Neuronal Signaling of Gut Microbiota-Derived Metabolites in the Regulation of Host Energy and Glucose Homeostasis

Abstract

Currently, over 40% of American adults have obesity and over 50% have impairments in glucose homeostasis. The gut microbiota plays a salient role in host metabolic health, partially through the generation of metabolites which can act as signaling molecules at the intestine and peripheral tissues. Diet is the primary regulator of gut microbiota composition, and many metabolites are derived from bacterial alteration of dietary components, highlighting that diet is critical for both the composition of the microbes and their functional output. As such, the studies in this dissertation investigated how diet impacts metabolic homeostasis via the gut microbiota and its metabolites. In the first study, we investigated the efficacy of plant-based flour supplementation to improve WD-induced metabolic perturbations and found large intestinal butyrate production was positively associated with improvements in glucose homeostasis. Therefore, we next investigated the acute effects of large intestinal butyrate signaling on glucose homeostasis in WD-fed rodents, infusing butyrate into the proximal colon during glucose tolerance tests and euglycemic clamps. We found that colonic butyrate infusion improved glucose tolerance partly through reductions in hepatic glucose production, identifying a novel colonic nutrient sensing pathway dependent on colonic FFAR2 and GLP-1 action on vagal afferent neurons. Additionally, a previous study examined the small intestinal metabolome of lean, chow-fed and obese, WD-fed rats and found WD-fed rats had drastically reduced gut indole levels. Indole metabolites reduce inflammation in various tissues, including the brain, via the aryl hydrocarbon receptor (AhR). Therefore, in our final study, we investigated how AhR signaling in the mediobasal hypothalamus regulates metabolic homeostasis, finding that AhR is required for energy and glucose homeostasis in mice. Further, chronic central AhR agonism reverses impairments in energy balance in diet-induced obese mice. Overall, the studies included in this dissertation elucidate endogenous signaling mechanisms of specific gut microbiota-derived metabolites, identifying novel targetable pathways in the treatment of T2D and obesity.