Speaker Affiliation:
Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School

Hosted By:
Matthew Ostrowski, PhD
Thomas Schmidt, PhD
Michigan Microbiome Project

Abstract: Bariatric surgery is the most effective treatment for obesity and obesity-related type 2 diabetes. As a result of its minimal side-effect profile, sleeve gastrectomy (SG) is currently the safest and most commonly performed bariatric surgery in the United States. Moreover, this procedure is associated with changes in gut metabolites. In previous work, we discovered that the host-produced compound cholic acid-7-sulfate (CA7S) is a gut-restricted TGR5 agonist with anti-diabetic properties and that this metabolite is elevated following SG. In new studies, we have elucidated a microbiome-dependent pathway by which SG increases CA7S production. We found that a microbial metabolite, lithocholic acid (LCA), is increased in murine portal veins post-SG and by activating the vitamin D receptor, induces hepatic sulfotransferase expression to drive CA7S production. An SG-induced shift in the microbiome increases expression of the bile acid transporters Asbt and Ostα in the distal ileum, a change that in turn facilitates selective transport of LCA across the gut epithelium. Cecal microbiota transplant from SG animals is sufficient to recreate the pathway in germ-free (GF) animals. Activation of this gut-liver pathway leads to CA7S synthesis and GLP-1 secretion, for the first time causally connecting a microbial metabolite with the improvement of diabetic phenotypes following bariatric surgery. This study provides evidence that the microbiome, and specifically, the microbial metabolite LCA, affects host metabolism, illustrating the importance of studying metabolite transport and signaling in the enterohepatic axis.

Zoom Meeting: https://umich.zoom.us/j/99830183560