. And the immune system has really been my focus—neuroimmunomodulation. So when we think about the gut microbiota, we’re often thinking about the obvious things that have an effect on it, like antibiotics. But we don’t often consider some of the less obvious things that have an effect on microbiota, like pesticides we find in the environment and in our food.

Kaczor: When you say pesticides, so you’re talking about Roundup, glyphosate, that kind of thing? Zwickey: Sure. Roundup (or glyphosate) is one of the more common pesticides that we find in the environment. There have been studies that detect it in urine. So we are getting measurable levels of glyphosate in our diet. That might come from eating foods that are not organic, or if you live out in the country, it could come from places like your well water, where glyphosate has been sprayed on crops around you and has leached into the well water. The reason that we worry about that is that glyphosate actually has an effect on an enzyme that affects all bacteria. In fact, it affects everything except mammals. So insects like bees that are going to pollinate our fruits and vegetables can be killed by glyphosate.

But when we think about glyphosate with respect to humans, we have to remember that we have this microbial community within us, and it is susceptible to glyphosate. Some really recent data has shown that not all microbes in our gut are responsive to glyphosate. Many microbes can

use tryptophan and other ring-based amino acids without needing the shikimate pathway, which is what glyphosate blocks. But Lactobacillus and Bifidobacterium, 2 of the big ones, require the shikimate pathway, and glyphosate can kill them. Kaczor: In our world of clinical medicine, we always have outliers who can’t seem to hold the Lactobacillus population in their gut. They’ll go through courses of probiotics, we’ll change brands a few times, and it just keeps going back down to nothing. We probably should be looking more closely at their glyphosate exposure in their urine. Zwickey: Absolutely. You can actually measure their consumption and keep in mind that for most probiotics they’re not going to become commensals. So what we need to be doing is addressing the metabolites that make our endogenous Lactobacillus and our endogenous Bifidobacterium grow. (continued on page 32)




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And for that, we’re really looking at short-chain fatty acids. Thinking about the metabolites might give us a different direction to go therapeutically. You might want to use a postbiotic or a prebiotic, as opposed to a probiotic.

Researchers went to the grocery stores, took apples off the shelves, blended them up like you would for a smoothie, and then measured pesticide content. And what they discovered was that apples that were not organic had 300-fold more neonicotinoids.

Kaczor: You mentioned bees earlier. Can you talk a bit about how some of the compounds that are used in bee farming can affect the gut. Zwickey: We know about the problem with the bees, and we’ve targeted a particular pesticide, the neonicotinoids, as one of the culprits for killing off our bee population. But glyphosate is clearly involved in this one as well. When you kill the bees’ microbiota, they get infectious disease—usually mites and viruses. A study came out a few years ago out of Boston on giving probiotics to the bees. They’re actually putting Lactobacillus plantarum into the hives. And guess what? The bees recover. Kaczor: I’m out in the country, and I would love it if they would spray Lactobacillus on the plants instead of manure. Zwickey: Yeah, no kidding. But the issue around the neo­nicotinoids gets even more interesting when we start looking at how neonicotinoids are being administered onto plants these days. Historically we would spray pesticides on the plants, but apple growers and other fruit growers noticed that they were still getting worms in their apples. And more recently, trees are either injected with the pesticide or the pesticide is sprayed at the bottom of the tree so that it goes into the root system. And that way you don’t have any worms in your apples, but that also means that you can’t wash pesticide off of those fruits.

In another study out of Boston, researchers went to the grocery stores, took apples off the shelves, blended them up like you would for a smoothie, and then measured pesticide content. And what they discovered was that apples that were not organic had 300-fold more neonicotinoids. When we encourage people to eat apples, we need to encourage them to eat organic apples, because you can’t get the pesticides out of there. And neonicotinoids affect the human gut microbiome as well.

Kaczor: Can you talk about environmental influences on the gut during pregnancy? Zwickey: So one of the things that I have studied for a long time is vaccinations. People worry about vaccinations with respect to ADHD, autism, and neurodevelopment. And we’re discovering that it’s probably not related to vaccinations. It’s probably related more to antibiotic exposure. There’s great data now looking at antibiotic exposure in the first year of life for a child, but now they’ve gone backwards and they’ve looked at maternal antibiotic exposure, and 80% of women are exposed to antibiotics during pregnancy. That’s a huge number. If a woman is exposed to an antibiotic during pregnancy, we look at the fetal microbiome and then the microbiome of the offspring when the infant is born, and we see that within 60 days, we can get it back to 89% of normal, but it never reaches 100%.

That’s interesting because one of the things we notice in kids with autism and kids with neurodevelopmental delay is that they’re missing certain species of microbes. Are they missing species of microbes because mom was on an antibiotic? Are they missing species of microbes because mom was on some other medication? There’s now data (continued on page 34)



showing that when moms are on antidepressants, it can have an effect on their microbiome. And there’s a great Nature paper that came out a couple of years ago, 2018, that showed that nonantibiotic drugs are absolutely able to influence microbiome. Some of them kill off different species of microbes, and some of them make different species of microbes overgrow. So here we are with what some might call a health emergency when we look at incidence of autism at 1 in 60 for males these days, and we know that there’s a microbiome relationship, but we’re not paying attention to all the various things that have an effect on the microbiome, especially of a developing child. Kaczor: What can you tell us about preservatives in food? Zwickey: A preservative is designed specifically to kill microbes, and that’s good. We don’t necessarily want pathogenic microbes in our food supply. But if it’s designed to kill microbes, it is probably going to kill off some of your gut microbes as well. So again, there’s so much that has an effect on our gut microbes—BPAs, plastics, diesel—all of these things have an effect on the microbial community. And what we need to remember is that we’re never going to be able to control everything that has an effect on your gut microbes. So instead we have to be thinking about how we can constantly be doing things that make them happy. Making them happy is eating plant-based foods, plant-based fibers.

There was some really interesting research that came out of the University of California, San Diego, that showed that 30 plant-based fibers per week is important for maintaining the diversity, the alpha diversity of our gut microbiome. And 30 is a lot. That’s not 30 servings, that’s 30 different fibers. We need the diversity of the fibers to feed the diversity of our microbiome. So if you’re only eating tomatoes as your vegetable, for example, you need to add some more different varieties of plant-based fibers in order to truly maintain that healthy gut microbiome.


Heather Zwickey, PhD, is a professor of immunology and chair of the Department of Health Sciences at the National University of Natural Medicine in Portland, Oregon. She launched the Helfgott Research Institute, which advances the science of natural medicine. Zwickey founded the school of graduate studies and developed masters programs in research, nutrition, and global health. Zwickey has received the Champion of Naturopathic Medicine Award from the American Association of Naturopathic Physicians. She currently leads a National Institutes of Health– funded clinical research training program focused on integrative medicine research and studies the gut-brain axis in neuroinflammation.

A lot of times people in the exercise industry promote the goal of 10,000 steps a day. Well, in the nutrition industry, maybe the goal should be “get your 30 different plant-based foods.” That includes nuts, spices, and all these things that we don’t necessarily consider when we think of plant-based foods Kaczor: I tell people, “To tend their culture, tend your culture.” You’ve got a culture in your gut, and you need to tend it. Zwickey: Yeah. You say tend the culture, I say, feed the beast. You’ve got this little beast in your gut, and it gets mad if you don’t feed it. Kaczor: The concept is that the microbiome is an entity unto itself. And actually we should treat it like we treat any organ. You wouldn’t consciously take in chemical compounds that are toxic to your heart, right? Zwickey: Exactly. This is an abbreviated and lightly edited version. You can hear the entire interview on the Natural Medicine Journal Podcast.


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