Natural Medicine Journal Gastrointestinal Health Special Issue 2020 by Diversified Communications

MAY 2020 SUPPLEMENT

SPECIAL ISSUE

Gastrointestinal Health

Probiotics in the Management of IBS Low-FODMAP Diet Helps IBD Sufferers How Vitamin D3 Affects the Gut Microbiota

Natural Ingredients That Improve Digestive Disorder Symptoms Colon Cancer: Incidence, Testing, and Risk Factors

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SPECIAL ISSUE

GASTROINTESTINAL HEALTH MAY 2020 VOL. 12, NO. 51 (SUPPL)

Contents

ABSTRACTS & COMMENTARY

Meta-Analysis Concludes Probiotics Effectively Reduce IBS Symptoms

Vitamin D Alters Gut Microbiome

Healing the Gut Naturally

Treatment of IBS Without Constipation with Rifaximin Versus a Spore-Based Probiotic

Low-FODMAP Diet in the Management of Quiescent Inflammatory Bowel Disease

EXPERT INTERVIEW

Clinical Considerations to Reduce Risk of Colon Cancer

Interview with Tina Kaczor, ND, FABNO

SPONSORED INTERVIEW

Enhancing Viral Immunity via the Gut Microbiome

Interview with Ross Pelton, RPh, CCN

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Contributors 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 including her latest book The Definitive Guide to Thriving After Cancer that she wrote with Lise Alschuler, ND, FABNO. Gazella is the co-creator and Chief Executive Officer of the iTHRIVE Plan, an innovative online wellness program specifically for cancer survivors. ALENA GUGGENHEIM, ND, is an assistant professor of anesthesiology and perioperative medicine at Oregon Health and Science University in Portland, OR. Guggenheim specializes in the care of children and adults with chronic pain and joint hypermobility disorders. She enjoys working with patients with EhlersDanlos Syndrome and associated complex symptoms. She likes to help patients navigate healthcare options and empower them to make informed decisions. RONALD HOFFMAN, MD, is a physician in private practice of integrative medicine in New York City. He is a graduate of Columbia College and Albert Einstein College of Medicine. Since 1984, he has served as Medical Director of the Hoffman Center in Manhattan. Hoffman is past president of the American College for the Advancement of Medicine. Hoffman is the host of Intelligent Medicine, a nationally syndicated radio program, and he produces the daily Intelligent Medicine podcast. He is a Certified Nutrition Specialist, and the author of several books, including How to Talk with Your Doctor (About Complementary and Alternative Medicine). For more information, visit drhoffman.com.

TINA KACZOR, ND, FABNO, is editorin-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 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. ELEONORA NAYDIS, ND, LAC, FABNO, is a naturopathic physician, board certified in naturopathic oncology, and a licensed acupuncturist in the state of Washington. She holds an undergraduate degree in chemistry from Florida International University, and is a 2004 graduate of Bastyr University with dual degrees in naturopathic medicine and acupuncture. In addition to her private practice, Naydis has worked as an attending physician at Bastyr Integrative Oncology Research Center. For more information, you can visit her website at www.treeofhealthmedicine.com. JACOB SCHOR ND, FABNO, is a graduate of National College 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 Natu ropathic 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 Abstracts & Commentary editor.

EDITOR-IN-CHIEF Tina Kaczor, ND, FABNO

MESSAGE FROM THE PUBLISHER

ABSTRACTS & COMMENTARY EDITOR Jacob Schor, ND, FABNO

Integrative Approaches to Gastrointestinal Health

PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry 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 © 2020 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.

According to the National Institute of Diabetes and Digestive and Kidney Diseases, approximately 60 to 70 million Americans have a digestive disease. In addition, the American Cancer Society estimates that 1 in 23 men and 1 in 25 women will be diagnosed with colon cancer this year and about 24,000 people will be diagnosed with stomach cancer. Issues involving the gastrointestinal (GI) tract are diverse, common, disruptive, and sometimes deadly. That’s why we devoted an entire issue of the Natural Medicine Journal to this important topic. In this issue you will find several Abstracts & Commentary addressing clinical studies about probiotics and irritable bowel syndrome, vitamin D3 and the gut microbiota, how an herbal formula can improve digestive disorder symptoms, and the low-FODMAP diet. In addition, our editor-in-chief, Tina Kaczor, ND, FABNO, provides important information on how to reduce risk of colon cancer. There is also a sponsored podcast about the connection between viral immunity and the gut microbiome, which is timely given our present Covid-19 crisis. We now know that the health of the GI tract significantly and systemically impacts overall wellness. That’s why helping patients enhance GI health is a key clinical objective. We hope you find this special issue of the Natural Medicine Journal interesting and useful. And if you do, we hope you pass it along to a colleague. I’d like to extend a special thanks to the contributors, reviewers, and the Natural Medicine Journal team who came together to create this special issue. In health,

Karolyn A. Gazella Publisher, Natural Medicine Journal

ABSTRACT & COMMENTARY

Meta-Analysis Concludes Probiotics Effectively Reduce IBS Symptoms Research sheds light on strains and dosage REFERENCE

Liang D, Longgui N, Guoqiang X. Efficacy of different probiotic protocols in irritable bowel syndrome: a network meta-analysis. Medicine (Baltimore). 2019;98(27):e16068. OBJECTIVE

A meta-analysis designed to assess efficacy of the different types of probiotic protocols used to treat irritable bowel syndrome (IBS) symptoms. METHOD

The authors searched various databases including PubMed, Medline, Embase, Web of Science, and Cochrane Central Register of Controlled Trials between January 2006 and April 2019. They analyzed a total of 14 placebo-controlled randomized trials that featured 1,695 patients. In this analysis, the 2 primary multistrain protocols featured in the studies showing efficacy were: DUO = Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, and Streptococcus thermophilus Pro = Bifidobacterium lactis Bb12, Lactobacillus acidophilus La5, Lactobacillus delbruecki subsp bulgaricus LBY-27, and Streptococcus thermophilus STY-31 KEY FINDINGS

The researchers found that protocols with a daily dose of 1010 colony-forming units (CFU) that combined Lactobacillus and Bifidobacterium strains were more effective than single strains or overdosing protocols. The DUO protocol demonstrated the most efficacy with diarrhea-type IBS, while Pro was more effective for undifferentiated-type IBS. Researchers also considered the probiotic protocols safe, with adverse events not statistically different from placebo.

PRACTICE IMPLICATIONS Rome Criteria are used to diagnose and classify functional gastrointestinal disorders such as IBS. Rome IV is the most recent version of these criteria and changed the term from functional gastrointestinal disorders to disorders of gut-brain interaction (DGBI); of these, IBS is the most common worldwide.1 While IBS prevalence has grown considerably, it may be even more common than previously thought due to self-diagnosis and self-management. Interestingly, a 2019 online survey that compared Rome IV–based IBS to self-diagnosed IBS found that nearly 69% of the survey respondents met the Rome IV criteria, but only 21% of the respondents were consulting a physician for their symptoms.2

By Ronald Hoffman, MD, and Karolyn A. Gazella The fact that this meta-analysis identified which probiotic strain combinations were effective at relieving symptoms of the different IBS classifications is clinically helpful. This analysis also confirms that multistrain probiotic formulations are more effective than a single strain, which is something that many clinicians have seen in their practice.

