Metabolites Produced or Altered by the Gut Microbiota Impact Metabolic Homeostasis

Abstract

Obesity and type 2 diabetes (T2D) are rising, impacting the health and economic burden of millions of individuals. Both the large and small intestine harbors a distinct microbiome, and microbes impact host health at least in part via production of metabolites that act as signaling molecules at the intestine and other metabolic tissues. As diet is a critical modulator of the gut microbiome and metabolome, the experiments outlined in this dissertation aimed to characterize the interaction of the diet with regional specific microbiomes and subsequent effect on metabolic homeostasis via bacterially-derived metabolites. Specifically, we analyzed the cecal microbiome and small intestinal metabolome in rats fed a chow, high fat diet (HFD), or a HFD supplemented with oligofructose, a prebiotic known to decrease body weight and adiposity in rodents. We further characterized short chain fatty acid production and absorption following meal consumption and identified butyrate as a potential regulator of host metabolic health. We therefore also aimed to determine how butyrate impacts glucose metabolism, in 1) HFD-fed mice given butyrate directly into the portal vein, to mimic absorbed butyrate, 2) primary murine hepatocytes, and 3) rats given portal vein butyrate during a basal-insulinemic clamp. We show that butyrate acts at the hepatocyte to decrease glucose production and FOXO1 nuclear translocation and acts as an HDAC inhibitor in the liver. We also characterized the small intestinal metabolome in rats fed chow, HFD, or HFD supplemented with oligofructose. We found that bile acids are robustly regulated by diet, with several bile acids altered in HFD, and those effects reversed with prebiotic supplementation. We therefore chose two bile acids, taurocholic acid (TCA) and glycodeoxycholic acid (GDCA) to investigate for their impact on body weight and glucose metabolism. GDCA attenuated the development of obesity via increased energy expenditure, whereas TCA worsened glucose tolerance during high fat-feeding. The data outlined in this dissertation provide a foundation for future studies to determine the exact mechanism by which butyrate and specific bile acids impact host metabolic health to identify novel targets for the prevention or treatment of obesity and T2D.