Human gut bacterial cell surface polysaccharides as a microbial nutrient source and target of immunoregulatory proteins shape gut microbiota structure and function

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PROJECT SUMMARY The gut microbiota has been linked to many aspects of human health and disease. These finding have ignited efforts to precisely modulate gut microbiota composition and function to promote health-associated features. The nutrient landscape within the gut shapes, and is influenced by, the gut microbiota. Bacteria respond to available nutrients and utilize them to support their own metabolism, sharing the metabolic by-products with other bacteria and the host. Carbohydrates within the gut, both consumed in the diet and produced by the host, impact gut bacteria composition and function via their utilization as a carbon source. The biological function of the polysaccharides that cover gut bacteria however, remains unclear. Bacterial cell surface polysaccharides act as a barrier between the microbe and its environment, enhancing bacterial growth and survival through mechanisms that include resistance to toxic small molecules, nutrient adaptation, and immune evasion. The central hypothesis I will test in this proposal is that microbiota bacterial polysaccharides modulate gut community structure and function via utilization as a nutrient by other community members, and through interaction with soluble immunoregulatory proteins. AIM 1 will employ isolated bacterial polysaccharides and in vitro growth assays to identify genetic features that enable utilization of bacterial polysaccharides. AIM 2 will define whether bacterial polysaccharides are consumed in vivo by cultured, genome sequenced microbial communities installed in gnotobiotic mice using microscopic recoverable paramagnetic beads coated in polysaccharides. AIM3 will test whether cell surface polysaccharides from probiotic dietary supplements alter gut microbiota polysaccharide utilization and recognition of community members by immunoregulatory proteins in the gut lumen of gnotobiotic mice. This series of experiments that blends chemistry, glycobiology, genomics, and gnotobiotic mouse models will define mechanisms of bacterial polysaccharide utilization, increase understanding of how nutrients in the gut shape the microbiota, and suggest a bioactive component of bacterial dietary supplements. These combined finding should improve development of microbiota-derived and -directed therapeutics for targeted microbiota manipulation. This award will also support by career development. During completion of the supervised portion of this grant I will gain critical computational research skills that includes bacterial genome sequencing and annotation, bacterial RNA-sequencing to characterize function, and metagenomic analysis. Ultimately, this award will facilitate my successful transition into an independent academic position at a research-intensive university where I will lead, teach, and mentor an interdisciplinary group of students, postdocs, and clinicians defining mechanisms of microbiota assembly, function, and regulation with a goal to translate my findings into methods for targeted microbiota manipulation to improve human health.