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 Visceral Hypersensitivity Brain-gut Interactions HPA axis Autonomic dysfxn Genetic Factors Twin studies SERT polymorphisms Psychologic Anxiety/panic Depression Somatization
Pathophysiology of IBS: A Work in Progress Motility Abnormalities Gut Microbiota and Immune Activation Visceral Hypersensitivity Brain-gut Interactions HPA axis Autonomic dysfxn Genetic Factors Twin studies SERT polymorhisms Psychologic Anxiety/panic Depression Somatization
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 Firmicutes Bacteriodes 2-fold increase in IBS Gastroenterology 2011;141:1792
Differences in gut microflora between Health and IBS n Extensive variability in flora amongst IBS pts & controls n General observations from IBS pts 1 : Fewer Lactobacillus, Bifidobacteria, coliforms Greater instability of microbiota n Quantative PCR suggests 2 : 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 Altered Permeability Increased Antigen Presentation Mast Cell Activation Insults Extra GI Symptoms Systemic Cytokines & Chemokines Talley & Fodor. Gastroenterol 2011;141:1555 IBS Altered Enteric Neuronal & Smooth Muscle Function
The Gut Microbiota: A Potential IBS Treatment Target Antibiotics? Probiotics? Prebiotics? Diet? Other drugs? Prokinetics Purgatives
What are probiotics? 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
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
B. infantis improves IBS symptoms in RCT 2.5 Bifantis Placebo * 2 *P <.05 1x10 8 CFU/cc 1.5 1 0.5 * * * * * * 0 Abdominal Pain Bloating Incomplete evacuation Gas Straining Bowel satisfaction Composite score Whorwell, Am J Gastroenterol 2006; 101:1581
Bifidobacterium normalizes cytokine profiles in IBS P = 0.001; N=77 IL-10:IL-12 ratio 200 175 150 100 52 50 Pre-treatment Post-treatment 175 96 85 86 56 Composite scores 60 50 40 30 20 10 24.56 Likert score 30.15 VAS score 34.64 42.35 40.52 52.14 n n 0 B. infantis 35624 L. salivarius 4331 Placebo Healthy volunteers Symptom improvement associated with normalization of cytokine ratio, suggesting an anti-inflammatory effect of B. infantis in IBS Composite score = sum of scores for abdominal pain, bloating, and bowel movement difficulty 0 B. infantis 35624 L. salivarius 4331 Placebo O Mahony L, et al. Gastroenterology. 2005;128:541-551.
The Gut Microbiota: A Potential IBS Treatment Target Antibiotics? Probiotics? Prebiotics? Synbiotics? 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: χ 2 =5.26, df=4 I 2 =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 Xu D, et al. Gastroenterology 2014;146:484 Lactobacilli
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 Permeability Tight junction Piche T et al. Gut 2009;58:196-201 Gut 2009;58:196-201
Supernatant of colonic biopsy of IBS patients increases permeability of Caco-2 cells Gut 2009;58:196-201.