Dissecting the chemical signals that determine dietary xenobiotic metabolism in the gut microbiome

About This Grant

Project Summary/Abstract The gut microbiome encodes an immense repertoire of metabolic enzymes that shape the diet-microbiome- host interface by performing diverse chemical transformations on dietary small molecules. The gut microbiome can only metabolize a specific dietary compound if it both encodes and expresses the necessary metabolic enzymes. Typically, bacterial cells upregulate metabolic enzyme expression in response to the target substrate or its breakdown products. However, we have discovered that human gut Bacteroidetes integrate orthologous environmental signals into their metabolic gene regulation. Gut microbial metabolism of the widely-used artificial sweetener stevia follows this pattern: specific gut bacterial species and human microbiome communities metabolize the main compound in stevia, rebaudioside A (RebA), but this metabolism is regulated by orthogonal signals and not RebA itself. This microbial metabolism and its novel regulation strategy may impact why humans exhibit interpersonal variability in their stevia response: stevia is linked to contradictory outcomes in host glucose sensitivity and hyperglycemia, and bacterial RebA metabolites circulate in humans following stevia consumption. This proposal presents a plan to define the substrate-independent signaling pathways that activate RebA metabolism in gut microbes and determine how these pathways modulate host response to these compounds. I have identified a small molecule that activates RebA metabolism by the common gut commensal Bacteroides xylanisolvens, determined a gene locus necessary for RebA metabolism in this bacterium, discovered this substrate-independent metabolism applies to other dietary compounds beyond RebA, shown that human microbiomes exhibit extensive interpersonal variation in RebA metabolism, and demonstrated that circulating metabolite profiles in the host differ based on the RebA metabolic capacity of their microbiome. In Aim 1, I will characterize the substrate-independent mechanism that activates metabolism of diverse dietary glycosides, including RebA, by B. xylanisolvens and assess whether the abundance of these metabolic genes can explain metabolic variability across human microbiomes. In Aim 2, I will investigate RebA metabolism and its consequences for host physiology and hyperglycemia in vivo. If successful, my research will uncover a unique regulatory paradigm for bacterial dietary compound metabolism and whether gut microbial catabolism of a widely-consumed artificial sweetener can modulate host metabolic health. This project will provide learning opportunities scientifically to execute cutting-edge microbiology, biochemistry, pharmacology, analytical chemistry, endocrinology, and genetics research and professionally to improve teaching, mentorship, and scientific writing and presentation skills. I am confident this project, these training plans at Yale University, and support from my thesis advisor Dr. Andrew Goodman will advance my development as an independent scientist in preparation for a research career.