The issue of high doses is also important and relates to the intended clinical use of the probiotic formulation. In this meta-analysis, dosages of more than 1010 CFU were not more effective at treating IBS symptoms. Some research indicates high-dose probiotics can actually promote bacterial proliferation that exacerbates GI symptoms. This was the case in a 2018 Based on data from the International study featuring patients with small Classification of Diseases, Tenth intestinal bacterial overgrowth (SIBO) Revision (ICD-10), IBS is classified who found an increase in symptoms 5 as a functional disorder of the large including brain fog, gas, and bloating. intestine that causes abdominal pain, Results of this meta-analysis are cramping, bloating, and changes in consistent with another analysis bowel habits that can include diarrhea, published by Dale et al in 2019 in the constipation, or alternating diarrhea journal Nutrients.6 In that analysis, 11 and constipation.3 In addition, based randomized placebo-controlled trials on Rome IV classification, IBS can of probiotics were evaluated, with 7 of present with distinct bowel patterns:4 the studies finding significant improvement in IBS symptoms. That analysis 1. Diarrhea predominant (IBS-D) also showed that multistrain supple2. Constipation predominant (IBS-C) ments were more effective than single 3. Mixed diarrhea and constipation strain. All of the studies that showed (IBS-M) benefit with the multistrain probiotics 4. Unclassified and not fitting into any used 1 or both of Lactobacillus spp of the 3 subtypes (IBS-U) (continued on page 8)

ABSTRACT & COMMENTARY

and Bifidobacterium spp. Dosage wasn’t addressed in that meta-analysis. In addition to the meta-analysis by Liang et al reviewed here, other studies have found multistrain probiotics to be safe with no serious adverse events and only a limited number of mild to moderate side effects.7 Given that gut dysbiosis and intestinal permeability contribute to IBS symptoms,8 it makes sense that probiotics would be clinically effective for this common condition.9 This latest meta-analysis sheds some light on which strains may be effective for which subtype and at what dose. In addition, this analysis and other studies illustrate the favorable safety profile of probiotic interventions for this condition. There’s a great deal of interindividual variation in response to various probiotic formulas. This may reflect the antecedent status of a subject’s microbiome, dietary factors that support or interfere with the therapeutic response to administration of exogenous organisms, and concurrent use of medications that modify the intestinal flora, as well as unique genetic factors that may determine a person’s receptivity to the introduction of novel microbiota. When it comes to probiotics for IBS, it may truly be “different strokes for different folks.” With this information, clinicians can confidently choose from the many multistrain probiotics available on the market for their patients struggling with IBS.

DON’T MISS OUT

“

In this meta-analysis, dosages of more than 1010 CFU were not more effective at treating IBS symptoms. Some research indicates high-dose probiotics can actually promote bacterial proliferation that exacerbates GI symptoms.

REFERENCES

”

1 Schmulson MJ, Drossman DA. What is new in Rome IV. J Neurogastroenterol Motil. 2017;23(2):151-163. 2 Van den Houte K, Carbone F, Pannemans J, et al. Prevalence and impact of self- reported irritable bowel symptoms in the general population. United European Gastroenterol J. 2019;7(2):307-315. 3 ICD10Data.com. Irritable bowel syndrome. https://www.icd10data.com/ICD10CM/ Codes/K00-K95/K55-K64/K58-. Accessed March 25, 2020. 4 Lacy BE, Patel NK. Rome Criteria and a diagnostic approach to irritable bowel syndrome. J Clin Med. 2017;6(11). pii:E99. 5 Rao SSC, Rehman A, Yu S, Andino NM. Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis. Clin and Transl Gastroenterol. 2018;9(6):162. 6 Dale HF, Rasmussen SH, Asiller ÖÖ, Lied GA. Probiotics in irritable bowel syndrome: an up-to-date systematic review. Nutrients. 2019;11(9):2048. 7 Jafari E, Vahedi H, Merat S, et al. Therapeutic effects, tolerability and safety of multi-strain probiotic in Iranian adults with irritable bowel syndrome. Arch Iran Med. 2014;17(7):466-470. 8 Menees S, Chey W. The gut microbiome and irritable bowel syndrome. F1000Res. 2018;7:F1000 Faculty Rev-1029. 9 Camilleri M, Gorman H. Intestinal permeability and irritable bowel syndrome. Neurogastroenterol Motil. 2007;19(7):545-552.

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ABSTRACT & COMMENTARY

Vitamin D Alters Gut Microbiome

Results from a randomized, double-blinded, dose-response study REFERENCE Charoenngam N, Shirvani A, Kalajian TA, Song A, Holick MF. The effect of various doses of oral vitamin D3 supplementation on gut microbiota in healthy adults: a randomized, double-blinded, dose-response study. Anticancer Res. 2020;40(1):551-556.

DESIGN This randomized, double-blinded, dose-response study investigated the effects of vitamin D3 supplementation on gut microbiota.

PARTICIPANTS Twenty adults with low vitamin D status (defined as serum 25-hydroxyvitamin D [25(OH)D] of less than 30 ng/mL).

STUDY MEDICATION AND DOSAGE Participants received either 600, 4,000, or 10,000 IU per day of oral vitamin D3.

OUTCOME MEASURES Researchers collected stool samples at baseline and 8 weeks to identify gut microbiota using 16S rRNA gene amplification and sequencing.

KEY FINDINGS Baseline serum 25(OH)D was associated with increased relative abundance of Akkermansia and decreased relative abundance of Porphyromonas (P<0.05). After the intervention, data analysis showed a dose- dependent increase in relative abundance of Bacteroides, with a significant difference between the 600 IU group and the 10,000 IU group (P=0.027), and Parabacteroides, with a significant difference between the 600 IU group and the 4,000 IU group (P=0.039). Increased serum 25(OH)D was associated with increased beneficial bacteria and decreased pathogenic bacteria.

Jacob Schor, ND, FABNO

PRACTICE IMPLICATIONS Vitamin D3 supplementation was linked to a dose-dependent increase in bacteria associated with decreased inflammatory bowel disease activity. This is not the first time D3 supplementation has been connected with shifts in gut microbiota. A number of studies have monitored gut microbiota with varying findings. A November 2019 paper by Naderpoor et al reported results of their randomized clinical trial giving vitamin D to 26 vitamin D–deficient, overweight people and the impact this had on their fecal microbiota.1 This study defined vitamin D deficiency as ≤50 nmol/L (equivalent to 20 ng/ mL) in contrast to Charoenngam’s 30 ng/mL line. Naderpoor’s participants received a 100,000 IU loading dose followed by 4,000 IU daily for 16 weeks. Vitamin D supplementation in this earlier trial increased abundance of gut microbiota of the Nevertheless, genus Lachnospira. After supplementation, participants whose vitamin D there is something blood levels increased to greater than intriguing about the 75 nmol/L had a higher abundance of genus Coprococcus and lower idea that exposing one’s abundance of genus Ruminococcus compared to those whose vitamin D abdomen to the sun levels remained below 50 nmol/L.

“

might change

”

We also have data from a 2015 study gut microbiota. by Cantarel et al that examined vitamin D supplementation (5,000 IU per day) for 90 days in women (n=70) with multiple sclerosis (MS) and 8 healthy controls. Fecal microbiome testing showed decreased abundance of genus Ruminococcus and increased Akkermansia and Faecalibacterium in this small group. The MS patients not on the drug glatiramer treatment showed an increase in Coprococcus, Akkermansia, and Faecalibacterium after vitamin D supplementation.2

Do we know what these various findings mean? There is some consensus that vitamin D supplements alter the gut microbiome. These various studies do not suggest a consistency in these alterations, though some do agree that Akkermansia increases. In recent years, Akkermansia muciniphila has received favorable attention, and many consider increased numbers of it beneficial.

(continued on page 12)

ABSTRACT & COMMENTARY

Akkermansia exerts control on basal metabolism and immunity.3 Thus, seeing an increased abundance would be considered a good thing, especially in the overweight or obese people in Naderpoor’s study.

and the effects differ from vitamin D supplementation. Again, the changes vary between studies.5,6 Nevertheless, there is something intriguing about the idea that exposing one’s abdomen to the sun might change gut microbiota.

Reading in Charoenngam et al that “Baseline serum 25(OH)D was associated with increased relative abundance of Akkermansia and decreased relative abundance of Porphyromonas (P<0.05)” perked up my antennae. It is the bacteria Porphyromonas gingivalis that have been isolated from Alzheimer’s disease brains, and this finding is the basis of an intriguing theory that this neurodegenerative condition is triggered by chronic reactions to these bacteria.4 While not widely accepted as causative yet, the idea that vitamin D is associated with decreases in Porphyromonas populations has a certain appeal.

Although we prefer to consider data from human studies, there is one mouse study on vitamin D supplementation that should be mentioned in this discussion.

Somewhere we should mention that several papers suggest that ultraviolet light exposure will alter the gut microbiome,

In a July 2018 paper, Ghaly et al describe a study in which they gave high-dose vitamin D to mice treated with dextran sodium sulfate to trigger colitis.7 The mice receiving the highest doses of vitamin D (10,000 IU/kg) experienced the most severe colitis. The problem with reading studies done with mice is that we don’t know how to extrapolate results to humans, and this situation is a good example. Still, it wouldn’t hurt to have this study in the back of our minds when supplementing with vitamin D in high doses until we are certain that some people will not have a similar response.

