A microbial metabolite remodels the gut-liver axis following bariatric surgery

Bariatric surgery is the most effective treatment for type 2 diabetes and is associated with changes in gut metabolites. In previous work, bile acid analysis following sleeve gastrectomy revealed a gut-restricted TGR5 agonist, cholic acid-7-sulfate, with anti-diabetic properties. However, the mechanism by which SG results in increased CA7S levels has not been elucidated. Here, we report that CA7S production is driven by a sulfotransferase enzyme, Sult2A1, in the liver post-SG and requires a microbiome. We found that a microbial metabolite, lithocholic acid, is increased in murine portal veins post-SG and induces hepatic Sult2A1 expression by activating the vitamin D receptor. SG leads to increased expression of the bile acid transporters Asbt and OSTa, which in turn facilitate selective transport of lithocholic acid across the gut epithelium. Activation of this gut-liver pathway leads to CA7S synthesis and GLP-1 secretion, thus causally connecting a microbial metabolite with the improvement of diabetic phenotypes.