Decoding the polymicrobial interactions in bile acid metabolism by the gut microbiome. - Abstract The complex interplay between the gut microbiome and the host is mediated by the constant exchange of macromolecules of both host and microbial origin, among which bile acids (BAs) hold profound importance. Microbes convert host-derived primary bile acids into secondary bile acids, such as 7α-dehydroxylated deoxycholic acid (DCA) and lithocholic acid (LCA), which constitute a significant part of the gut metabolome and influence the chemical environment of the gastrointestinal lumen. In this proposed project, I will test the hypothesis that cross-species metabolism is necessary to shape the bile acid pool that modulates the structure and function of microbial communities in the gut. To test this hypothesis, I will focus on pathways of 7α-dehydroxylation of bile acids, which create the most abundant secondary bile acids in humans and mice: DCA and LCA. While the 7α-dehydroxylation of bile acids is attributed to bacteria encoding the bile acid-inducible (bai) operon, our preliminary findings suggest an alternative mechanism in a microbial community devoid of the bai. I hypothesize that a subset of this community orchestrates the 7α-dehydroxylation reaction through an uncharacterized pathway involving polymicrobial cross-feeding of intermediates. Through combinatorial testing, quantitative LC/MS methods, and comparative genomics approaches, we aim to elucidate the chemical substrates and the microbial and genetic determinants necessary to complete this alternative polymicrobial pathway. Furthermore, bacterial cross-feeding facilitates the chemical modifications of BAs that shift the overall chemical property of the luminal space, which impacts the diversity and the ecology of the microbial community in the gut. I will investigate this reciprocal relationship between bile acids and the microbiome by focusing on a model opportunistic pathogen, Clostridiodes difficile. The effects of BA on C. difficile are multifaceted and complex, and the role of the microbiome in modulating the chemical environment to inhibit C. difficile proliferation is not fully understood. I will determine how shifts in the microbial composition in the gut and the subsequent alteration in the bile acid metabolism impacts the growth of a single organism, C. difficile. Ultimately, a deeper mechanistic understanding of microbial bile acid will significantly contribute to our knowledge of the origin of the abundant bioactive and physiologically relevant metabolites in the gut. Moreover, it contributes to unraveling the complex interplay between the chemical landscape and bacterial ecology in the gut to harness the microbiome to combat pathogens and improve gut health.
