A dense community of microbes lives within the gastrointestinal (GI) tract of each human. This intestinal microbiota is composed of 10-100 trillion microbial cells and it impacts numerous aspects of human biology including immune status and metabolism. Aberrant intestinal microbiota composition has been linked to inflammatory bowel diseases and to obesity, yet the factors contributing to microbiota alterations are currently ill defined. The goal of this proposal is to gain insight into how the intestinal microbiota is impacted by specified changes in host diet. Our long-term goal is to integrate the microbiota into the emerging paradigm of personalized medicine, with a focus on microbiota-targeted diagnostics and therapeutics to treat or prevent obesity, inflammatory bowel diseases, and other microbiota-relevant diseases. Species of abundant gut-dwelling bacteria, such as Bacteroides thetaiotaomicron (B. theta), devote vast portions of their genomes to the utilization of undigested dietary plant polysaccharides (i.e., dietary fiber). Mechanisms that link dietary polysaccharide intake to alterations in microbiota composition and function are integral to human biology.
The aims of this proposal are to (i) gain mechanistic insight into the function of an operon conserved in Bacteroides required for use of abundant dietary plant polysaccharides called fructans;(ii) determine how model microbiotas composed of bacterial species with differing relative abilities to utilize the dietary fructan, inulin, adapt within the gnotobiotic mouse gut to dietary inulin supplementation;(iii) determine if host epithelial gene expression and systemic or mucosal cytokine levels can be differentially modulated by diet-induced alterations in model microbiotas composed of B. theta and Bifidobacterium species. To pursue (i) above, we will use genetic tools and biochemical assays to investigate the function of genes within B. theta's fructan utilization operon. Comparative genomics and fructan-growth assays will elucidate the genomic basis for the spectrum of fructan utilization capability that exists in the Bacteroides.
In aim (ii), germ-free mice, which lack a gut microbiota, will be colonized with simplified model microbiotas composed of B. theta strains, Bacteroides species, and/or Eubacterium rectale, a member of the gut-dominant Firmicutes division. Surveys of bacterial gene expression, species density, and gut fructan content will illuminate how model communities composed of dominant members of the microbiota disparate for fructan use, adapt in composition and function to elevated dietary inulin.
In aim (iii), germ-free mice are co-colonized with B. theta and one of two Bifidobacterium species discordant for inulin use. Functional and compositional adaptation of bacteria in vivo to dietary inulin will be characterized, as in aim (ii). These results will determine whether we can predict, based on genomic and functional data, how a change in diet (inulin-enrichment) will impact a model microbiota. Host responses will be monitored to determine if epithelial gene expression and systemic and/or mucosal cytokine responses may be modulated via diet-induced changes in the microbiota.

Public Health Relevance

A dense and complex community of microbes resides within each person's gastrointestinal tract that plays many important roles in our health, including aiding in our absorption of energy and nutrients from the foods we eat. Alterations in composition of the gut-resident microbial community are associated with certain disease states, such as obesity and inflammatory bowel disease. The goal of this research project is to understand the impact of dietary fiber on the intestinal microbial community and the host to determine how we may avoid or reverse deleterious changes within our intestinal microbiota to improve human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085025-04
Application #
8460013
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Karp, Robert W
Project Start
2010-06-07
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$317,176
Indirect Cost
$118,941
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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