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The Human Microbiome in Health and Disease

The Human Microbiome in Health and Disease. Curtis Huttenhower 10- 21- 11. Harvard School of Public Health Department of Biostatistics. What’s metagenomics ?. Total collection of microorganisms within a community. Also microbial community or microbiota.

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The Human Microbiome in Health and Disease

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  1. The Human Microbiome inHealth and Disease Curtis Huttenhower 10-21-11 Harvard School of Public Health Department of Biostatistics

  2. What’s metagenomics? Total collection of microorganisms within a community Also microbial communityormicrobiota Total genomic potential of a microbial community Study of uncultured microorganisms from the environment, which can include humans or other living hosts Total biomolecular repertoire of a microbial community

  3. Valm et al, PNAS 2011

  4. What to do with your metagenome? Reservoir of gene and protein functional information Comprehensive snapshot of microbial ecology and evolution Who’s there? What are they doing? Who’s there varies: your microbiota is plastic and personalized. What they’re doing is adapting totheir environment:you, your body, and your environment. Who’s there and what they dodiffer during disease and treatment. Public health tool monitoring population health and interactions Diagnostic or prognostic biomarker for host disease

  5. Slides by Dirk Gevers The NIH Human Microbiome Project (HMP): A comprehensive microbial survey • What is a “normal” human microbiome? • 300 healthy human subjects • Multiple body sites • 15 male, 18 female • Multiple visits • Clinical metadata www.hmpdacc.org

  6. A functional perspective on thehuman microbiome 100 subjects 1-3 visits/subject ~7 body sites/visit 10-200M reads/sample 100bp reads Healthy/IBD BMI Diet Metagenomic reads BLAST Functional seq. KEGG + MetaCYC CAZy, TCDB,VFDB, MEROPS… ? Geneexpression SNPgenotypes Taxon abundances Enzyme family abundances Pathway abundances Enzymes and pathways HUMAnN HMP Unified MetabolicAnalysis Network http://huttenhower.sph.harvard.edu/humann

  7. HUMAnN: Metabolic reconstruction Vaginal Oral (BM) Gut Oral (SupP) Oral (TD) Skin Nares ← Pathways→ ← Samples → Vaginal Skin Nares Oral (SupP) Oral (BM) Oral (TD) Gut ← Pathways→ ← Samples → Pathway coverage Pathway abundance

  8. A portrait of the healthy human microbiome:Who’s there vs. what they’re doing ← Subjects → ← Phylotype abundance → ← Phylotype abundance → Oral (BM) Oral (SupP) Oral (TD) Nares Vaginal Skin Gut ← Pathway abundance → ← Pathway abundance → ← Subjects →

  9. Linking function to community composition Plus ubiquitous pathways: transcription, translation, cell wall, portions of central carbon metabolism… ← 52 posterior fornix microbiomes → Phosphate and peptide transport Lactobacillus crispatus Lactobacillus jensenii Sugar transport Embden-Meyerhof glycolysis, phosphotransferases Lactobacillus gasseri Lactobacillus iners F-type ATPase, THF ← Taxa and correlated metabolic pathways → AA and small molecule biosynthesis Gardnerella/Atopobium Candida/Bifidobacterium Eukaryotic pathways

  10. Linking communities to host phenotype Top correlates with BMI in stool Body Mass Index Normalized relative abundance Vaginal pH (posterior fornix) Vaginal pH, community metabolism, and community composition represent a strong, direct link between phenotype and function in these data. Vaginal pH (posterior fornix)

  11. So that’s normal – what about disease? With Matthew Meyerson, Alex Kostic LEfSe:LDA Effect Size http://huttenhower.sph.harvard.edu/lefse Nicola Segata

  12. So that’s normal – what about disease? • Treatments: • Antibiotics • Immunosup. • Mesalamine • Steroids • Location: • Mucosal (biopsy) • Luminal (stool) • Genetics: • ~200 loci, IBD-targeted ~1-4K 16S reads/sample Qin 2010 ~1-2Gbp 75bp shotgun reads/sample

  13. Microbes and their environment:What’s disease, what’s treatment, and what’s unrelated? ~200 OSCCAR+PRISM individuals • Multiple Factor Analysis: • Form of Principal Components Analysis • Separates individuals by similar patterns of variation in thegut microbiota

  14. Microbes and their environment:What’s disease, what’s treatment, and what’s unrelated? ~200 OSCCAR+PRISM individuals ?