LISTEN TO NATURAL MEDICINE JOURNAL ON THE GO.

The other thing that wouldn’t hurt is to adopt the view that part of the mechanism of action of vitamin D may be in shifting the gut microbiome rather than systemic biochemical effects on cells within the body. This won’t be the first time we have to step into this paradigm. We’ve already had to adjust our understanding of metformin’s mechanism.8 REFERENCE

PODCAST SERIES https://itunes.apple.com/us/podcast/natural-medicine-journal-podcast/id1112377770?mt=2

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1 Naderpoor N, Mousa A, Fernanda Gomez Arango L, Barrett HL, Dekker Nitert M, de Courten B. Effect of vitamin D supplementation on faecal microbiota: a randomised clinical trial. Nutrients. 2019;11(12):pii: E2888. 2 Cantarel BL, Waubant E, Chehoud C, et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Investig Med. 2015;63:729-734. 3 Xu Y, Wang N, Tan HY, Li S, Zhang C, Feng Y. Function of Akkermansia muciniphila in obesity: interactions with lipid metabolism, immune response and gut systems. Front Microbiol. 2020;11:219. 4 Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333. 5 Ghaly S, Kaakoush NO, Hart PH. Effects of UVR exposure on the gut microbiota of mice and humans. Photochem Photobiol Sci. 2020;19(1):20-28. 6 Ghaly S, Kaakoush NO, Lloyd F, et al. Ultraviolet irradiation of skin alters the faecal microbiome independently of vitamin D in mice. Nutrients. 2018;10(8):pii: E1069. 7 Ghaly S, Kaakoush NO, Lloyd F, et al. High dose vitamin D supplementation alters faecal microbiome and predisposes mice to more severe colitis. Sci Rep. 2018;8(1):11511. 8 Zhang W, Xu JH, Yu T, Chen QK. Effects of berberine and metformin on intestinal inflammation and gut microbiome composition in db/db mice. Biomed Pharmacother. 2019;118:109131.

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ABSTRACT & COMMENTARY

Healing the Gut Naturally

An intervention study shows gastrointestinal benefits of natural agents PUBLICATION

Ried K, Travica N, Dorairaj R, Sali A. Herbal formula improves upper and lower gastrointestinal symptoms and gut health in Australian adults with digestive disorders. Nutr Res. 2020;76:37-51. OBJECTIVE

To determine whether a combination of natural agents for gut health is tolerable and effective in adults with gastrointestinal symptoms DESIGN

Single-arm study using differing doses of intervention over 3 consecutive 4-week periods

“

Tina Kaczor, ND, FABNO

Overall, the intervention significantly improved the frequency and severity of upper and lower GI symptoms by 60% to 80%.

”

INTERVENTION

As noted in the table, this formulation comprised singleserving sachets of 5 grams each. The researchers asked participants to mix this with water or with food. They assessed compliance by questionnaire as well as sachet count at the end of each visit.

Table 1. Ingredient composition of each 5 g (1 sachet) of

Total study time was 16 weeks, with the first 4 weeks (month 0) used as a control period to establish baseline symptoms. During the first intervention phase (month 1), participants consumed a single sachet of the formulation daily for 4 weeks. In the second intervention phase (month 2), participants consumed 2 sachets daily for 4 weeks. For the third and final intervention phase (month 3), participants were able to choose their preferred dose: 0, 1, or 2 sachets daily. During month 3, there were 2 participants who chose not to take the formula, 13 participants who chose to take 1 sachet daily, and 28 participants who continued to take 2 sachets daily.

Participants received a sachet of the following combination of ingredients (Table 1 from publication under review here; the abbreviation NC stands for “nutrition care”):

the NC Gut Relief Formula

Ingredients

Curcuma longa rhizome as Cumerone

Per 5-g sachet

™

30.37 mg

Equiv. Curcumin (6.38 mg)

Glutamine

2.5 g

Quercetin

200 mg

Glucosamine hydrochloride

500 mg

Equiv. Glucosamine (415.05 mg) A vera (inner leaf/gel without latex & rind)

2.5 mg

Equiv. A vera leaf fresh (500 mg) Equiv. Aloe polysaccharides (187.5 mg) Equiv. Aloin (as barbaloin) (0.02 μg) Ulmus rubra (slippery elm) bark powder

500 mg

Guar gum

100 mg

Pectin

100 mg

Peppermint oil Dibasic sodium diphosphate Equiv, equivalent. Reprinted under Creative Commons 4.0 license.

3 mg 260 mg

PARTICIPANTS

A total of 43 adults, all with gastrointestinal (GI) symptoms, completed the study. All but 1 participant had lower GI s ymptoms (n=42). Most participants also had upper GI symptoms (n=32). The average age was 50 years, and 75% were women. All participants (n=43) completed the questionnaires at all time points. Nearly all participants (n=42) completed intestinal permeability testing at week 4 (baseline) and week 16 (study end). Stool analysis at weeks 4 and 16 was completed in 86% of participants (n=37).

One-third of the participants with upper GI symptoms (11 out of 32) were taking a proton pump inhibitor (PPI) at the start of the study. OUTCOME PARAMETERS

This study used both subjective and objective outcome parameters. Subjective outcome parameters The researchers used measurements at the end of the baseline period, which is also the start of month 1, as baseline symptoms. Participants completed validated questionnaires at the start of the study and at the end of each month of the study. Upper GI symptoms were assessed using: • Leeds Short-Form Dyspepsia Questionnaire • GERD-Q Questionnaire • GERD QoL Questionnaire • GERD-HRQL Questionnaire Lower GI symptoms were assessed using: • Bristol Stool Chart • Birmingham IBS Symptom Questionnaire • IBS-QoL Questionnaire Researchers assessed other symptoms such as fatigue, mouth ulcers, nervousness, rashes, and palpitations by questionnaire as well. They also assessed pain severity, type, location, and history using a 10-point visual pain scale. Objective outcome parameters The researchers took objective measures at baseline (end of month 0) and at the end of the study (end of month 3). These included: • A Helicobacter breath test • Gut microbial profiles using polymerase chain reaction • Assessment of intestinal permeability using lactulose/ mannitol (L/M) urine testing • Blood tests to assess tumor necrosis factor-alpha, interleukin (IL)–1beta, IL-6, and IL-8

KEY FINDINGS

Baseline symptoms did not vary significantly during the control period of 4 weeks (month 0); therefore, baseline symptomology was considered consistent without intervention. Baseline measurements used for comparison in the study were established at week 4 (the start of month 1). Overall, the intervention significantly improved the frequency and severity of upper and lower GI symptoms (including indigestion, heartburn, nausea, constipation, diarrhea, abdominal pain, and troublesome flatulence) by 60% to 80%. It also improved physical functioning, energy levels, mood, and sleep 60% to 80% from baseline values. Specifically, after 12 weeks of intervention, intestinal permeability significantly improved, from 53% of participants having normal L/M ratios at baseline to 90% of participants at week 16 (P<0.001). This did not correlate to the number of sachets consumed. Participants on PPIs (n=11) were reported to have a slightly smaller improvement in intestinal permeability than those not taking PPIs (paper did not show data). The participants with normal or hard stools had a better chance of normalizing their intestinal permeability with the formula. Of the participants who had high intestinal permeability at baseline, all of those who had normal stool, 90% of those who had hard stool, and 66% of those with soft stool had normalized intestinal permeability at the end of the study. Nearly half of the participants who began the study on a PPI (n=11) no longer needed it at the end of the study. Given the low number of participants taking a PPI, statistical significance was not achieved. Over the course of the study, many of the participants were able to reintroduce foods they did not tolerate prior to the intervention, including but not limited to: fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) foods such as garlic, onion and beans; spicy foods; acidic foods (eg, tomatoes and citrus foods); and caffeine. Gut microbial commensal bacteria increased, in particular Clostridium spp, Lactobacillus spp, and Faecalibacterium prausnitzii. These all benefit immune and gut health. The majority of the participants tolerated the formula well, with 93% finding it easy to take. Taste was favorable in 45%, with 37% reporting neutral feelings about taste and 7% disliking it completely.

ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS Unlike so many studies that are designed to use a single herb or constituent for a specific sign or symptom, this study used a generalized formula for a wide variety of GI complaints. The study also used agents that are familiar to practitioners of natural medicine. That such a simple, cost-effective combination can be broadly applicable has appeal from a practical perspective. It is also nice to see a study using a formulation designed to heal the gut, rather than merely reduce symptoms. This formulation represents a typical naturopathic protocol, where the goal is to enhance the body’s ability to heal itself. The formulation used in this study follows a logical combination of diverse gut-supportive natural agents. While there are many gut formulas available, those meant to correct gut permeability are likely to contain demulcent plants (eg, slippery elm, marshmallow root), immune-supportive polysaccharides (eg, aloe vera inner leaf, arabinogalactans), prebiotics and/or synbiotics (eg, pectin, guar gum), anti- inflammatories (eg, curcumin, quercetin, chamomile), and the amino acid glutamine, which is well known as a preferred carbon source for enterocytes. Pancreatic or brush border enzymes are commonly added to a gut-healing formula to relieve symptoms while the gut heals. The current study under review did not use enzymes in any form. Also, regardless of the details of any gut-healing supplement protocol, patients generally follow the protocol alongside a simple diet that removes foods and beverages that may damage the mucosal lining (eg, high-sugar foods, alcohol, foods to which the patient is sensitive or allergic). Each of the ingredients used in this study’s formulation has prior evidence suggesting relief of GI symptoms when taken individually. The authors contend that this is the first study to combine these proven natural agents into 1 serving. Presumably the ease of use allows for better compliance than taking each agent separately. In contrast, taking the combination as single agents would allow for some individualization at the discretion of the prescriber. Regardless of how it is

delivered, the formulation used in this study is a good representation of a typical protocol, and the results are in keeping with clinical observation. Curcumin, which has been shown to reduce IBS symptoms in an 8-week trial,1 has several gut-specific actions including stimulating bile secretion (ie, cholagogue effect), promoting healthy gut microflora, and improving wound healing through its anti-inflammatory action.2 Quercetin has also been shown to affect the gut microbiota, often in concert with fiber in the diet.3,4 Glucosamine hydrochloride also has beneficial effects on the gut flora.5 Slippery elm bark is a classic herbal demulcent, often used when soothing of the throat or gut is therapeutically indicated. In one study that used a combination of natural agents including slippery elm, symptoms of constipation-predominant IBS were significantly improved.6 Pectin and guar gum have each been proven beneficial to gut health and lessening of GI symptoms.7,8 During the final 4-week phase of the current study under review, most of the participants with loose stool chose to continue the higher dose of the intervention. The authors speculated that this may be due to noticeably better stool-firming effect from higher doses of soluble fibers. In addition to the bulking effects, guar gum has been shown to increase Lactobacillus and Bifidobacterium, which led to an improvement in quality of life in IBS patients in 1 study.8 Aloe vera gel, or aloe vera inner leaf, is traditionally used for stomach complaints of all kinds. It is hepatoprotective, antiulcerative, and anti-inflammatory.9 In 1 small study of 79 patients with gastroesophageal reflux disease (GERD), aloe was able to reduce symptoms of reflux as effectively as the medications omeprazole or ranitidine.10 It is essential to note that the study currently under review used the inner leaf only. The latex, or outer leaf, contains the potent laxative emodin. This should be avoided unless a laxative effect is desired. No matter how many times this is stressed, inevitably some people will take a whole-leaf product and have loose stools or even

(continued on page 18)

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ABSTRACT & COMMENTARY

diarrhea. Fortunately, this is easily remedied by swapping the whole-leaf product for one using inner leaf only. Peppermint oil is an interesting addition to this formula. There is good evidence for its use in IBS. A meta-analysis of 16 clinical trials involving 651 participants concluded that peppermint oil significantly reduced symptoms of IBS (P<0.005).11 However, among the many constituents of peppermint oil is menthol, a potent phenolic that gives peppermint its distinct scent. Menthol is commonly found in topical creams for sore muscles due to its antispasmodic effects. In keeping, relaxing smooth muscles of the GI tract on contact may have a therapeutic or untoward effect. The relaxation upon menthol’s contact with muscle can elicit reflux symptoms in some people when the muscle of the lower esophageal sphincter is relaxed.9 Conversely, menthol may have a therapeutic role in relieving diffuse esophageal spasm.12 While reflux may be a concern, the current study under review did not report any worsening of reflux in participants with or without GERD. Also, as with any essential oil taken orally, direct irritation of the stomach lining is a risk. Whether it is the adsorption of the peppermint oil to the fibers in the formula or whether the dose (3 mg) was so small that there were no side effects, it appears the peppermint oil did not adversely affect any participants in the current study. To be clear, peppermint oil is considered therapeutic for gut health as an antispasmodic, an antimicrobial, and an anti- inflammatory, and its role in this formula does follow prior evidence.13 For example, peppermint oil has been shown to speed gastric emptying in a small trial of 10 healthy volunteers, which may be therapeutic for some.14 The Canadian Gastroenterology Association has recommended peppermint oil as part of initial therapies for IBS, prior to beginning prescription drugs in patients.15 Peppermint has also been used traditionally for stomach complaints of various kinds. The 2 forms that are least likely to cause any side effects are peppermint leaves as tea and enterically coated oil of peppermint, which does not dissolve in the stomach. Some studies have demonstrated that enterically coated peppermint oil can reduce pain from IBS.16

According to the average scores of participants reporting upper GI symptoms, there was significant improvement in nearly every parameter on the upper GI questionnaires. Almost half of those taking a PPI were able to go off of their drug by the end of the 4-month study. There was no notation of how long these participants had been taking their PPIs, but experience dictates that the longer a person has been taking an acidblocking agent, the longer it takes to get off it. The rebound effect of sudden acid production in a stomach that lacks a proper mucosal barrier from extended PPI use can induce symptoms of gastritis. All practitioners should proceed with caution when a patient chooses to go off a PPI, particularly those who may not have proper sensory innervation to their stomach (eg, diabetics, the elderly). The populations at high risk for dysplasia and cancer should also approach discontinuation with caution, if at all. That said, when patients can safely discontinue PPIs, they, in partnership with their practitioners, should pursue this since the PPIs have been associated with lower-bowel dysfunction, including small intestinal bacterial overgrowth (SIBO).17 The use of objective measures of intestinal permeability and stool microbiology strengthened the findings of this study. Given the subjectivity of symptoms, such objective measures remove the risk of bias, particularly in studies such as this one where there is no control arm for comparison. Since this is the first study of its kind, repeating these results with a larger cohort and adding a conventionally treated arm would provide a higher level of evidence as well as a “real world” scenario for treatment. The lesson is not in the novelty of the agents used in this study. This study does not bring any new or exotic constituent to light. To the contrary, this study validated the use of familiar natural agents commonly used by integrative practitioners and traditional healers alike. Empirical usage of many natural treatments continues in lieu of evidence due to their efficacy, which requires success a good amount of the time to be noticeable. Therefore, the high success rate of this gut formula is not surprising, nor are the study results suspect. Unfortunately, many studies are done on singular natural agents or plant constituents in search of a definitive

ABSTRACT & COMMENTARY

mechanism of action, which does not represent traditional or modern natural medicine practices. More studies using combinations of natural agents that mimic current practices are needed if practitioners are expected to use evidence-based natural medicine effectively. REFERENCES

1 Bundy R, Walker AF, Middleton RW, Booth J. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study. J Altern Complement Med. 2004;10(6):1015-1018. 2 Peterson CT, Vaughn AR, Sharma V, et al. Effects of turmeric and curcumin dietary supplementation on human gut microbiota: a double-blind, randomized, placebo-controlled pilot study. J Evidence-based Integr Med. 2018;23:2515690X18790725. 3 Tamura M, Hoshi C, Kobori M, et al. Quercetin metabolism by fecal microbiota from healthy elderly human subjects. PLoS One. 2017;12(11). 4 Combet E, Edwards CA, Alkhaldy AA. Colonic metabolism of the common dietary polyphenol quercetin-3-O-rutinoside (Rutin)–impact of age and gut health. FASEB J. 2016;30(1_supplement):611-690. 5 Navarro SL, Levy L, Curtis KR, Lampe JW, Hullar MAJ. Modulation of gut microbiota by glucosamine and chondroitin in a randomized, double-blind pilot trial in humans. Microorganisms. 2019;7(12):610. 6 Hawrelak JA, Myers SP. Effects of two natural medicine formulations on irritable bowel syndrome symptoms: a pilot study. J Altern Complement Med. 2010;16(10):10651071.

