Regulation of host energy metabolism by gut-derived microbial metabolites

About This Grant

PROJECT SUMMARY/ABSTRACT The intestinal microbiome produces a vast and diverse chemical repertoire of microbe-derived metabolites which influence many aspects of host energy metabolism. Despite great potential implications for obesity, type-2 diabetes, and other metabolic diseases, the mechanistic basis for these cross-kingdom metabolic interactions remains largely uncharacterized. My preliminary data demonstrates that lactic acid produced by the gut commensal Lactiplantibacillus plantarum (Lp) more than doubles Drosophila starvation survival by priming oxidative phosphorylation via a non-nutritive, GPCR-mediated signaling mechanism. Building on this discovery, this project will integrate high-throughput survival assays, untargeted metabolomics, mathematical modeling, and in silico screening of ligand-receptor interactions to systematically uncover how microbe- derived metabolites act as endocrine effectors of host energy metabolism. During the K99 phase of this project, I will utilize computational ligand-receptor screening to identify candidate GPCRs predicted to bind Lp–derived lactic acid and perform loss-of-function genetic tests to validate their necessity for enhanced oxidative phosphorylation and starvation survival. Next, I will profile the microbe-derived metabolite profile of an array of human-derived and environmental commensals using untargeted metabolomics and correlate metabolite abundance with host survival phenotypes to pinpoint novel metabolic effectors. During the R00 phase of this project, I will expand the in silico prediction of ligand–receptor interactions to candidate metabolic effectors identified during the K99 phase. I will determine their mechanisms of action by using targeted genetic knockouts, phosphoproteomic mapping, and transcriptomic analyses to delineate the downstream signaling cascades through which these metabolites rewire host energy metabolic pathways. Finally, candidate metabolites will be evaluated for their capacity to prevent or reverse obesity- and diabetes-like phenotypes in Drosophila. By elucidating the molecular mechanisms and signaling networks that underlie microbiome-host metabolic crosstalk, this work will establish fundamental knowledge and mechanistic insight for harnessing the vast potential of microbial metabolites to deliver new therapies for metabolic disease. Executing this project will provide the necessary technical and scientific training to facilitate a successful career as an independent researcher at the intersection of energy metabolism and microbiology. The thriving intellectual community at Stanford, combined with ample opportunities for networking, training, and collaboration in the Bay Area through the Chan-Zuckerberg Biohub ensures I am primed for success. This comprehensive training and research plan establishes a framework that will position me at the forefront of uncovering host-microbe metabolic interactions and create a unique research niche for success as an independent researcher.