42-OR: A Small Intestinal Bile Acid Modulates the Gut Microbiome to Improve Glucose Regulation following Bariatric Surgery

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide the most effective and durable therapy for type 2 diabetes (T2D). This work is aimed at identifying molecule mediators of bariatric surgery’s metabolic effects, in order to develop non-invasive interventions for T2D. Our previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we investigate the metabolic effects of LCA and the mechanisms of its downregulation post-SG. We find that LCA feeding to chow-fed mice worsens glucose tolerance, decreases respiratory exchange ratio, and increases adiposity. We also show that taurodeoxycholic acid (TDCA) is the only bile acid whose concentration is increased in the murine small intestine post-SG. Moreover, TDCA abundance is decreased in small intestinal tissue from patients with T2D. Treatment of cecal cultures with SG small intestinal contents or TDCA in vitro reduces the expression of bacterial bile acid-inducible (bai) operon and production of LCA. In vivo treatment of diet-induced obese mice with TDCA also suppresses the bai operon, reduces LCA levels and leads to improvements in host glucose handling. Abolishing gut microbiota or co-feeding LCA to TDCA-treated mice substantially diminishes the beneficial effects of TDCA on glucose regulation, demonstrating that TDCA’s glucoregulatory effects require the microbiota. This work has revealed that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.