Succinate communicates pro-inflammatory signals to host and regulates bile acid enterohepatic metabolism via the activation of SUCNR1 in a pig model

Succinate is produced by both host and microbiota as a signaling metabolite sensed extracellularly by succinate receptor 1 (SUCNR1). Despite the mounting evidence that have emphasized the importance of succinate-SUCNR1 axis in the modulation of intestinal inflammation and metabolism homeostasis, the underlying mechanisms for these effects have not been clarified. In the present study, we aimed to determine whether dietary succinate supplementation influences intestinal inflammatory response and to analyze the possible mechanisms by which the succinate-SUCNR1 axis regulates enterohepatic metabolism. Sixteen growing barrows were randomly assigned to two groups, fed a basal diet that consisted of a typical commercial diet or fed the basal diet supplemented with sodium succinate. Our data showed that dietary succinate supplementation increased the concentrations of pro-inflammatory cytokines via the activation of SUCNR1 in the intestine. And dietary succinate supplementation inhibited the expression levels of ileal Farnesol X receptor (FXR) and its target genes, blocked intestinal bile acid reabsorption, promoted hepatic bile acid secretion, finally caused bile acid enterohepatic circulation disturbance. Then, we demonstrated that the FXR transcriptional activity was inhibited by succinate-triggered pro-inflammatory signaling in vitro. Furthermore, dietary succinate supplementation impacted ileal microbiota composition and reduced the abundances of bile-salt hydrolase (BSH) enriched bacteria. Our observations suggest that succinate not only is a pro-inflammatory effector but also is a mediator for bile acid enterohepatic metabolism. We also identify a new role of succinate-SUCNR1 axis in the modulation of bile acid enterohepatic homeostasis.