Bile acids altered by high fat feeding and oligofructose supplementation impact metabolic homeostasis

Abstract

The gut microbiota is recognized as a contributor to host metabolic homeostasis, as obesity and diabetes are associated with unique gut microbiome signatures. Further, strategies aimed at beneficially shifting the gut microbiome, such as prebiotic treatment, show promise in ameliorating metabolic disease; however, the mechanisms are not yet understood. A potential contribution of the gut microbiota to host metabolism is via modification of host and diet-derived metabolites. For example, bile acids, crucial to lipid digestion and absorption, are modified by gut microbes in the small intestine. Bile acids have also been identified as signaling molecules in the intestine, liver, adipose, and nervous system, playing a role in metabolic homeostasis. Despite their importance, few studies have examined the impact of bile acid signaling on mediating the metabolic benefits of prebiotics. We hypothesized that bile acid homeostasis is altered with dietary factors that shift the gut microbiome, including high fat diet (HFD) feeding and supplementation with the prebiotic fiber oligofructose (OFS), and that taurocholic acid (TCA) and glycodeoxycholic acid (GDCA) that are increased with HFD feeding and OFS supplementation, respectively, would recapitulate the metabolic effects of these diets. Therefore, we conducted an untargeted metabolomics analysis on small intestinal contents of rats fed chow, HFD, or HFD supplemented with OFS, identifying bile acid metabolism as a primary contributor to the observed between-group differences. We then quantified bile acid levels in the small intestine, portal vein, and liver of rats fed chow, HFD, or HFD supplemented with OFS, and identified several bile acids of interest that are altered with HFD or OFS supplementation, including TCA and GDCA. Because these bile acids activate the bile acid receptors, FXR and TGR5, that known to impact metabolic homeostasis, we treated HFD-fed mice with 50 mg/kg GDCA or TCA daily for 12 weeks and measured body weight, adiposity, glucose tolerance, food intake, and indirect calorimetry. We found that GDCA treatment improved glucose tolerance, decreased body weight and adiposity, and increased energy expenditure compared to controls. Further, TCA worsened glucose tolerance independent of body weight. The results of this study implicate GDCA and TCA in the beneficial and detrimental effects of OFS and HFD-feeding, respectively; however, more research is necessary to determine the mechanism underpinning the metabolic effects of GDCA and TCA treatment. This work was supported by the NIH R01DK1804. 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.