7 Xu L, Yu W, Jiang J, Feng X, Li N. Efficacy of pectin in the treatment of diarrhea predominant irritable bowel syndrome. Zhonghua wei Chang wai ke za zhi= Chinese J Gastrointest Surg. 2015;18(3):267-271. 8 Giannini EG, Mansi C, Dulbecco P, Savarino V. Role of partially hydrolyzed guar gum in the treatment of irritable bowel syndrome. Nutrition. 2006;22(3):334-342. 9 Hatlebakk JG, Berstad A. Pharmacokinetic optimisation in the treatment of gastro-oesophageal reflux disease. Clin Pharmacokinet. 1996;31(5):386-406. 10 Panahi Y, Khedmat H, Valizadegan G, Mohtashami R, Sahebkar A. Efficacy and safety of Aloe vera syrup for the treatment of gastroesophageal reflux disease: a pilot randomized positive-controlled trial. J Tradit Chinese Med. 2015;35(6):632636. 11 Grigoleit H-G, Grigoleit P. Peppermint oil in irritable bowel syndrome. Phytomedicine. 2005;12(8):601-606. 12 Parvataneni S, Vemuri-Reddy SM. Role of peppermint oil in diffuse esophageal spasm in the geriatric population. Cureus. 2020;12(3). 13 Oldfield EC, Copare J, Da J. Peppermint Oil: Clinical Uses in the Treatment of Gastrointestinal Diseases. Vol 3.; 2015. 14 Inamori M, Akiyama T, Akimoto K, et al. Early effects of peppermint oil on gastric emptying: a crossover study using a continuous real-time 13 C breath test (BreathID system). J Gastroenterol. 2007;42(7):539-542. 15 Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol. 2019;2(1):6-29. 16 Weerts ZZRM, Masclee AAM, Witteman BJM, et al. Efficacy and safety of peppermint oil in a randomized, double-blind trial of patients with irritable bowel syndrome. Gastroenterology. 2020;158(1):123-136. 17 Compare D, Pica L, Rocco A, et al. Effects of long-term PPI treatment on producing bowel symptoms and SIBO. Eur J Clin Invest. 2011;41(4):380-386.

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ABSTRACT & COMMENTARY

Treatment of IBS Without Constipation with Rifaximin Versus a Spore-Based Probiotic

Evaluation of symptom severity, quality of life, and rectal sensation REFERENCE

Catinean A, Neag AM, Nita A, Buzea M, Buzoianu AD. Bacillus spp. spores—a promising treatment option for patients with irritable bowel syndrome. Nutrients. 2019;11(9):1968. OBJECTIVE

The aim of this study was to compare rifaximin followed by a nutraceutical or low–fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet to stand-alone therapy with a spore-based probiotic (MegaSporeBiotic) in patients with irritable bowel syndrome (IBS) without constipation. DESIGN

A nonblinded, prospective, randomized, controlled clinical study. Participants were randomized to 3 groups: • G1, in which participants received a 10-day course of rifaximin (1,200 mg) followed by a 24-day course of a nutraceutical containing Bifidobacterium longum W11, soluble fiber, and vitamins B1, B2, B6, and B12. • G2, in which participants received a 34-day course of Bacillus spp probiotic (Bacillus licheniformis, Bacillus indicus HU36™, Bacillus subtilis HU58™, Bacillus clausii, Bacillus coagulans, all from the MegaSporeBiotic brand). • G3, in which participants received a 10-day course of rifaximin (1,200 mg) followed by a 24-day low-FODMAP diet. The researchers obtained outcome measures at baseline, day 10 (for groups G1 and G3), day 34, and day 60. PARTICIPANTS

This study included 90 patients with IBS without constipation based on Rome III criteria. Patients were aged 18 to 75 years with a normal colonoscopy in the last 5 years, blood counts within reference values, and normal fecal calprotectin. Patients with documented food allergies, gluten intolerance or celiac disease, diabetes, thyroid disease, intestinal inflammatory disease or other organic diseases, eating disorders (anorexia or bulimia), probiotics 1 month before the study, antibiotic treatment in the previous 6 months, or specific diets were excluded. STUDY PARAMETERS ASSESSED

Researchers evaluated patients based on the IBS severity score (IBS-SS), quality of life for IBS patients (IBS-QL), and a rectal volume sensation test. KEY FINDINGS

IBS-SS improved at each outcome measurement for G1, G2, and G3 and, interestingly, improved equally by the end of the study. The MegaSporeBiotic group, G2, did have earlier symptom improvement at the 3rd visit (day 34). Quality-of-life scores and the rectal volume sensation testing also improved in every group, with similar outcomes in each group. 20 ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, MAY 2020 SUPPLEMENT—VOL. 12, NO. 51 (SUPPL)

Alena Guggenheim, ND

PRACTICE IMPLICATIONS Irritable bowel syndrome is a common disorder that affects approximately 10% of the population, with significant gaps in reliable and cost-effective treatment strategies.1 Our understanding of pathophysiology is rapidly expanding using systemic biology. The current proposed model is a complex web of dysfunction of the gut microbiota, altered intestinal permeability, altered motility, gastrointestinal (GI) immune-cell activation, visceral hypersensitivity, and abnormal gut-brain interactions.2 Rifaximin first emerged as an effective treatment option to alter GI microbiota in 2011 with the TARGET trial, which eventually led to the FDA approval of rifaximin as a treatment for IBS with diarrhea in 2015.3 This study aims to show that nonantibiotic therapy may also be effective to treat IBS with diarrhea (IBS-D) through the alteration of the microbiome via a spore-based probiotic. This study does contain multiple significant limitations, many of which the authors acknowledge. These include a lack of blinding and placebo, moderate rather than severe symptoms at baseline, a lack of breath testing for small intestinal bacterial overgrowth (SIBO), and the use of Rome III rather than Rome IV criteria. The researchers used Rome III because this study started prior to ROME IV, and the authors note that 90% of participants also met the new criteria. There are additional limitations not discussed by the authors. The first, and perhaps most important, is that the rifaximin treatment group was undertreated in both dose and duration. The current universally accepted (continued on page 22)

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ABSTRACT & COMMENTARY

dosage of rifaximin for IBS-D is 550 mg 3 times daily (1,650 mg total daily dose) for 14 days.4 This study used 1,200 mg total per day for 10 days, which is 52% of the effective dose. This introduces a significant source of outcome bias toward the spore-based probiotic intervention. Improved outcome measures could strengthen this trial. First off, the authors used a rectal volume sensation test at baseline and at each visit. This testing is invasive, uncomfortable, and poorly supported in the literature as an outcome measure for IBS-D.5 In place of rectal volume sensation testing, a noninvasive, 3-hour lactulose breath test would improve

study design. This would have allowed the authors to include patients with SIBO only, or could have stratified responders in each treatment group based on SIBO status. Rezaie et al found that patients with a positive lactulose breath test for SIBO do respond significantly better to rifaximin therapy compared to IBS-D patients with a normal breath test.6 Including 3-hour lactulose breath testing in this study would have clarified which patients were the best candidates for spore-based probiotic treatment versus rifaximin therapy. Using 2 treatment groups (rifaximin/low-FODMAP diet versus spore-based probiotic) or 2 treatment groups and a

Intragroup Results for IBS-SS 400

350

300

250

200

150

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Visit 1

Visit 2

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n G1 (Rifaximin/Nutraceutical) n G2 (MegaSporeBiotic) n G3 (Rifaximin/Low-FODMAP)

