Conflicts of interest: none. ILSI/ILSI North America Annual Meeting 24 January 2012, Phoenix, Arizona

Transcription

1 Conflicts of interest: none ILSI/ILSI North America Annual Meeting 24 January 2012, Phoenix, Arizona

2 Studying the human microbiome using high throughput meta omics data Marie Joossens for Jeroen Raes VIB VUB Belgium vub.be

3 Last 7y: developing approaches to study microbial population variation and its functional impact from meta omics data Raes et al., Genome Biology 2007 Foerstner et al. EMBO reports 2005 Von Mering et al., Science 2007 Harrington et al., PNAS 2007 Raes et al., Curr Opin Microbiol 2007 Gianoulis*, Raes* PNAS 2008 Raes et al., MSB 2011

4 Data handling is tough, interpretation is difficult: many technical and biological factors influence the end result Raes and Bork, Nat Rev Microbiol, 2008 MareNostrum supercomputer Barcelona

5 Comparative metagenomics as a tool to compare microbial communities as a whole What s the functional difference between sample A and B? What s the phylogenetic difference between sample A and B? Comparing total gene pool of diverse environments Same environments (human intestine), different hosts e.g. patient vs. reference Same host, different timepoints

6 MetaHIT European partners in the international human microbiome consortium Metagenomics of the human intestinal tract Creation of a reference gut gene and genome pool Determining metagenomic variation within the European population, investigation of determining factors Studying microbiome variation in disease (Inflammatory Bowel Disease, Obesity) Functional follow up studies of disease related genes and species MetaHIT partners CBS DTU, Denmark EMBL, Germany (now +VIB/VUB) HUVH, Spain IEO, Italy INRA, France SDU, Denmark WU, The Netherlands Sanger centre, UK Genoscope, France Bejing Genome Centre, China Danone research Novo Nordisk, Denmark UCB Pharma, Spain

7 124 individuals 3.3 mio genes

8 Ultra deep Illumina sequencing (BGI, Shenzen) allows almost complete coverage 580 Gbases (~200 human genomes!) First ultra short read metagenome +unknown genes (grand total: ~ gene families) +known genes with unknown functions Known functions Qin, Li, Raes et al. Nature 2010

9 Substantial overlap in gut microbiota composition between individuals 1/3 rd of species present in almost all individuals 1500 species total 160 species/ individual

10 Gut gene core (minimal metagenome present in all individuals) gene families housekeeping genes for general bacterial survival, but also specific functionalities rare in currently sequenced genomes (+unknowns!) Qin, Li, Raes et al. Nature 2010

11 What determines the microbiota composition? Comparing nationalities shows very little influence of ethnicity Quantitative species composition comparison based on phylomarkers (40 universal single copy genes) Blue: danish Red: french Orange: italian Yellow: japanese

12 Each individuals gut microbiota can be classified in a limited number of cross national enterotypes 85 Illumina danish metagenomes 33 international sanger metagenomes 155 US 16S rrna pyrosequencing Arumugam*, Raes* et al. Nature 2011

13 Enterotypes are stable constellations of co occurring species, with 3 main drivers ecosystem optima

14 What do they mean? No correlation to measured host properties (age, sex, BMI, nationality) Functional composition (e.g. vitamin production pathways, metabolism) Many unknowns or unclear trends, maybe factors we haven t taken into account yet? Confirmation: Morotomi et al Biol Pharm Bull 2011 Clustering based on functional content

15 Long term dietary patterns? Short term dietary intervention > no effect Wu et al Science 2011

16 Rare biomarkers correlate with host properties, proof of principle for future disease studies Method pool see Gianoulis*, Raes* et al. PNAS 2009 & Raes et al Mol Sys Biol 2010; Arumugam*, Raes* et al. Nature 2011

17 Gut specific pathway modules: a powerful tool for gut meta omics data annotation, interpretation and metabolic modeling Advantage 1: Interpretation improvement Butyrate metabolism is down and H 2 S production + mucus degradation is up vs. long lists of genes, species and orthologous groups Advantage 2: Sensitivity & Specificity increase Less multiple testing issues Pathways as they occur in gut, not as they are in KEGG You see what you need to see

18 Extending cellular level systems biology to whole ecosystems ( eco systems biology ) metagenomics, metatranscriptomics, meta metabolomics Computational integration will be main challenge Raes and Bork, Nat Rev Microbiol 2008

19 Metagenomics and transcriptomics indicate that small intestine microbiota is tuned for fast carbohydrate uptake Zoetendal*, Raes* et al., ISME 2012

20 Eco systems biology of the human intestinal microbiota in Crohn s disease NIH HMP concordant/discordant twin study Janet Jansson (Berkeley), Claire Fraser (U.Maryland), Robert Hettich (Oak Ridge National Lab) Metagenomics Metaproteomics Ecosystem network reconstruction and its variation in disease 454 tag phylotyping Meta metabolomics

21 Wrap up: Gut microbiota for personalized medicine Microbiota is characterizable using meta omics combined with dedicated computational tools Microbiota is linked to disease, interpretation through specific metabolic models Specific diagnostic & prognostic markers for disease are possible Enterotype based diagnosis ( bad enterotypes?) Enterotype specific drug treatment (different metabolism of chemical compounds) Your genome matters your microbiome even more!

22 Functional diversity of the human gut microbiome Plateau is not reached yet new cohorts add more (unknown) gene families +unknown genes +known genes with unknown functions known functions Spanish + Danish cohort, 124 individuals Data from Qin, Li, Raes et al Nature 2010 Same, + 73 individuals from Chinese (diabetes) cohort (collab w. Junjie Qin, Wang Jun, BGI)

23 Acknowledgments Raes VIB, Brussels Falk Hildebrand Youssef Darzi Gwen Falony Gipsi Lima Mendez Karoline Faust Shujiro Okuda Anh Nguyen Roberto Garcia Sara Vieira Silva Samuel Chaffron Marie Joossens Ugent Peter Vandenabeele Wim Declerq EMBL Peer Bork Mani Arumugam and many others Universiteit Wageningen Erwin Zoetendal Michiel Kleerebezem Willem De Vos The MetaHIT consortium Dusko Ehrlich Wang Jun/Junjie Qin (BGI) Joel Dore (INRA) and many others HMP Curtis Huttenhower (Harvard) Dirk Gevers (Broad) Jacques Izard (Forsyth) Berkeley/U. Maryland/Oak Ridge Janet Jansson Claire Fraser Ligget Robert Hettich

24 Thanks for your attention Positions available: