The human gut harbors a dense and complex community of microbes known as the intestinal microbiota. This microbial ecosystem is connected to many facets of human biology in health, but can also contribute to several diseases including inflammatory bowel diseases, obesity, and colon cancer. Diet is a major determinant of both the microbial species, or phylotypes, that inhabit one's microbiota, as well as the functions carried out by these species. Specifically, dietary microbiota-accessible carbohydrates (MACs), the main component of dietary fiber, serve as the primary metabolic input for the gut microbiota. Modern diets have significantly less dietary fiber relative to those from traditional societies, an observation that has been linked to the decrease in microbiota diversity (e.g., less microbial species) in individuals from industrialized countries. Low diversit microbiotas, in turn, have been correlated with markers of metabolic syndrome and inflammation, and increased dietary fiber appears to improve microbiota diversity and health. Yet large gaps still exist in understanding how dietary MACs influence microbiota diversity and whether dietary MAC depletion can result in irreversible loss of phylotypes within the microbiota. This proposal aims to define the influence of dietary MACs on microbiota diversity and microbial metabolism and to determine how extinct microbial phylotypes can be successfully reintroduced into low diversity communities.
In Aim 1, mice harboring a human microbiota (`humanized') eating defined diets will be used to determine the major consequences that restricting dietary MACs has on metabolites, genes, and species within the gut. To determine whether a diet- induced reduction in microbiota diversity can be reversed upon re-introduction of MACs, mice will be deprived of MACs, followed by reintroduction of MACs, and their microbiota composition and function will be defined. The effect of MAC depletion over multiple generations on diversity loss will also be determined. Microbiota functionality will be assessed by metagenomic, short-chain fatty acid, and metabolomic analyses.
In Aim 2, the microbiota of humans undergoing a dietary intervention with fiber supplements will be assessed. Alterations in microbiota composition and functionality will be compared using fiber supplements that vary in structural complexity. Gene content and small molecule metabolites will be similarly defined using metagenomic, short-chain fatty acid, and metabolomic analyses. The goal of Aim 3 is to identify the best method to introduce bacterial phylotypes to restore diversity into humanized mice that harbor a low diversity microbiota. Microbiota reprogramming strategies include transplanting (i) an intact microbiota from a high- diversity donor, (ii) a complex culturable microbiota from high-diversity stool, or (iii) defined communities composed of culturable type strains. Successful strategies, defined as those that significantly increase microbiota diversity, will be tracked over time to determine the kinetics of new strain establishment.

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Karp, Robert W
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Stanford University
Schools of Medicine
United States
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