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