ABSTRACT & COMMENTARY

placebo group would have improved the clarity of the results. Blinding could remove another source of bias; however, it is impossible to blind therapeutic diet versus usual diet, and this is an ongoing challenge in nutrition research. The impact of the therapeutic interventions in this study was buried in confusing and cumbersome tables, so I have highlighted positive results in a graph form that illustrates the study’s findings (page 22). This graph represents the study results and shows us how effective these therapies are compared to each other. It also highlights the fact that all 3 treatment groups continued to improve even after interventions were discontinued at visit 3 (day 34). One of the most exciting aspects of this study is the cost efficacy of spore-based probiotic versus rifaximin. The dose of rifaximin used in this study costs approximately $1,300, and the recommended dose is closer to $2,000. Insurance coverage often requires multiple drug failures and prior authorizations, if the treatment is covered at all. The dose and duration of the spore-based probiotic used in this study retails for $55. This represents a significant advantage of spore-based probiotic therapy. The authors did not report side effects or participant dropouts, so it is difficult to calculate these factors into a cost-benefit ratio. It should also be noted that outcomes were similar for spore-based probiotic therapy versus the treatment group following a low-FODMAP diet. The low-FODMAP diet has emerged as an effective dietary strategy to treat IBS-D.7 While it is exciting to have an effective dietary tool for IBS, this diet is highly restrictive and has wide-reaching psychosocial and nutritional implications.8 In my experience, the low-FODMAP diet is a more stressful diet compared to other, perhaps even more restrictive diets, because food choice is not intuitive. Patients must be constantly using handouts and apps and, thus, must become hypervigilant to successfully follow this diet. In this regard, spore-based probiotic therapy offers a significant advantage.

CONCLUSION While this study has multiple methodological issues that introduce bias, it is important to acknowledge that the results of this study improve our understanding of treatment options for IBS-D. Spore-based probiotic therapy as a standalone therapy was associated with improvements to IBS severity scores, quality of life, and rectal volume sensation that were equal to those associated with rifaximin therapy followed by low-FODMAP diet or probiotic therapy. Symptoms continued to improve with all 3 interventions after treatment was discontinued, as evidenced by improved IBS severity scores at day 60 versus day 34 when treatment ended. The most significant error in the study was the inadequate dose of rifaximin for treatment. Despite this, spore-based probiotic therapy offers a significantly easier treatment at less than 5% of the cost of rifaximin. Further research is needed before claiming that spore-based probiotic therapy is as effective as rifaximin, but it may certainly be considered when navigating treatment options with IBS-D patients. REFERENCES

1 Sperber AD, Dumitrascu D, Fukudo S, et al. The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: a Rome Foundation working team literature review. Gut. 2017;66:1075-1082. 2 Chey WD, Shah ED, DuPont HL. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review. Therap Adv Gastroenterol. 2020;13:1756284819897531. 3 Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364(1):22-32. 4 Cangemi DJ, Lacy BE. Management of irritable bowel syndrome with diarrhea: a review of nonpharmacological and pharmacological interventions. Therap Adv Gastroenterol. 2019;12:1756284819878950. 5 Nozu T, Kudaira M. Altered rectal sensory response induced by balloon distention in patients with functional abdominal pain syndrome. Biopsychosoc Med. 2009;3:13. 6 Rezaie A, Heimanson Z, McCallum R, Pimentel M. Lactulose breath testing as a predictor of response to rifaximin in patients with irritable bowel syndrome with diarrhea. Am J Gastroenterol. 2019;114(12):1886-1893. 7 Zahedi MJ, Behrouz V, Azimi M. Low fermentable oligo-di-mono-saccharides and polyols diet versus general dietary advice in patients with diarrhea-predominant irritable bowel syndrome: a randomized controlled trial. J Gastroenterol Hepatol. 2018;33(6):1192-1199. 8 Staudacher HM. Nutritional, microbiological and psychosocial implications of the low FODMAP diet. J Gastroenterol Hepatol. 2017;32 Suppl 1:16-19.

ABSTRACT & COMMENTARY

Low-FODMAP Diet in the Management of Quiescent Inflammatory Bowel Disease Results of a placebo-controlled, 4-week trial REFERENCE

Cox SR, Lindsay JO, Fromentin S, et al. Effects of low FODMAP diet on symptoms, fecal microbiome, and markers of inflammation in patients with quiescent inflammatory bowel disease in a randomized trial. Gastroenterology. 2020;158(1):176188.e7. STUDY OBJECTIVE

To investigate the effects of low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet on persistent gut symptoms, the intestinal microbiome, and circulating markers of inflammation in patients with quiescent inflammatory bowel disease (IBD) DESIGN

Multicenter, randomized, parallel, singleblinded, placebo-controlled, 4-week trial PARTICIPANTS

Fifty-two patients (27 patients in the low-FODMAP–diet group and 25 patients in the control diet group) aged ≥18 years, with quiescent Crohn’s disease (CD) and ulcerative colitis (UC), from 2 large gastroenterology clinics in London, United Kingdom (UK). Patients were limited to those with ongoing gut symptoms meeting Rome III criteria for irritable bowel syndrome with diarrhea predominant (IBS-D), IBS with mixed bowel habits (IBS-M), or unsubtyped IBS (IBS-U), functional bloating or diarrhea, abdominal pain, bloating, and/or diarrhea on 2 or more days during the baseline screening week with inadequate relief, and who were naïve to a low-FODMAP diet. Quiescent IBD was determined by physician global assessment, absence of IBD flare in the prior 6 months, fecal calprotectin <250 µg/g, and C-reactive protein (CRP) <10 mg/L.

STUDY PARAMETERS ASSESSED

1. Gut symptoms

• IBS symptom severity scale (IBS-SSS) • Bristol stool form scale (BSFS) • Gastrointestinal symptom rating scale (GSRS) 2. Health-related quality of life (HR-QoL) • UK-specific IBD questionnaire 3. Disease activity • Harvey-Bradshaw Index for CD • Partial Mayo Score for UC 4. Patient-perceived IBD control • IBD control questionnaire 5. Stool parameters, including • Inflammatory markers • Fecal calprotectin • Fecal microbiome composition • Short-chain fatty acids 6. T-cell phenotypes in blood • Flow cytometry PRIMARY OUTCOME MEASURES

Primary outcome: Change in IBS-SSS. Secondary outcomes: Other measures of gut symptoms (total IBS-SSS score, proportion of patients achieving a 50-point IBS-SSS reduction, global symptom questionnaire; and GI symptom rating scale), disease-specific HR-QoL, stool frequency and consistency, clinical disease activity, inflammatory markers, dietary intake, microbiome composition and function, short-chain fatty acid concentrations, and peripheral T-cell phenotype. KEY FINDINGS

The low-FODMAP diet group had greater relief in gut symptoms, higher HR-QoL scores, and lower abundance of gut microbes that regulate immune response. There were no differences in microbiome diversity and markers of inflammation between the 2 groups.

Eleonora Naydis, ND, LAc, FABNO PRACTICE IMPLICATIONS The low-FODMAP diet has been found to benefit people with IBS. There is evidence that it can also help reduce persistent gastrointestinal symptoms in quiescent IBD, such as Crohn’s disease and ulcerative colitis.1,2 IBD is characterized by periods of remission and relapse. Current treatments are aimed at decreasing inflammation during the relapse and extending time in remission. However, many patients with quiescent IBD continue to have gastrointestinal symptoms. It is unclear why but could possibly be due to concurrent presence of IBS, low-grade inflammatory process, or the psychological impact of IBD.3 The low-FODMAP diet limits foods high in certain types of sugars that are poorly absorbed by the digestive tract. These sugars are abbreviated as FODMAP, which stands for fermentable oligosaccharides (fructans and galacto-oligosaccharides), disaccharides (lactose), monosaccharides (fructose), and polyols (sorbitol and mannitol). Due to limited absorption, foods high in FODMAPs will move more slowly through the digestive tract and draw more water inside the lumen of the small intestine. Once FODMAPs pass down to the large intestine, they are fermented by colonic bacteria, a process that generates gas in the bowel. This increased amount of fluid and gas in the gut can lead to bloating, pain, and diarrhea in susceptible individuals.

