The role of gut microbiome in IBS

Chung Owyang, MD H. Marvin Pollard Professor of Internal Medicine

Professor of Molecular and Integrative Physiology Chief, Division of Gastroenterology

Director, Pollard Institute for Medical Research

1

Pathophysiology of IBS: A Work in Progress

Motility Abnormalities

Brain-gut Interactions • HPA axis • Autonomic dysfxn

Genetic Factors • Twin studies

• SERT polymorphisms

Psychologic • Anxiety/panic • Depression • Somatization

Visceral Hypersensitivity

Pathophysiology of IBS: A Work in Progress

Motility Abnormalities

Brain-gut Interactions • HPA axis • Autonomic dysfxn

Genetic Factors • Twin studies

• SERT polymorhisms

Psychologic • Anxiety/panic • Depression • Somatization

Gut Microbiota and

Immune Activation Visceral

Hypersensitivity

Subclinical mucosa inflammation in IBS

Nat Rev Gastroenterol Heptol 2010;7:163

Increased intestinal permeability and visceral hypersensitivity in IBS

Pain 2009;146:41-6.

Neuro-immune interaction in IBS

Nat Rev Gastroenterol Heptol 2010;7:163

Abnormal innate and adaptive immune activity in the gut of IBS patients

Nat Rev Gastroenterol Heptol 2010;7:163

Roles of gut microbiota on IBS

n  Post infectious variant of IBS n  Antibiotic use may be a risk factor for

IBS n  Some IBS pts have small bowel

bacterial overgrowth n  Germ-free animals show abnormal gut

epithelial and immune function

Gut microbiota studies in human n  Studies of gut microbiota have been

difficult because of methodological challenges

n  Many bacteria do not survive through cultures

n  Recent deep molecular analysis of the 16S RNA subunit for bacteria allows comprehensive sequencing of bacteria gene in fecal samples

Gut dysbiosis in IBS

Gastroenterology 2011;141:1792

Firmicutes

Bacteriodes 2-fold increase in IBS

Differences in gut microflora between Health and IBS

n  Extensive variability in flora amongst IBS pts & controls n  General observations from IBS pts1:

–  Fewer Lactobacillus, Bifidobacteria, coliforms –  Greater instability of microbiota

n  Quantative PCR suggests2: –  Decreased Lactobacillus sp in IBS-D –  Increased Veillonella sp in IBS-C –  Considerable overlap between IBS and controls

Spiller. Aliment Pharmacol Ther 2008;28:385 Malinen et al. Am J Gastroenterol 2005;100:373 Kassinen et al. Gastroenterol 2007;133:24

Clustering analysis of IBS and control stool samples

Gut 2012;61:997

Gut dysbiosis in IBS

n  ↑ Clostridium cluster XIVa in IBS –  Proinflammatory flagellin

protein (degrades mucous layer)

–  ↑ SCFA (hyperalgesia)

Gut 2012;61:997

Commensal bacteria may have pro- and anti-inflammatory properties

Dysbiosis and IBS

-Dysbiosis -Genetic

Susceptibility -Environmental

Insults

Altered Permeability

Increased Antigen

Presentation

Mast Cell Activation

Extra GI Symptoms

Systemic Cytokines

& Chemokines IBS

Altered Enteric

Neuronal & Smooth Muscle

Function Talley & Fodor. Gastroenterol 2011;141:1555

The Gut Microbiota: A Potential IBS Treatment Target

Prebiotics?

Antibiotics? Probiotics?

Diet? Other drugs? Prokinetics Purgatives

•  Literal meaning: “For life” (Elie Metchinikoff, 1907)

•  Live micororganisms, which, when consumed in adequate amounts, confers a health benefit on a host” (Food & Agricultural Organization of the United Nations and the WHO, 2001)

Preidis, Versalovic. Gastroenterol 2009;136:2015

What are probiotics?

Interaction between probiotic with host mucosa

Lebeer S et al. Nature Reviews. Microbiology 2010;8:171

Utility of probiotics for IBS: A systematic review and meta-analysis

16 RCTs met selection criteria for systematic review n  Heterogeneity in probiotic species. Study design,

outcome assessments and patient populations render interpretation difficult

10 studies adequate for meta-analysis n  Pain relief was observed with Bifidobacterium breve,

Bifidobacterium longum, and Lactobacillus acidophilus species

Brenner DM, et al. Am J Gastroenterol 2009;104:1033; Oritz-Lucas M, et al. Rev Esp Enferm Dig 2013;105:19

0

0.5

1

1.5

2

2.5

AbdominalPain

Bloating Incompleteevacuation

Gas Straining Bowelsatisfaction

Compositescore

Bifantis Placebo

* * * * * *

*

*P < .05

B. infantis improves IBS symptoms in RCT

1x108 CFU/cc

Whorwell, Am J Gastroenterol 2006; 101:1581

Bifidobacterium normalizes cytokine profiles in IBS

52

96

56

175175

85 86

0

50

100

150

200

B. infantis35624

L. salivarius4331

Placebo Healthyvolunteers

Pre-treatment Post-treatment

n  Symptom improvement associated with normalization of cytokine ratio, suggesting an anti-inflammatory effect of B. infantis in IBS

n  Composite score = sum of scores for abdominal pain, bloating, and bowel movement difficulty

O’Mahony L, et al. Gastroenterology. 2005;128:541-551.

IL-1

0:IL

-12

ratio

P = 0.001; N=77

24.56

34.64

40.52

30.15

42.35

52.14

0

10

20

30

40

50

60

B. infantis35624

L. salivarius4331

Placebo

Likert score VAS score

Com

posi

te s

core

s

The Gut Microbiota: A Potential IBS Treatment Target

Prebiotics? Synbiotics?

Antibiotics? Probiotics?

Diet? Other drugs? Prokinetics Purgatives

Rifaximin for Global Improvement in IBS: A meta-analysis

Measure Outcomes

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: χ2=5.26, df=4 I2=24% p=0.26

Menees et al. AJG 2012

Administration of rifaximin prevents stress-induced inflammation and barrier dysfunction

Inflammatory Cytokines mRNA

Inflammatory Cells

Intestinal Permeability

Tight Junction Proteins mRNA

Xu D, et al. Gastroenterology 2014;146:484

Administration of rifaximin modulates bacterial load and community composition

Lactobacilli Xu D, et al. Gastroenterology 2014;146:484

Gut Microbiota & IBS: Key Points

n  Subclinical mucosa inflammation and impaired permeability are common among IBS patients

n  Mounting evidence that gut microbiota of IBS patients differ from healthy subjects

n  Microbial fingerprinting may identify subgroup of IBS who may respond to modulation of gut microbiota

n  Well designed studies with more homogenous patient population, better dietary control and outcome assessments are needed to confirm the beneficial effects of probiotics and antibiotics in the treatment of IBS

Impaired mucosal barrier in IBS

Piche T et al. Gut 2009;58:196-201 Gut 2009;58:196-201

Tight junction

Permeability

Supernatant of colonic biopsy of IBS patients increases permeability of Caco-2 cells

Gut 2009;58:196-201.