The Role of the Gut Microbiome on Functional Bowel Symptomss3.gi.org/meetings/bp2016/16ACG_BestPrac_0018.pdf · · 2016-02-03• Relative benefits of empiric vs. breath test guided

William D. Chey, MD, FACG

The Role of the Gut Microbiome on Functional Bowel Symptoms

William D. Chey, MD, FACGTT Nostrant Professor of Medicine

University of Michigan Health SystemAnn Arbor, Michigan

Factors Influencing the Gut Microbiome

Parkes et al. Am J Gastroenterol 2008

2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology

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Talley & Fodor. Gastroenterol 2011;141:1555

Dysbiosis and IBS

• Dysbiosis

• Genetic Susceptibility

• Environmental Insults

Altered Permeability

Increased Antigen

Presentation

Mast Cell Activation

ExtraGI

Symptoms

Systemic Cytokines

& Chemokines IBS

Altered Enteric

Neuronal & Smooth Muscle

Function

Functional/Medical Foods?

Antibiotics?Probiotics?Prebiotics?Synbiotics?

Diet? FMT?

The Gut Microbiota: A Potential IBS Treatment Target


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Diet? FMT?


Food: Metabolic & Functional Consequences


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Low-FODMAP Diet vs. Australian Diet in IBS

30 IBS patients and 8 HVs: 1 week baseline followed by 21 days of low-FODMAP diet or typical Australian diet before crossing over to other diet. Significant benefits for overall IBS symptoms, bloating, pain, and wind (p<0.001). Benefits for King’s Stool Chart only for IBS-D (p<0.04)

Halmos, et al. Gastroenterology 2014; 146:67

VAS(0-100 mm)

20

60

-7 21

40

p<0.001

7

20

60

-7 21

40

7

Day Day

BaselineTypical Aust.Low FODMAP

1414

IBS Healthy Contols

Halmost et al. Gut 2015;64:93-100

FODMAP Effects on the Microbiome

• Low FODMAP diet: higher fecal pH – 7.37 [7.23-7.51] vs. 7.16 [7.02-7.3]; P=.001

• LFD and Australian diets: similar SCFA levels

• LFD: increased microbial diversity and reduced total bacterial abundance – 9.63 [9.53-9.73] vs. 9.83 [9.72-9.93] log10 copies/g; P<.001

• Australian diet – increased butyrate-producing Clostridium cluster XIVa (P<.001) and mucus-

associated Akkermansia muciniphila (P<.001), but decreased Ruminococcus torques.

• “The functional significance and health implications of such changes might lead to caution about reducing FODMAP intake in the longer term”

• “The low FODMAP diet should not be recommended for asymptomatic populations.”


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Chumpitazi et al. Aliment Pharmacol Ther 2015; 42: 418–427

FODMAP Microbiome Biomarkers and Response to the Low-FODMAP Diet

• Thirty-three children with IBS completed the study.

• Less abdominal pain occurred during the low FODMAP diet vs. typical U.S. childhood diet

• Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity

– e.g., Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii

• Responders also enriched at baseline for 3 Kyoto Encyclopedia of Genes and Genomes orthologues

– two relate to carbohydrate metabolism




Diet? FMT?


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Interfere with growth or survival of

bacteria in gut lumen

Improve mucosal barrier function

and mucosal immune system

Affect systemic immune system

Possible Mechanisms of Probiotic Activity

Adapted from Rijkers GT, et al. J Nutr. 2010;140:671S-676S

Utility of Probiotics for IBS: A Statistical Review and Meta-analysis

• Forty-three RCTs included• RR of IBS symptoms persisting with probiotics vs placebo

was 0.79 (95% CI 0.70-0.89)– Probiotics had beneficial effects on global IBS, abdominal pain,

bloating, and flatulence scores– Effects of individual species or combinations marginal to non-

existent– NNT = 7 (95% CI 4-12.5)– NNH - 35

Ford AC, et al. Am J Gastroenterol 2014; 109:S2


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Proportion Reporting Adequate Reliefof IBS Symptoms

*p=.027

*p=.004

N=88/60 N=91/49

B. lactis CNCMI-2494 (1.25×1010 cfu), S. thermophilus & L. bulgaricus (1.2×109 cfu)Roberts et al. BMC Gastroenterology 2013, 13:45

Pro

po

rtio

n o

f R

esp

on

der

s(S

GA

)

L. paracasei F19, L acidophilus La5 & Bif Bb12 in doses of 3x109 to 7x109 ; 4 capsules qd

Begtrup et al. Scand J Gastro 2013, 48:1127

*P = .027N=88/60 N=91/49

20

0

40

60

80

100 Treatment Follow-up

Months

Placebo (64)

Probiotic (67)

3 6 3 6

No significant differences at 6 months

Ad

equ

ate

Rel

ief

of

IBS

Proportion Reporting Adequate Reliefof IBS Symptoms


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Diet? FMT?

