Bacteriotherapy in IBD Harry SOKOL Micalis Gastroenterology - PowerPoint PPT Presentation

Oxford Inflammatory Bowel Disease MasterClass Bacteriotherapy in IBD Harry SOKOL Micalis Gastroenterology Department Saint-Antoine Hospital AVENIR team U1057

Disclosures  Consulting for Danone, Astellas, Enterome

Outline  The gut microbiota  Why targeting the gut microbiota in IBD?  Therapeutic interventions targeting the microbiota  Microbiota as a biomarker

Outline  The gut microbiota  Why targeting the gut microbiota in IBD?  Therapeutic interventions targeting the microbiota  Microbiota as a biomarker

The human intestinal microbiota Food - faecal microbiota : Epithelium >10 11 µorg/g Microbiota - hundreds of species … - adapted and µbiota functionally stable … - nutrition, physiology, immunity & protection - genetic repertoire : ~150 x human genome Photo: V.Rochet host Section of mouse caecum Health <-> Disease

> 1250 species identified belonging to 3 major phyla Wilson et al 1996 Suau et al 1999 Actinobacteria Bonnet et al 2002 Bacteroidetes Hold et al 2002 Hayashi et al 2002 Hayashi et al 2003 Wang et al 2003 Mangin et al 2004 Manichanh et al 2006 Eckburg et al . 2005 Firmicutes

High Inter-individual variability at the bacterial level, but ……………………………………… PJ Turnbaugh et al. Nature 2009 ; Qin et al. Nature 2010

High Inter-individual variability at the bacterial level, but some species are present in everyone Core microbiome Faecalibacterium prausnitzii SL3 3 Roseburia intestinalis M50 1 Bacteroides vulgatus ATCC 848 Bacteroides sp. 9_1_42FAA Ruminococcus sp SR1 5 Coprococcus comes SL7 1 Bacteroides sp. 2_1_7 Bacteriodes xylanisolvens XB1A Ruminococcus torques L2-14 Bacteroides sp. 2_2_4 Bacteroides sp. D4 Bacteroides dorei Ruminococcus obeum A2-162 Ruminococcus lactaris Bacteroides capillosus Bacteroides finegoldii Clostridium sp M62 1 Clostridium nexile PJ Turnbaugh et al. Nature 2009 ; Qin et al. Nature 2010

High Inter-individual variability at the bacterial level, but stability at the functional level PJ Turnbaugh et al. Nature 2009 ; Qin et al. Nature 2010

Outline  The gut microbiota  Why targeting the gut microbiota in IBD?  Therapeutic interventions targeting the microbiota  Microbiota as a biomarker

Why targeting the gut microbiota in IBD?  Role of fecal stream in post operative recurrence of CD  Animal model of colitis depend on gut microbiota  Spontaneous colitis in some genetically modified mice can be transmitted to WT mice via the gut microbiota (TRUC mice, NLRP6 KO…)  Polymorphisms of innate immunity genes involved in bacterial sensing : associated with IBD (GWAS)

Genes in IBD Crohn’s Disease Ulcerative colitis 140 risk loci 133 risk loci Identified in 30 110 23 GWAS Biological processes involved in IBD loci Epithelial Barrier Innate Immunity Autophagy Adaptive immunity Khor et al. Nature 2011 ; Jostins et al. Nature 2012

Genes in IBD Crohn’s Disease Ulcerative colitis 140 risk loci 133 risk loci Microbiota Identified in 30 110 23 GWAS Biological processes involved in IBD loci Epithelial Barrier Innate Immunity Autophagy Adaptive immunity Khor et al. Nature 2011 ; Jostins et al. Nature 2012

…and the Microbiota is abnormal in IBD patients Composition Morgan, Tickle, Sokol et al. Genome Biology 2012

…and the Microbiota is abnormal in IBD patients Actinobacteria Bacteroidetes Proteobacteria Firmicutes Composition Morgan, Tickle, Sokol et al. Genome Biology 2012

