The long-term goal of this project is to understand how cooperation and competition between microbes shapes the composition of human gut microbial communities (microbiota). These dynamics produce interpersonal differences in microbial community composition that far exceed the interpersonal differences in our genomes. This microbial variation is linked to disease predisposition inside and outside of the gut and also to individual response to therapeutics. Although significant progress has been made documenting the diversity of the human gut microbiota, much less is known about the underlying principles that explain how these communities form and change. This lack of knowledge means that we cannot identify which microbial pathways represent appropriate targets for therapeutic intervention, how to shift the balance of species in the gut, or how to successfully introduce new species into these communities. Thus, understanding how metabolites are exchanged between human gut microbes and which of these networks represent the fundamental mechanisms that determine community structure is an important goal. To address this challenge, this grant application describes experiments to dissect the discovery that largely unappreciated small molecules related to vitamin B12 (corrinoids) determine human gut microbial community composition.
Aim 1 will examine how the unique features of corrinoid transporters in the human gut microbiome impact the assembly and function of these systems.
Aim 2 will test the hypothesis that the greater than 30 different types of corrinoid utilization systems in the human gut microbiome are specialized for acquisition of distinct corrinoids.
Aim 3 examines whether different corrinoids (and by extension, the microbes that produce these molecules) induce shared or distinct responses in prominent human symbionts. Completion of these studies will produce a mechanistic understanding of how corrinoids from diet and microbial sources determine community composition in the human gut. Understanding these mechanisms of community interaction provides a basis for therapeutic applications to alter the composition of gut microbial communities.
Interpersonal variation in gut microbial community composition is largely unexplained but is important to understand because these communities are implicated in numerous diseases. This proposal describes experiments to define why vitamin B12 and related compounds shape the composition of these microbial communities. These studies will also determine how intentional manipulation of this process could be used to shift the balance of species in the human gut.
|Wexler, Aaron G; Schofield, Whitman B; Degnan, Patrick H et al. (2018) Human gut Bacteroides capture vitamin B12 via cell surface-exposed lipoproteins. Elife 7:|
|Schofield, Whitman B; Zimmermann-Kogadeeva, Maria; Zimmermann, Michael et al. (2018) The Stringent Response Determines the Ability of a Commensal Bacterium to Survive Starvation and to Persist in the Gut. Cell Host Microbe 24:120-132.e6|
|Lim, Bentley; Zimmermann, Michael; Barry, Natasha A et al. (2017) Engineered Regulatory Systems Modulate Gene Expression of Human Commensals in the Gut. Cell 169:547-558.e15|
|Perry, Rachel J; Peng, Liang; Barry, Natasha A et al. (2016) Acetate mediates a microbiome-brain-?-cell axis to promote metabolic syndrome. Nature 534:213-7|
|Wexler, Aaron G; Bao, Yiqiao; Whitney, John C et al. (2016) Human symbionts inject and neutralize antibacterial toxins to persist in the gut. Proc Natl Acad Sci U S A 113:3639-44|
|Cullen, T W; Schofield, W B; Barry, N A et al. (2015) Gut microbiota. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 347:170-5|
|Tan, Yunhao; Zanoni, Ivan; Cullen, Thomas W et al. (2015) Mechanisms of Toll-like Receptor 4 Endocytosis Reveal a Common Immune-Evasion Strategy Used by Pathogenic and Commensal Bacteria. Immunity 43:909-22|
|Degnan, Patrick H; Barry, Natasha A; Mok, Kenny C et al. (2014) Human gut microbes use multiple transporters to distinguish vitamin B?? analogs and compete in the gut. Cell Host Microbe 15:47-57|
|Degnan, Patrick H; Taga, Michiko E; Goodman, Andrew L (2014) Vitamin B12 as a modulator of gut microbial ecology. Cell Metab 20:769-778|
|Palm, Noah W; de Zoete, Marcel R; Cullen, Thomas W et al. (2014) Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158:1000-1010|
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