Human Microbiome Research at NIH: Past, Present & Future
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1 Human Microbiome Research at NIH: Past, Present & Future Cindy D. Davis OFFICE OF DIETARY SUPPLEMENTS 1
2 None Disclosure Slide
3 The Human Microbiome Ø We are a composite of species: eukaryocc, bacterial, archeal- 10x more microbial cells than human Ø Gut Microbiota= microbes in our GI tract, ~100 trillion organisms Ø Microbiome= their colleccve genome, >100 Cmes as many genes as human genome
4 What Do Microbes Do For Us? Ø Provide ability to harvest nutrients Ø Produce addiconal energy otherwise inaccessible to the host Ø Produce vitamins Ø Metabolize xenobioccs Ø Prevent colonizacon by pathogens Ø Assist in the development of a mature immune system
5 KosCc et al. Genes and Development 27: , 2013 Human IntesCnal Microbiota over the Lifespan Dominguez- Bello M.G. et al. Gastronenterology 14): , 2011
6 Diet Shifts Microbial Community and Affects Exposure to Dietary Metabolites Ø Shift in gut microbial community and metabolites with diet Ø High-protein/Low-carbohydrate diet also: 1. Decreased proportion of butyrate in fecal SCFAs 2. Reduced Roseburia/ Eubacterium rectale group of bacteria 3. Reduced concentrations of fiber-derived phenolic acids Russell et al., Am. J. Clin. Nutr. 93: , 2011
7 David, L.A. et al., Nature, 505: , 2014 Diet Alters Microbial Activity and Gene Expression Short- term consumpcon of diets composed encrely of animal or plant products: Ø Alters microbial community structure Ø Overwhelms inter- individual differences in gene expression Ø Modifies metabolic pathways
8 Bacteria Can Generate New Metabolites from Dietary Components Food Component Bacterial Metabolite Soy Fiber Plant Lignans Equol Butyrate Enterodiol, Enterolactone Ellagic Acid Urolithins A and B Hops Linoleic Acid 8- Prenylnaringenin Conjugated Linoleic Acid
9 Ley et al. PNAS 444: , 2006 Human Gut Microbes and Obesity Ø 12 Unrelated obese subjects on fat or carbohydrate restricted diet Ø Monitored for one year Ø Increase in Bacteroidetes correlates with change in weight
10 Diet, Microbial Metabolism and Cardiovascular Disease Hazen, S.L. Curr. Opin. Lipidol. 25: 48-53, 2014
11 Microbes (Numbers and Types) Food Components and Energy Microbial Metabolite(s) Disease Risk
12 Human Microbiome Project ( ): a community resource (hdp://commonfund.nih.gov/hmp) Phase 1: Survey of the microbiome in humans Who s there? $175 million: Common Fund & cofunding from NHGRI + NIAID + NIDDK + NIDCR + NIAMS + ORWH + NCCAM + ODS Healthy cohort study Is there a core microbiome? Clinically healthy 300 male/female y.o. 5 major body regions (18 body sites) Up to 3 visits in 2 yrs No ancbioccs, probioccs, immunomodulators Microbiome- associated condicons Skin: eczema, psoriasis, acne GI/oral: esophageal adenocarcinoma, necroczing enterocolics, pediatric IBS, ulceracve colics, Crohn s Disease Urogenital: bacterial vaginosis, circumcision, sexual histories DemonstraCon Projects
13 In healthy American adults, the microbial community composicon in each part of the body is unique. PCoA2 (4.4%) PCoA1 (13%) Ø For each person, est. 1,000 bacterial species and 2,000,000 bacterial genes. Ø Total pool, est. 10,000 species and 8,000,000 genes. Human Microbiome Project ConsorCum, Nature 486: , 2012
14 Microbial composicon of healthy adult microbiomes is highly variable Microbial composi2on of each body site community Airway Skin Oral (1) Oral (2) Oral (3) GI Tract Urogenital Phylum level GeneCc potencal of each microbiome is less variable Microbial metabolic pathways of each body site community Ø A core microbial composicon may not occur with host phenotype. Ø However, a core metagenomic and/or funcconal profile may occur with host phenotype OFFICE OF DIETARY SUPPLEMENTS 14