…and the Microbiota is abnormal in IBD patients Secretion system Actinobacteria Bacteroidetes Cyst/Meth Metab. Proteobacteria Butanoate Metab. Lys biosynth Firmicutes Pentose Ph pathway Composition Functions Morgan, Tickle, Sokol et al. Genome Biology 2012

…and the Microbiota is abnormal in IBD patients Secretion system Actinobacteria Bacteroidetes Cyst/Meth Metab. Proteobacteria Butanoate Metab. Lys biosynth Firmicutes Pentose Ph pathway Composition Functions % Difference 14 12 Changes in microbial function 10 8 in IBD : more consistent than 6 4 changes in composition 2 0 Composition Function Morgan, Tickle, Sokol et al. Genome Biology 2012

Outline  The gut microbiota  Why targeting the gut microbiota in IBD?  Therapeutic interventions targeting the microbiota  Microbiota as a biomarker

Therapeutic interventions targeting the microbiota Normal microbiota Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Normal microbiota Antibiotics Devastation Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Normal microbiota IBD associated dysbiosis Antibiotics Devastation Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Normal microbiota IBD associated dysbiosis Antibiotics Fecal Probiotics Prebiotics Transplantation Devastation Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Normal microbiota IBD associated dysbiosis Antibiotics Fecal Probiotics Prebiotics Transplantation Devastation Restored ecosystem Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Normal microbiota IBD associated dysbiosis Antibiotics Fecal Probiotics Prebiotics Transplantation Other Devastation Restored ecosystem Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Normal microbiota IBD associated dysbiosis Antibiotics Fecal Probiotics Prebiotics Transplantation Other Devastation Restored ecosystem Adapted from Lozupone et al. Nature 2012

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Crohn UC Pouchitis

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Prevention of + disapointing postoperative recurrence Crohn UC Pouchitis

Prevention of post operative recurrence in CD  Nitroimidazoles are effective but is not well tolerated  Probiotics are not effective so far (but high heterogeneity between studies) Dohertiy al. APT 2010

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Prevention of + disapointing postoperative recurrence Crohn Prevention of recurrence Low evidences Low evidences UC Pouchitis

S. boulardii does not prevent relapse of CD S. boulardii 1g/j vs placebo N=165 patients Steroid- or salicylate- induced remission Boureille et al. CGH 2013

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Prevention of + disapointing postoperative recurrence Crohn Prevention of recurrence Low evidences Low evidences + Flare ND UC Pouchitis

Rifaximin-Extended Intestinal Release Induces Remission in Patients With Moderately Active CD 402 patients with 400, 800, and 1200 mg rifaximin-EIR, moderately active CD x2/d for 12 weeks. Prantera et al. Gastroenterology 2013

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Prevention of + disapointing postoperative recurrence Crohn Prevention of recurrence Low evidences Low evidences + Flare ND + Prevention of relapse ND UC Pouchitis

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Prevention of + disapointing postoperative recurrence Crohn Prevention of recurrence Low evidences Low evidences + Flare ND + Prevention of relapse ND UC + Flare ND Pouchitis

2-week triple antibiotic therapy (amoxicillin, tetracycline, and metronidazole) produced improvement, remission, and steroid withdrawal in active UC Patients with active ulcerative colitis (Mayo scores of 6 – 12). Okhusa et al. AJG 2010

2-week triple antibiotic therapy (amoxicillin, tetracycline, and metronidazole) produced improvement, remission, and steroid withdrawal in active UC Patients with active ulcerative colitis (Mayo scores of 6 – 12). Steroid withdrawal rates in steroid- dependent cases ( n = 100). Okhusa et al. AJG 2010

Therapeutic interventions targeting the microbiota Antibiotics Probiotics Prevention of + disapointing postoperative recurrence Crohn Prevention of recurrence Low evidences Low evidences + Flare ND + Prevention of relapse ND UC + Flare ND + + Pouchitis

Therapeutic interventions targeting the microbiota Normal microbiota IBD associated dysbiosis Antibiotics Fecal Probiotics Prebiotics Transplantation Other Devastation Restored ecosystem Adapted from Lozupone et al. Nature 2012

Fecal transplantation IBD-associated microbiota Healthy microbiota