Leveraging the Gut Microbiome to Regulate Hepatic Gluconeogenesis

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Project Summary/Abstract: The objective of this Mentored Clinical Scientist Career Development Award is to elucidate the underlying mechanisms by which gut microbes regulate hepatic gluconeogenesis and thereby coordinate host nutrient homeostasis in health and disease. Non-alcoholic fatty liver disease (NAFLD) is the most-prevalent chronic liver disease worldwide and can progress to cirrhosis and liver cancer. The absence of approved pharmaceutical treatments for NALFD identifies a significant unmet need. Whereas the gut microbiome contributes to NAFLD, the underlying mechanisms are incompletely defined. Our published and preliminary data demonstrate that gut microbes play a key role in regulating hepatic gluconeogenesis through portal vein metabolites, providing a clear rationale for this research. We propose the central hypothesis that specific biologically-active microbial metabolites are transported by the portal circulation to the liver, where they downregulate hepatic gluconeogenesis in health, and that ultra-processed western diets disrupt this pathway to contribute to the excess glucose production observed in NAFLD. Specific Aim 1 will identify the specific microbes and downstream metabolites that regulate hepatic gluconeogenesis. Mice will be colonized with defined microbial consortia and in vivo glucose production assays and in vitro primary mouse hepatocyte cultures will determine the specific microbial metabolic components that control hepatic glucose production. Mice with diet-induced hyperglycemia and NAFLD will be colonized with specific microbes or administered metabolites to restore normal hepatic gluconeogenesis. Specific Aim 2 will define the maladaptive changes in gut microbiome function that contribute to excess hepatic gluconeogenesis in human NAFLD. Donor stool from patients with NAFLD and controls will be used to create mice with humanized gut microbiomes. Portal vein serum metabolomics and microbial whole genome sequencing will be used to identify microbes and microbial-metabolites that contribute to excess hepatic gluconeogenesis in human NAFLD. This research is significant because it will identify novel mechanisms by which the microbial component of the gut-liver axis regulates hepatic gluconeogenesis in health and disease. This research project will be performed in the context of a comprehensive career development plan that will permit the investigator to acquire expertise in metabolomics, microbiome engineering, and bioinformatics analysis. The work will be conducted at Weill Cornell Medical College, which together with The Rockefeller University and Memorial Sloan Kettering Cancer Center constitutes the highly stimulating Tri-Institutional research network. Seminars and specialized coursework will augment tailored guidance from the candidate’s co-mentors, as well as from a distinguished advisory committee with complementary expertise. The candidate’s ultimate goal is to become an independent investigator whose research program integrates expertise in the gut microbiome with hepatic metabolism in order to advance the management of chronic metabolic diseases, including NAFLD.