Colonic butyrate lowers hepatic glucose production via FFAR2-dependant GLP-1 receptor neuronal signaling

Hyperglycemia is a hallmark characteristic of type II diabetes, due in part to increased hepatic glucose production (HGP). The gut microbiota is now recognized as an important contributor to host energy and glucose homeostasis, and our lab has demonstrated that the gut microbiota can impact HGP. One mechanism that the gut microbiome may be impact HGP is through alterations in gut-derived metabolites from breakdown of ingested foodstuff. Specifically, short chain fatty acids (SCFAs) are bacterial metabolites produced primarily in the distal intestine from dietary fibers, and when administered exogenously, SCFAs improve glucose tolerance. However, the mechanisms underlying the effects of SCFAs on glucose tolerance are not fully understood. Given that SCFAs bind to free fatty acid receptors (FFARs) 2 and 3 localized on enteroendocrine cells to induce gut peptide release, and gut peptides regulate HGP via a gut-brain-liver neuronal axis, we propose colonic SCFAs activate a neuronal signaling mechanism to lower HGP mediated via gut peptide signaling. We infused SCFAs into the colon (50min at 0.01mL/min) during a basal insulin euglycemic clamp in rats. Compared with saline infusion, colonic administration of 10mM butyrate increased the glucose infusion rate needed to maintain glycemia due to a reduction in HGP. This was associated with increased portal concentrations of GLP-1 following butyrate infusion compared to saline. We investigated the role of colonic FFAR2 signaling, which is known to induce release of GLP-1, through either co-administration of a FFAR2 antagonist with butyrate or by colon-specific FFAR2 lentiviral knockdown; both abolished the HGP-lowering effect. Next, co-administering a GLP-1 receptor antagonist with 10mM butyrate during a clamp abolished the butyrate-induced reduction of HGP. Additionally, hepatic or celiac branch vagotomy abolished the HGP-lowering effect of colonic butyrate, suggesting a celiac afferent and hepatic efferent neuronal signaling pathway. Together, these studies uncover a FFAR2, GLP-1 receptor, vagal-dependent signaling mechanism by which colonic butyrate lowers HGP. Research presented was supported under NIH award R01DK121804. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.