  15. Microbes and their environment:What’s disease, what’s treatment, and what’s unrelated? ~200 OSCCAR+PRISM individuals Firmicutes (Clostridia) Bifidobacteria Proteobacteria (Enterobacteriaceae)

  16. Environment and disease:You are your microbes’ environment: age, sampling, and treatment ~200 OSCCAR+PRISM individuals Firmicutes Escherichia Stool vs. biopsy Immunosuppresion Bifidobacterium Dorea Age Antibiotics

  17. But what about IBD? Ruminococcus Roseburia Faecalibacterium • In this cohort, main effects are asuperset of previous findings • Eggerthella in UC, weaker eff. than CD • Willing 2010 • Roseburia (Lachnospiraceae) down • Frank 2007, Willing 2010 • Ruminococcus down • Willing 2010, Joossens 2011 • Also correctly classify environment • Proteobacteria up (immunosup.) • Frank 2007, Willing 2010 • Faecalibacterium down (ileal) Willing 2010, Frank 2011, Joossens 2011 • And hey, what about… • Diet? Sample handling? Assay? Ileal involvement Eggerthella

  18. But what about functional detail?IBD in the MetaHIT cohort Up in CD Down in CD MetaHITseqs. → HUMAnN → pathway abundances DNA maintenance CC + growth Sugar utilization Signaling + secretion Iron + drug transport UC

  19. What about the host?A preview of host genetics With GwangPyoKo All linked to the same family of Clostridiales Genotyped microbiomes: 98 women(twin pairs + mothers)vaginal microbiomes + HPV phenotypes Host genetics matter when not trumped by additional environment innate immune sensor glycoprotein glycoprotein extracellular signal transduction glycoprotein glycoprotein unch. TF glycoprotein glycoprotein

  20. A model forhost genetics and the microbiome Many genes exert indirect control over many bugs due to polygenic immunity and disease phenotypes. A few genes exert strong control over a few bugs. A few bugs and many functions are strong proximal indicators or controllers of disease. Many genes exert strong distal control over many bugs due to founder effects. Environment exerts strong proximal control over many bugs.

  21. Ask both what you can do for your microbiomeand what your microbiome can do for you

  22. Thanks! Human Microbiome Project George Weinstock Karen Nelson Joe Petrosino Owen White MihaiPop Pat Schloss MakedonkaMitreva Erica Sodergren VivienBonazzi Jane Peterson Lita Proctor SaharAbubucker Yuzhen Ye Beltran Rodriguez-Mueller Jeremy Zucker QiandongZeng MathangiThiagarajan Brandi Cantarel Maria Rivera Barbara Methe Bill Klimke Daniel Haft Dirk Gevers Nicola Segata Xochi Morgan Levi Waldron HMP Metabolic Reconstruction Bruce Birren Mark Daly Doyle Ward Eric Alm Ashlee Earl Lisa Cosimi Ramnik Xavier Harry Sokol Joseph Moon FahSathira Tim Tickle Jacques Izard JeroenRaes Karoline Faust Wendy Garrett Michelle Rooks Interested? We’re recruiting graduate and rotation students! VagheeshNarasimhan Josh Reyes Matthew Meyerson Alex Kostic ShujiOgino Charlie Fuchs http://huttenhower.sph.harvard.edu

  23. Proteoglycan degradationby the gut microbiota Glycosaminoglycans(Polysaccharide chains) AA core

  24. Proteoglycan degradation:From pathways to enzymes Enzyme relative abundance 10-8 10-3 • Heparan sulfate degradation missing due to the absence ofheparanase, a eukaryotic enzyme • Other pathways not bottlenecked by individual genes • HUMAnN links microbiome-wide pathway reconstructions → site-specific pathways → individual gene families

  25. Niche specialization in human microbiome function Metabolic modules in theKEGG functional catalogenriched at one or morebody habitats ← Pathway abundance→ ← ~700 HMP communities→ • 16 (of 251) modules strongly “core” at 90%+ coverage in 90%+ individuals at 7 body sites • 24 modules at 33%+ coverage • 71 modules (28%) weakly “core” at 33%+ coverage in 66%+ individuals at 6+ body sites • Contrast zerophylotypes or OTUs meeting this threshold! • Only 24 modules (<10%) differentially covered by body site • Compare with 168 modules (>66%) differentially abundant by body site

  26. Patterns of variation in human microbiome function by niche

  27. Patterns of variation in human microbiome function by niche • Three main axes of variation • Eukaryotic exterior • Low-diversity vaginal • Gut metabolism • Oral vs. tooth hard surface • Only broad patterns: every human-associated habitat is functionally distinct!

  28. LEfSe: the TRUC murine colitis microbiota With Wendy Garrett

  29. But what about functional detail?IBD in the MetaHIT cohort Up in CD Down in CD Bifidobacterium UC Age

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