The microbial community (microbiota) that inhabits the human distal gut provides physiologic attributes that humans have not evolved, including the ability to process otherwise indigestible dietary glycans. Species in this community have evolved strategies to compete for the dozens of different glycans that inundate their environment. These complex carbohydrates vary immensely in chemical structure and digestibility, a feature that likely dictates the particular region of the gut (ileum, proximal or distal colon) in which each glycan is metabolized. The relationship between glycan availability and microbiota physiology in different gut regions has not been explored. However, this knowledge will be essential to understand the forces that shape the microbiota as well as to design strategies to manipulate its function using approaches like prebiotics (functional foods, most often glycans, designed to enrich the abundance and/or physiology of beneficial microbes). We will establish a tripartite colonization model using 1) germfree mice, 2) synthetic communities of fully sequenced human gut bacteria, and 3) a defined diet that contains variable amounts of all major dietary glycans that are typically consumed by humans. Using this model, we will test our central hypothesis that glycans in the intestine are present in a series of gradients (determined by their diet or hos origin and biochemical properties) and that individual bacterial species will be enriched in regions where their preferred glycans are abundant. Preliminary data suggest that the protective epithelial mucus layer is a major glycan niche that selects for a sub-community of gut bacteria based on the ability of only some species to metabolize the host-derived glycans present in mucus. Bacterial populations from the lumen and the mucus layer will be directly harvested along the length of the intestine or captured microscopically using laser-capture microdissection (LCM).
In Aim 1, transcription of bacterial genes that are known to respond to specific glycans will be used as biosensors to measure variation in bacterial glycan metabolism between separate gut regions. The abundance of individual dietary glycans will be subsequently varied to observe the corresponding changes in microbiota metabolism.
In Aim 2, the abundance of 44 different human gut Bacteroidetes species, for which we have empirically measured several dozen glycan-degrading phenotypes, will be measured in the mucosa and lumen along the length and width of the gut. Assembly of this community will be observed in both the absence and presence of 43 additional sequenced bacterial species representing the other dominant phyla in the human gut. Although the human gut microbiota plays many beneficial roles, abnormalities in this community (dysbiosis) have been postulated to underlie pathological conditions such as inflammatory bowel disease and obesity. The proposed experiments will provide data regarding where and why different species assemble in response to one important and externally manipulable parameter (dietary glycans). Our results will facilitate approaches to intentionally manipulate the human microbiota to influence intestinal health.

Public Health Relevance

The hundreds of bacterial species that colonize the human gut are essential for the digestion of dietary carbohydrates and some have also evolved to degrade glycans found in host tissue. This project will measure the impact of variation in glycan-degrading traits in determining which regions of the gut different bacterial species colonize. Since some normal human gut bacteria are associated with diseases like inflammatory bowel disease, deciphering the forces that govern gut colonization may lead to strategies to manipulate these symbiotic microbes to restore health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-GDB-2 (MC))
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Sledjeski, Darren D
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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