Post on 21-Mar-2018
transcript
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
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
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
Gut dysbiosis in IBS
n ↑ Clostridium cluster XIVa in IBS – Proinflammatory flagellin
protein (degrades mucous layer)
– ↑ SCFA (hyperalgesia)
Gut 2012;61:997
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