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. Previous work uncovered a gut-restricted TGR5 agonist with anti-diabetic properties-cholic acid-7-sulfate (CA7S)-that is elevated following sleeve gastrectomy (SG). Here, we elucidate a micro-biome-dependent pathway by which SG increases CA7S production. We show that a microbial metabolite, lithocholic acid (LCA), is increased in murine portal veins post-SG and by activating the vitamin D receptor, induces hepatic mSult2A1/hSULT2A expression to drive CA7S production. An SG-induced shift in the microbiome increases gut expression of the bile acid transporters Asbt and Osta, which in turn facilitate selective transport of LCA across the gut epithelium. Cecal micro-biota 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, causally connecting a microbial metabolite with the improvement of diabetic phenotypes.

Automated summary

Bariatric surgery is the most effective treatment for type 2 diabetes, associated with changes in gut metabolites. Activation of the vitamin D receptor post-surgery leads to increased production of cholic acid-7-sulfate (CA7S), facilitating selective transport across the gut epithelium. Additionally, the microbiome-dependent pathway plays a crucial role in connecting a microbial metabolite with the improvement of diabetic phenotypes through CA7S synthesis and GLP-1 secretion.