The Role of Short-Chain Fatty Acid Sensing in Regulating Hepatic Glucose Production

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The prevalence of diabetes continues to rise unabated in the United States, creating a grave social and economic burden. Current pharmacological treatments are only moderately effective at lowering glycemia, while metabolic surgery is effective, yet highly invasive. Interestingly, both therapeutic options alter the gut microbiota, the collection of all the microbes residing in the gastrointestinal tract, highlighting the role of gut microbes in the development and amelioration of diabetes. The long-term goal of this project is to better understand the mechanisms of the gut microbiota impacting glucose homeostasis. Prebiotics represent one of the more promising dietary strategies to alter the gut microbiota composition and improve metabolic dysregulation. Treatment with oligofructose (OFS), a non-digestible fiber, lowers blood glucose levels, improves glucose tolerance, and increases production of short-chain fatty acids (SCFAs) in the distal intestine. As such, SCFA treatment also results in metabolic benefits, including weight loss and improved glucose tolerance. Despite this, how SCFAs improves glucose homeostasis, and whether these mechanisms are required for the beneficial effects of prebiotics, remains unknown. For example, small intestinal propionate infusion activates a gut-brain-liver axis to lower hepatic glucose production, but whether this pathway exists in the colon, where the majority of SCFAs are produced, is unknown. Furthermore, SCFAs can enter the portal vein and act on the liver, but their role in hepatic glucose regulation is not clear. Interestingly, butyrate and propionate can act as epigenetic regulators, inhibiting histone deacetylases (HDACs), but it is unknown whether SCFAs affect downstream hepatic transcription factors that directly regulate hepatic gluconeogenesis. This, with our preliminary data, led to the hypothesis that SCFAs improve glucose tolerance by directly and indirectly targeting hepatic glucose production (HGP), both pathways of which are responsible for mediating the beneficial effects of OFS treatment. By utilizing sophisticated in-vivo surgical and viral manipulations during glucose tolerance tests or pancreatic clamps, this hypothesis will be tested in 3 aims: 1) determine if preabsorptive SCFAs activates a colonic-brain-liver axis to lower HGP, 2) examine the ability of portal SCFAs to inhibit HDAC activity to lower HGP, and 3) determine if gut-brain-liver axis signaling or hepatic HDAC inhibition are responsible for the glucoregulatory benefits of prebiotics due to increased SCFAs. A better understanding of how prebiotics and SCFAs improve glucose homeostasis could lead to targeted therapies that reduce chronically elevated HGP during diabetes.