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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM099513-01A1
Application #
8411477
Study Section
Special Emphasis Panel (ZGM1-GDB-2 (MC))
Program Officer
Sledjeski, Darren D
Project Start
2013-03-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$302,709
Indirect Cost
$102,709
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Porter, Nathan T; Canales, Pablo; Peterson, Daniel A et al. (2017) A Subset of Polysaccharide Capsules in the Human Symbiont Bacteroides thetaiotaomicron Promote Increased Competitive Fitness in the Mouse Gut. Cell Host Microbe 22:494-506.e8
Tamura, Kazune; Hemsworth, Glyn R; Déjean, Guillaume et al. (2017) Molecular Mechanism by which Prominent Human Gut Bacteroidetes Utilize Mixed-Linkage Beta-Glucans, Major Health-Promoting Cereal Polysaccharides. Cell Rep 21:2030
Tamura, Kazune; Hemsworth, Glyn R; Déjean, Guillaume et al. (2017) Molecular Mechanism by which Prominent Human Gut Bacteroidetes Utilize Mixed-Linkage Beta-Glucans, Major Health-Promoting Cereal Polysaccharides. Cell Rep 21:417-430
Desai, Mahesh S; Seekatz, Anna M; Koropatkin, Nicole M et al. (2016) A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell 167:1339-1353.e21
Pudlo, Nicholas A; Urs, Karthik; Kumar, Supriya Suresh et al. (2015) Symbiotic Human Gut Bacteria with Variable Metabolic Priorities for Host Mucosal Glycans. MBio 6:e01282-15
Hickey, Christina A; Kuhn, Kristine A; Donermeyer, David L et al. (2015) Colitogenic Bacteroides thetaiotaomicron Antigens Access Host Immune Cells in a Sulfatase-Dependent Manner via Outer Membrane Vesicles. Cell Host Microbe 17:672-80
Abbott, D Wade; Martens, Eric C; Gilbert, Harry J et al. (2015) Coevolution of yeast mannan digestion: Convergence of the civilized human diet, distal gut microbiome, and host immunity. Gut Microbes 6:334-9
Lammerts van Bueren, Alicia; Saraf, Aakanksha; Martens, Eric C et al. (2015) Differential Metabolism of Exopolysaccharides from Probiotic Lactobacilli by the Human Gut Symbiont Bacteroides thetaiotaomicron. Appl Environ Microbiol 81:3973-83
Cuskin, Fiona; Lowe, Elisabeth C; Temple, Max J et al. (2015) Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism. Nature 517:165-169
Martens, Eric C; Kelly, Amelia G; Tauzin, Alexandra S et al. (2014) The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes. J Mol Biol 426:3851-65

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