ABSTRACT & COMMENTARY

Eating fewer FODMAP carbohydrates can help decrease these symptoms.4 The low-FODMAP diet limits fermentation in the colon; however, microbiome diversity did not significantly change between the low-FODMAP and control groups in this study. Patients in the low-FODMAP group had less Bifidobacterium adolescentis, Bifidobacterium longum, and Faecalibacterium prausnitzii species, believed to regulate immune response, but this finding did not affect the inflammatory markers. The takeaway from this study is that a low-FODMAP diet can be used for patients with quiescent IBD for persistent IBS-like gastrointestinal symptoms such as gas, bloating, flatulence, and frequent stools. A low-FODMAP diet can improve the quality of life, but it does not seem to have a significant effect on inflammation for patients in remission. Larger and longer-term studies are needed. Once symptomatic relief is obtained, long-term plans should be in place to address further nutritional needs of the patients. Other considerations for management of functional gastrointestinal symptoms in IBD should include careful rule out of underlying conditions and monitoring of inflammation.

“

The takeaway from this study is that a low FODMAP diet can be used for patients with quiescent IBD for persistent IBS-like gastrointestinal symptoms such as gas, bloating, flatulence, and frequent stools.

”

Repeated fecal calprotectin measurement for monitoring inflammation is useful.5 A partial list of underlying conditions to consider includes small intestinal bacterial overgrowth (SIBO),6 increased intestinal permeability,7 prior surgical care and resulting adhesions, and the effect of underlying psychological conditions, such as anxiety. Additional recommendations for management of IBD should include exercise, as there is evidence that exercise decreases the risk of future relapses.8 Counseling, cognitive behavioral therapy (CBT), mindfulness therapies, and hypnosis have been helpful for patients to manage their condition.9 Acupuncture and moxibustion therapy demonstrated good outcomes for IBD compared to oral sulfasalazine.10 Aloe vera gel and curcumin have been studied for IBD as well. 11 REFERENCES

1 Zhan YL, Zhan YA, Dai SX. Is a low FODMAP diet beneficial for patients with inflammatory bowel disease? A meta-analysis and systematic review. Clin Nutr. 2018;37(1):123-129. 2 Pedersen N, Ankersen DV, Felding M, et al. Low-FODMAP diet reduces irritable bowel symptoms in patients with inflammatory bowel disease. World J Gastroenterol. 2017;23(18):3356-3366. 3 Quigley EMM. Overlapping irritable bowel syndrome and inflammatory bowel disease: less to this than meets the eye? Ther Adv Gastroenterol. 2016;9(2):199212. 4 Monash University. Discover the research behind the low FODMAP diet. Monash U niversity. https://www.monashfodmap.com/ibs-central/i-have-ibs/research/. Accessed May 5, 2020. 5 Heida A, Park KT, van Rheenen PF. Clinical utility of fecal calprotectin monitoring in asymptomatic patients with inflammatory bowel disease: a systematic review and practical guide. Inflamm Bowel Dis. 2017;23:894-902. 6 Ricci JER Jr, Chebli LA, Ribiero TCDR, et al. Small-intestinal bacterial overgrowth is associated with concurrent intestinal inflammation but not with systemic inflammation in Crohn’s disease patients. J Clin Gastroenterol. 2018;52(6):530-536. 7 Chang J, Leong RW, Wasinger VC, et al. impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology. 2017;153:723-731.e1. 8 Jones PD, Kappelman MD, Martin CF, et al. Exercise decreases risk of future active disease in patients with inflammatory bowel disease in remission. Inflamm Bowel Dis. 2015;21:1063-1071. 9 Ballou S, Keefer L. Psychological interventions for irritable bowel syndrome and inflammatory bowel diseases. Clin Transl Gastroenterol. 2017;8:e214. 10 Jun J, Yuan L, Huirong L. Acupuncture and moxibustion for inflammatory bowel diseases: a systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med. 2013;2013:158352. 11 Langmead L, Feakins RM, Goldthorpe S, et al. Randomized, double-blind, placebo-controlled trial of aloe vera gel for active ulcerative colitis. Ailment Pharmacol Ther. 2004;19(7):739-747.

EXPERT INTERVIEW

Clinical Considerations to Reduce Risk of Colon Cancer An interview with Editor-in-Chief Tina Kaczor, ND, FABNO

Colon cancer is one of the most preventable cancers, and yet it is the third leading cause of cancer deaths after lung cancer, and prostate for men and breast cancer for women. Natural Medicine Journal’s publisher, Karolyn Gazella, recently sat down with our editor-in-chief, Tina Kaczor, ND, FABNO, to discuss how clinicians can help patients reduce their risk of developing colon cancer. Kaczor has been working in oncology for 2 decades and is a Fellow of the American Board of Naturopathic Oncology. This was an excerpt of our conversation. You can listen to our whole discussion here, on iTunes, or wherever you listen to our podcast.

Question: Colon cancer is considered a preventable cancer, and yet it’s still a leading cause of cancer death. Why is that? Answer: Many of the risk factors for colon cancer are a product of our modern lifestyles—lifestyle habits, what we’re eating, how we’re sleeping, and our stress levels. Colon cancer rates are higher in Westernized societies in general.

How and when it’s diagnosed has a lot to do with why it’s a leading cause of cancer death. Ultimately, it’s not just the prevalence and the incidence of colorectal cancer, but at what stage it’s diagnosed. The higher the stage that it is found at, the more likely it will be to result in death. Question: That brings us to an important topic, which is screening. Can you take us through the types of screening tests and recommendations? Answer: Screening for colorectal cancer, just like any cancer, is really governed by the country. So what we do here in the United States is not the same in other countries. But the US Preventative Services Task Force recommendations include stool tests, endoscopy, and imaging.

There are three types of stool tests: • Guaiac-based fecal occult blood test that’s sometimes done in office or at-home. It is looking for blood in the stool. • The fecal immunochemical test (FIT) test is similar to the guaiac test, it just uses antibodies to detect blood in the

stool. What I like about this test is that vitamin C doesn’t interfere with the results as it can with the guaiac-based test. • The FIT test combined with a DNA test looks for blood as well as abnormal DNA, so it’s a more sensitive test. This one requires an entire bowel movement to be collected and sent out to a lab, so it’s more involved. But it does offer a little bit more specificity since blood in the stool can be from so many causes besides colorectal cancer. Endoscopy includes flexible sigmoidoscopy, which looks at the rectum and the descending colon but not the transverse or ascending colon. That’s usually done every 5 years, unless it’s done with those stool tests for blood, in which case it can be done every 10 years. The other type of endoscopy is colonoscopy, which scopes the entirety of the colon. It’s an intervention of sorts, because it will remove polyps, it’ll remove suspicious lesions, and it will biopsy suspicious areas. There is one imaging that is approved and it’s a virtual colonoscopy. Sounds great, no invasion, but it involves the same prep as a colonoscopy. Then they insufflate, which is a fancy word of saying they pump air into your whole colon, which can be uncomfortable. After that they put you through a CT scanner, so there’s a mild amount of radiation involved. If they see a polyp or anything suspicious, they still have to go back and do a colonoscopy with a real scope to get a sample. The other reason I’m not a huge fan of virtual colonoscopies is that they can miss one of the most likely polyps to become cancer, and that’s the sessile polyps. The recommendation for which type of colonoscopy to get has to do with patient preference, other medical conditions they may have, and risks and benefits to each of these.

EXPERT INTERVIEW

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still for long periods of time is a risk factor, so if someone has a job that keeps them at a desk all day, that should be taken into account.

We can say with some level of confidence that regular coffee consumption reduces the incident risk of colorectal cancer between 26% to 50%.

Hyperglycemia is also associated with colorectal cancer.

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Question: When should people be tested?

Answer: Someone with low to average risk should start testing at age 50 according to the Centers for Disease Control and Prevention (CDC). The American Cancer Society says to start at 45 years old, and that screening should also be done in people with low to average risk—those without any family history or people with symptoms. Both agree screening should end at 75 years old because of increased risk of perforation— which is still low, even in older adults. I find that interesting because your risk of colorectal cancer does not suddenly go down at that age. It actually keeps going up well into your late 70s and your 80s. For example, someone over 80 years old is at 10 times the risk of someone in their 50s.

