Our other genome - the foundation for new approaches in medicine. S. Dusko Ehrlich, INRA, MetaHIT coordinator Paris, June 4, 2010

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1 Our other genome - the foundation for new approaches in medicine S. Dusko Ehrlich, INRA, MetaHIT coordinator Paris, June 4,

2 The human intestinal metagenome 3.3 million bacterial gene catalog 150-fold human genome 85% of abundant gut genes from a cohort of 124 Europeans 70-86% of genes from the US & Japanese studies March 2010 Major media, week of 4 Mar 10 Mar (Nature Author & Referee Services): ABC News; Boston Globe; CBC (Canada); FOX News; MSNBC/NBC; New York Times; San Francisco Chronicle; Washington Post ; BBC News; Independent ; AP ; AFP (France); Reuters; ABC (Australia) ; The Australian Spiegel (Germany); Le Monde; Le Figaro; Dagens Nyheter (Sweden).

3 The MetaHIT (Metagenomics of the Human Intestinal Tract) Consortium European Commission FP7 project, coordinated by INRA (S. Dusko Ehrlich) 12 European and 1 Chinese Institutions; 9 public, 4 private 21.2 M /4 yrs (11.4 M from the EC); 100 scientists clinicians Started on March 2008 microbiologists immunologists genomics bioinformatics stakeholders

4 The human intestinal microbiota is a forgotten organ 100 trillion microorganisms ; 10-fold more cells than the human body; 2 kg of mass! Interface between food and epithelium In contact with the 1st pool of immune cells and the 2nd pool of neural cells of the body with a major role in health & disease!

5 Perturbation of intestinal microbiota in many pathologies Frailty in seniors Van Tongeren et al., 2005 Crohn Seksik et al., 2003; Sokol et al., 2006, 2008, 2009 Ulcerative colitis Sokol et al., 2008; Martinez et al., 2008 Pouchitis Lim et al., 2009, Kühbacher et al., 2006 Obesity Ley et al., 2007; Kalliomäki et al., 2008 Type-2 diabetes Cani and Delzenne, 2009 Type-1 diabetes Dessein et al., 2009; Wen et al., 2008 Coeliac disease Nadal et al., 2007; Collado et al., 2009 Allergy Kirjavainen et al., 2002; Björkstén, 2009 Autism Finegold et al., 2002; Paracho et al., 2005 Colorectal cancer Mai et al., 2007; Scanlan et al., 2008 HIV infection Gori et al., 2008 * Indications from animal models, effects of antibiotics or probiotics, clinical studies; courtesy of Joël Doré

6 The MetaHIT approach to relation between microbes & us Establish a reference gene set by metagenomic & genomic sequencing of the Human GI tract microbes Develop generic tools for profiling the GI tract microbiota genes : arrays and high throughput DNA sequencing Use the profiling tools to search association of microbial genes and disease in Inflammatory Bowel Diseases and Obesity Carry out function analysis to go from associations to mechanisms Bioinformatics overlays all activities

7 4 firmicute species The MetaHIT barcode Obesity study, 80 individuals Three clinical studies (in progress; unpublished) Obesity 177 Danes lean: n = 67 ; obese: n = 110 IBD Crohn Disease 21 Spaniards patients: n = 8 ; healthy: n = 13 IBD Ulcerative Colitis 24 Spaniards patients: n = 12; healthy: n = 12 BMI 60 million sequences per individual are used to establish bacterial gene profiles 42

8 Bacterial Species are Associated to Chronic Disease Four species discriminant for obesity Lean Five species discriminant for Crohn Healthy Patients Obese Three species discriminant for UC Healthy For 45% of individuals four firmicute species discriminate obesity with 81 % accuracy Patients A small number of species fully discriminate the IBD phenotypes Causal agents? Contributors? Consequence?

9 Where do these studies lead to and when? Diagnostic & prognostic tests - soon - arrays, sequencing, Q-PCR; immunomarkers (?) Better treatments - next - personalized medicine Responders/non-responders Novel treatments last: target our other genome! - modulation of microbiota Promoters (pre-biotics: FOS, others?) Inhibitors ( soft AB-like?? Re-purposing?) - transplantation of microbiota; biobanking

10 Let s go there together France is the place to do it!! The world-wide leadership in the field exists & the necessary expertise can easily be networked (clinicians, microbiologists, genomics, bio-informatics...) The tools are available and can easily be strengthened (cohorts for different diseases, gene profiling techniques, informatics, function analysis...) Target Inflammation!? Motivation is high and will rise even further with new discoveries the field is ripe! (scientists, research institutions, government...)

11 We can build together new approaches in medicine, targeting our other genome Network Work Leadership Improve health and well-being of many 11