Project 1 will use a translational research pipeline for human gut microbiota-directed diagnostics and therapeutics we developed based on gnotobiotic mice harboring microbiota transplanted from three types of adult twin pairs discordant for obesity and/or its associated metabolic abnormalities [LeanMetabolicallyHealthy-Obese Metabolically Unhealthy (LnMH/ObMUN), LnMH/ObMH, ObMH/ObMUN]. Its goal is to (i) establish a causal role of the gut microbiota in obesity and associated metabolic phenotypes, (ii) obtain mechanistic insights about the interactions between diet and members of the gut microbiota that produce these phenotypes, (iii) conduct tests of the effects of manipulating diet and bacterial taxa on phenotypes transmitted by ObMUN microbiota. Project 1 has 4 aims. (1) Determine the effects of microbiota, collected from twin pairs at the end of the each of their two in-home diet periods, on body composition/metabolic phenotypes of recipient adult gnotobiotic mice given a diet homologous to that consumed at the time the donor's microbiota was collected or the other diet that twins will have consumed (cross-over diet group). Within-pair, between-twin pair comparisons and across discordant pair type comparisons will be performed. (2) Co-house gnotobiotic mice harboring intact uncultured microbiota from discordant pairs to determine if (i) microbiota from the LnMH donor prevents or ameliorates development of obesity- and obesity-associated metabolic dysfunction in mice colonized with the ObMH or ObMUN co-twin's microbiota, and how prevention/amelioration correlates with invasion of bacterial taxa from the microbiota of one cagemate to the other, and later comparable co-housing experiments involving ObMH and ObMUN mice. (3) Determine if bacterial culture collections prepared from microbiota samples characterized in Aim 2 also transfer discordant donor phenotypes to gnotobiotic mice;perform co-housing experiments to identify invasive cultured taxa associated with phenotypic rescue in different diet contexts. (4) Execute a testing matrix in which a culture collection from a representative ObMUN or ObMH co-twin are introduced to separate groups of gnotobiotic mice fed a representative USA diet high in saturated fats and low in fruits and vegetables, alone or with a lead probiotic consortium (invasive taxa identified from aims 2, 3), or a lead prebiotic (identified from in vitro screen), or a combination of the two (synbiotic lead). The therapeutic lead will be administered at the time of colonization with the culture collection (prevention arm) or 2 weeks after initial colonization (treatment arm). Metabolic profiling will be performed with Core A. Multi-omics datasets will be analyzed with existing tools and used to generate new analysis strategies with Project 3 and Core B.

Public Health Relevance

Efforts to characterize the human gut community in health and disease are producing vast amounts of data about its organismal and gene content and variations. A great challenge is to complement these efforts with a preclinical research pipeline that directly tests whether observed differences in microbiota configurations are a cause rather than effect of host physiology/disease. We will use such a pipeline to gain insights about the pathogenesis of obesity and associated metabolic abnormalities, and conduct preclinical tests for microbiota- directed therapeutics.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
2P01DK078669-06A1
Application #
8742500
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Seedorf, Henning; Griffin, Nicholas W; Ridaura, Vanessa K et al. (2014) Bacteria from diverse habitats colonize and compete in the mouse gut. Cell 159:253-66
Faith, Jeremiah J; Ahern, Philip P; Ridaura, Vanessa K et al. (2014) Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med 6:220ra11
Langille, Morgan G I; Zaneveld, Jesse; Caporaso, J Gregory et al. (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31:814-21
Ridaura, Vanessa K; Faith, Jeremiah J; Rey, Federico E et al. (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341:1241214
Smith, Michelle I; Yatsunenko, Tanya; Manary, Mark J et al. (2013) Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339:548-54
Bokulich, Nicholas A; Subramanian, Sathish; Faith, Jeremiah J et al. (2013) Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing. Nat Methods 10:57-9
Faith, Jeremiah J; Guruge, Janaki L; Charbonneau, Mark et al. (2013) The long-term stability of the human gut microbiota. Science 341:1237439
Rey, Federico E; Gonzalez, Mark D; Cheng, Jiye et al. (2013) Metabolic niche of a prominent sulfate-reducing human gut bacterium. Proc Natl Acad Sci U S A 110:13582-7
Ravussin, Yann; Koren, Omry; Spor, Ayme et al. (2012) Responses of gut microbiota to diet composition and weight loss in lean and obese mice. Obesity (Silver Spring) 20:738-47
Kau, Andrew L; Ahern, Philip P; Griffin, Nicholas W et al. (2011) Human nutrition, the gut microbiome and the immune system. Nature 474:327-36

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