So I don’t think we should stop thinking about colorectal cancer in our elderly patients. I do think we might want to turn to something less invasive like Cologuard, which is a stool test that can be done at home. It’s by no means as thorough or accurate as a colonoscopy, but it does find 94% of early-stage colorectal cancers. There is certainly a false negative rate and a false positive rate. So it has some drawbacks. Question: Which risk factors do you feel clinicians may not be paying enough attention to in their practice? Answer: The well-known risk factors are processed meat consumption, abdominal fat, body fat in general, smoking, height with taller people having higher risk, and age. Then there are lesser-known risk factors. One is occupation—sitting

And then there’s dysbiosis, which has to do with the microbes in the gut. There should be a predominance of beneficial bacteria in the gut. There’ll always be a little bit of candida, just like there’s a little bit of dandelion in someone’s lawn. It’s not consequential unless there’s a lot of the bad or pathogenic organisms. But more and more we’re seeing that what inhabits the gut as far as organisms, and in particular bacteria, is associated with colorectal cancer. So if someone has gas, bloating, diarrhea, IBS, and other GI issues, those should be taken into consideration, since these symptoms can signal dysbiosis. Question: What role does family history play in increasing one’s risk? Answer: When someone has a family history, they may want to get screened at an earlier age. If you have a first-degree relative (parent, child, or full sibling) with colorectal cancer or advanced adenomas diagnosed before 60 years of age, or 2 first-degree relatives at any age, you have a a 3- to 4-fold increased risk of colorectal cancer and should be screened much earlier. A guideline is to get screened when you’re 10 years younger than the earliest diagnosis of a first-degree family member. If they were diagnosed at 60 years of age or older, then colonoscopy screenings should start at 40 instead of 50. Question: What should clinicians tell their patients about diet? Answer: Generally, I think the advice should be around creating the proper flora in the gut. People hear that and they think probiotics. But prebiotics are just as valuable if not more so. Prebiotic food—soluble fibers, legumes, fruits, veggies, and polyphenols found in colorful foods—leads to a diversity in the gut. And we want the most diverse array of good organisms we can possibly have.

EXPERT INTERVIEW

I’m a fan of probiotics at times, but there are some times where a probiotic can actually lessen the diversity in the gut, which is the antithesis of what we want. It depends on the probiotic itself. So from a generic level I say, diversity of the gut. From a drill-down and specific level, things like a small amount of nuts on a daily basis is really important for gut health and has been associated with less colorectal cancer. Greens in general are important. Cruciferous vegetables, like kale, broccoli and cabbages are also key. And it has to do with not just gut health and the microbiota, it has to do with getting rid of carcinogens as you take them in. Because whether we’re breathing them in or we’re eating them or they’re going through our skin, we are exposed to things that we need to break down. Those crucifers help us do that. And maybe some green tea, which has been associated with less colorectal cancer risk. And of course I should say very specifically legumes. Beans have been associated with less colorectal cancer risk, and I have some concern about long-term diets that omit legumes. Question: What does the research tell us about coffee? Answer: Thankfully as a coffee lover, I’m happy to report that coffee consumption is associated with lower rates of colorectal cancer incidence. We can say with some level of confidence that regular coffee consumption reduces the incident risk of colorectal cancer between 26% to 50%, depending on how much you drink. There’s a dose-response relationship, meaning the more you drink, the more you reduce your risk. I will put a caveat to that of course, and that is, at some point coffee’s not good for your other systems, so you do want to drink it in moderation. Question: From a lifestyle standpoint, what are the top-3 things clinicians should focus on when talking to their patients? Answer: I would say body composition, exercise at any size, and minding the microbes of the gut. Those are the 3 lifestyle things that one can do.

Body composition has to do with fat deposition and muscle mass. There’s a fat-to-muscle ratio that we want to keep an eye on, but it’s not exact. And having been a clinician for 20 years, I can tell you there are some people whose bodies simply will not release their fat no matter what they do—whether it’s genetics, age, or some other factor. But we can still increase muscle mass under the fat. I tell people, “Lose as much fat as you can, get your BMI down below 25 if you possibly can and certainly below 30.” If you can’t, if you just hit a wall, build muscle. Because muscle is the antithesis of the fat, so they oppose each other, making opposing molecules. Fat makes molecules that increase inflammation. Muscle makes molecules that decrease inflammation. Next is exercise at any size. It doesn’t matter what you do, just staying active, having movement. You don’t have to run a marathon, but exercise to whatever capacity makes you slightly breathless. Exercise is far more important than any piece of diet or other advice. It reduces risk of colorectal cancer by 24% to 50%, depending on the studies you look at. Lastly, mind the microbes. Remember, colorectal cancer is happening right where the food and the bacteria are lying against the cells. More than in any other cancer, we affect risk directly by changing the environment of the inner colon. Question: What’s the connection between hormone replacement therapy and colon cancer? Answer: The rate of colorectal cancer incidence worldwide is 50% higher in men than it is in women. So there’s likely something going on with hormones. We assume it probably has something to do with estrogens. At this point it looks like estrogen itself prevents the incidence of colorectal cancer. But once colorectal cancer is present, it may be the opposite. It looks like while estrogen may prevent the initiation of cancer in the colon and rectum, it may actually cause more growth once cancer is present. So if somebody has a small amount of colorectal cancer, meaning it’s occult, it can’t be seen, it’s never been diagnosed, and they begin hormone replacement therapy, they may accelerate the growth of that cancer. (continued on page 30)

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EXPERT INTERVIEW

Question: What does the research tell us about aspirin use and colon cancer?

Question: Are there any nutrient deficiencies that can increase risk of colon cancer?

Answer: This is interesting. Some of the first data looking at the protection from aspirin of colorectal cancer diagnosis was incidental. It was found in studies involving people who were on aspirin to prevent stroke, for example. Watching what happened to participants over 10 and 20 years, they noticed that people who took aspirin had a lot less colorectal cancer. Since then there’s been retrospective and prospective studies looking at aspirin use and colorectal cancer incidence. An aspirin dose between 75 and 100 mg a day reduces the risk of colorectal cancer by about 10%. If the dose goes up to 325 mg a day, it looks like 35% reduction. And that’s according to a meta analysis that came out just last year that looked at a couple of dozen plus studies on this. So it’s clear that it protects.

Answer: Yes, clearly selenium deficiency, which is interesting because there’s a lot of selenium deficient soil in the United States. You could have selenium deficiency if you eat a standard American diet or if you happen to eat food grown in selenium-deficient soil. Vegetarians need to be mindful of this in particular because selenium is found in meat.

But we do have to remember that aspirin thins the blood. So if someone is young, active, accident-prone, likely to have a bleed for any reason, then we may not want to do full-dose aspirin because it’s hard to staunch a bleed if there is an injury. ABOUT THE EXPERT

Vitamin D deficiency has been linked to colorectal cancer incidence and outcomes. And interestingly colorectal cancer was one of the first cancers that vitamin D was linked to back in 1980. So vitamin D needs to be corrected and usually with a supplement no matter where along the continuum of colorectal cancer from prevention all the way to metastatic disease. And vitamin C, perhaps. There’s a little less evidence, but it looks like that may be a nutrient deficiency that’s linked to colorectal cancer. Not ingesting enough calcium is also likely linked to colorectal cancer. It’s not because people are deficient in calcium per se, they’re pulling it from their bone if they’re not ingesting enough. You’re never going to see it on a lab. It has to do with calcium as it passes through the lumen of the colon, because it binds certain bile acids. And it needs to bind those bile acids because they happen to promote colorectal cancer. So ingesting enough calcium is important not just for normalizing serum in the bloodstream without bone degradation, but also for gut health. So calcium would be on my list of things to take if somebody isn’t already eating dairy. Question: In addition to correcting underlying nutrient deficiencies, are there nutrients or herbs that may be helpful when we’re talking about reducing risk? Answer: Garlic is really high on the list and—this goes back to the biome—it has to do with compounds that are anticancer within the garlic sulfurous compounds. As far as supplements go, curcumin might be highest on the list because of its anti- inflammatory activity.

Natural Medicine Journal Gastrointestinal Health Special Issue 2020

Articles inside

Treatment of IBS Without Constipation with Rifaximin Versus a Spore-Based Probiotic

Healing the Gut Naturally

Meta-Analysis Concludes Probiotics Effectively Reduce IBS Symptoms Research sheds light on strains and dosage

Healing the Gut Naturally

Enhancing Viral Immunity via the Gut Microbiome

Clinical Considerations to Reduce Risk of Colon Cancer

Low-FODMAP Diet in the Management of Quiescent Inflammatory Bowel Disease

Vitamin D Alters Gut Microbiome