15 Analysis of both the metatranscriptome and metagenome in epidemiological studies Franzosa et al., PNAS E2329- E2338, 2014 OFFICE OF DIETARY SUPPLEMENTS 15
16 Microbial composicon may not be the most useful property Microbiome Property 10 most abundant microbial taxa in metagenomes of subjects in cohort 10 most abundant microbial metabolic genes in metagenomes of subjects in cohort 10 most abundant expressed microbial metabolic genes in metatranscriptomes of subjects in cohort Variability between subjects Highly variable Not variable Somewhat variable OFFICE OF DIETARY SUPPLEMENTS 16 Franzosa et al., PNAS 2014
17 Recall: the metagenome is the genecc blueprint of the microbiome. metabolism What func2onal proper2es do we need, to understand the role of the microbiome in the human: transcripts? proteins? metabolites? OFFICE OF DIETARY SUPPLEMENTS 17
18 Human Microbiome Project ( ) Phase 2: IntegraCve HMP ihmp what are they doing? Ø $25M, Common Fund & NIDDK + ORWH + NCCAM + ODS Biological properces of both the microbiome and the host Ø microbial composicon & mulc omics (i.e., transcripts, proteins & metabolites) from microbiome and host Ø longitudinal cohort studies Ø integrated datasets as a community resource Exemplar microbiome- associated human condicons: Dynamics of Pregnancy and Preterm Birth: Vaginal & gut microbiomes and host (mother, infant) properces Dynamics of Inflammatory Bowel Disease Onset: GI microbiome and host properces Dynamics of Type 2 Diabetes Onset: GI & nasal microbiomes and host properces OFFICE OF DIETARY SUPPLEMENTS 18
19 Dynamics of Pregnancy and Preterm Birth Study
20 Dynamics of Onset of Inflammatory Bowel Diseases
21 Dynamics of Type 2 Diabetes Onset
22 IntegraCve HMP website (hdp: hmp2.org) OFFICE OF DIETARY SUPPLEMENTS 22
23 Trans- NIH Microbiome Working Group (TMWG) established 2012 Ø Extramural program staff only, membership from 16 ICOs Ø Mission: Forum for microbiome- related investments at NIH IdenCfy, gaps, needs, challenges and opportunices Share upcoming funding opportunity annoucements (FOAs) Coordinate joint funding of applicacons Discuss development of joint FOAs Discuss development of microbiome review panel at CSR Serve as central source for external community TMWG: Ø Key points of contact at each IC Ø Current microbiome- related FOAs OFFICE OF DIETARY SUPPLEMENTS 23
24 Other NIH Microbiome Working Groups Ø PrebioCc/ProbioCc Working Group (PPWG) Promotes trans- agency collaboracons in advancing evidence base of probioccs and prebioccs Advance probiocc and prebiocc research and a deeper understanding of the role of gut microbes in human health Development of funding opportunity announcements Ø Microbiome Obesity Working Group (MOWG) Subset of the obesity research taskforce IniCates and facilitates various accvices for advancing our knowledge on the contribucon of the human gut microbiome to obesity Ø Microbiome Quality Control Project (MBQC) Composed of NIH intramural and HMP invescgators CollaboraCve effort to comprehensively evaluate methods for measuring the human microbiome (sample colleccon, techniques and protocols for analysis, and computaconal OFFICE OF DIETARY SUPPLEMENTS 24
25 OFFICE OF DIETARY SUPPLEMENTS 25
26 A Metagenomic View of our Dinner Plate Dutton and Turnbaugh, Curr. Opinions Clin. Nutr. and Metabolic Care 15: , 2012
27 Need to understand both the microbial community and what the microbes are doing Zoetendal et al. Gut 57: , 2008
28 1. Can experiments detect differences that mader? 2. Does the study show causacon or just correlacon? 3. What is the mechanism? 4. How much do experiments reflect reality? 5. Could anything else explain the results? Hange, Nature 2014
29 Cindy D. Davis hdp://ods.od.nih.gov
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