MeasureOutcomes

Response rates (%)Weight ARR NNT

Rifaximin Placebo

Sharara 27.0 9 1.4% 18% 5.6

Pimental 32.5 9 1.6% 23.5% 4.3

Lembo 52.3 44.2 25.2% 8.1% 12.3

Target 1 40.8 31.2 34.9% 9.6 10.4

Target 2 40.6 32.2 36.8% 8.4 11.9

Overall 43.3 34.2 100% 9.1 11.0

Heterogeneity: �2=5.26, df=4 I2=24% p=0.26Menees et al. AJG 2012;107:28

Rifaximin for Global Improvement in IBS: A Meta-analysis


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Rifaximin (n=1103) Placebo (n=829)

Any TEAE 52.5% 52.6%

Serious TEAE 1.5% 2.2%

TEAE resulting in discontinuation

2.0% 1.7%

Any GI TEAE 12.2% 12.2%

Nausea 3.1% 2.3%

Abdominal pain 2.4% 2.5%

Diarrhea 1.4% 1.3%

Vomiting 1.1% 0.6%

Any Infection TEAE 8.5% 9.5%

C. difficile colitis 0% 0%Schoenfeld, et al. APT 2014;39:1161

Pooled Safety Analysis of Rifaximin for Non-C IBS

• Data analyzed from 2 phase 3 and 1 phase 2b trials of rifaximin

TARGET 3: Study Design

Screening Open-Label Rifaximin 550 TID x 2 weeks

2w RFX 4w f/u

Non-Responders withdrawn and proceed to EOS

ObservationPhase

Up to 18w

2nd RepeatTreatment

4w f/u

4w f/u

Repeat Treatment

ObservationPhase

6w

6w

1st RepeatTreatment

2w RFX 4w f/u

4w f/u2w PBO

Ran

dom

ize

1:1

2w PBO

End

Follow up

4 W7-13 d PBO

2w RFX

Chey et al. DDW 2015

Study Day 1

Primary Evaluation Period

Open-label Treatment Phase Double-blind Treatment Phases

Responders followed; only

patientswith relapserandomized


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TARGET 3n = 2579

Experienced Relapse n = 692 (64%)*

No Relapsen = 382 (36%)

Rifaximin n = 328

Placebon = 308

Ope

n-La

bel

Doub

le-b

lind

Placebon = 283

Rifaximinn = 295

TARGET 3 - Subject Disposition

19

* 56 (5%) not randomized due to enrollment closure

Obs

erva

tion

n = 2331

1st Repeat Treatment

2nd Repeat Treatment

FDA Respondern = 1074 (46%)

FDA Non-Responder n = 1257 (54%)

Discontinued Earlyn = 248

Lembo A et al. American College of Gastroenterology Annual Meeting. Program no. 45.

TARGET 3: Response to Rifaximin Retreatment

p=.04p=.02


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Chey, et al. DDW 2015

Improvement in IBS-D Symptoms During First and Second Double-Blind Repeat Treatment Phases

1st Repeat Treatment 2nd Repeat Treatment

EndpointRFX

(n=328)PBO

(n=308)p-value

RFX (n=295)

PBO (n=283)

p-value

Abdominal Pain 53.0% 43.8% 0.0212 52.5% 44.9% 0.0549

Stool Consistency

45.1% 37.0% 0.0241 45.1% 38.5% 0.0799

Urgency 48.5% 39.6% 0.0251 46.8% 38.5% 0.0355

Bloating 50.3% 42.2% 0.0345 47.1% 35.0% 0.0017

Antibiotics for IBS: Points to Consider

• Reasons for symptom improvement remain unclear– SIBO vs. alteration of colonic microbiome/fermentation?

• Relative benefits of empiric vs. breath test guided therapy

• Benefits of other antibiotic therapies unclear

• Benefits appear transient– How can we predict who will respond?

– How can we increase the durability of response?

• Potential consequences of repeated, widespread antibiotic use?

Chey. AGA Perspectives 2009;4:5-8


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Diet? FMT?

Crowe KM, J Acad Nutr Diet 2013;113:1096http://www.fao.org/docrep/004/y2775e/y2775e08.htm

Functional Foods

• “A foodstuff that provides a health benefit beyond basic nutrition, demonstrating specific health or medical benefits, including the prevention and treatment of disease” (Food & Agricultural Organization, United Nations)

• Can be categorized as:

– Conventional foods that contain bioactive components

– Foods enriched or fortified with bioactive food compounds

– Synthesized food ingredients such as indigestible oligosaccharides that provide a health benefit, or serve as precursors to compounds that provide a health benefit


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Weinstock, Open Journal of Gastroenterology, 2014, 4, 329

Medical Foods

• “a food…formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” (US FDA)

• Serum-derived bovine immunoglobulin isolate

• >50% immunoglobulin

• Survives exposure to gastric acid

• Binds bacterial components in the small intestine

• Possible effects on permeability, immune function, and gut microbiome

Open label treatment with SBI 5 grams BID

SBI = serum bovine IgLBT = lactulose breath testWeinstock, Open Journal of Gastroenterology, 2014, 4, 329

Serum Bovine Ig/Protein Isolate for IBS-D & IBS-M

Pro

po

rtio

n w

ith

Go

od

Res

po

nse


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Diet? FMT?

Pinn & Brandt. ACG Annual Meeting 2013

Fecal Microbial Transplant for IBS

• 13 IBS patients with refractory disease – 54% women, average age 45 years (range: 23-75 years)

– Average time from FMT to data collection 11 months (6-18 months)

– Improved symptoms = 70%

– Abdominal pain = 72%

– Bowel habit = 69%

– Bloating = 50% and flatus = 45%

– Improved quality of life = 46%


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IBS Treatments Aimed at the Gut Microbiota: Summary

• Agents that influence the gut microbiota offer a potential target in patients with IBS

• Specific probiotics may improve IBS symptoms in a subset of patients

• Prebiotics remain to be adequately tested in clinical trials

• Antibiotics offer short term benefits to a subset of IBS sufferers

• Medical Foods and FMT require evaluation in RCTs

• Important questions remain regarding which patients are most likely to benefit from these strategies and whether they are safe if used over extended periods of time

Michigan Nutrition Center for Digestive Diseases


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Documents

The Role of the Gut Microbiome on Functional Bowel Symptomss3.gi.org/meetings/bp2016/16ACG_BestPrac_0018.pdf · · 2016-02-03• Relative benefits of empiric vs. breath test guided