Fig. 2

Bile acid (BA) biosynthesis and circulation along the gut-liver axis. (1) Hepatocellular BA homeostasis. The primary BAs such as cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized from cholesterol via BA synthesis enzymes such as CYP7A1. The hepatic uptake of BAs is mediated via sodium/taurocholate cotransporting polypeptide (NTCP). BAs, either taken up from portal blood or newly synthesized, are excreted into bile canaliculi via the bile salt export pump (BSEP). BAs inhibit CYP7A1 and induce BSEP via activation of FXR and NTCP transcription. Thus, the load of BA is maintained. BA synthesis is also inhibited by the FXR agonist and fibroblast growth factor receptor 4 (FGFR4), which is bound to intestinal FGF19. FGFR4 also inhibits lipogenesis and gluconeogenesis while promoting regeneration. (2) Intestinal BA transport in the ileal epithelial cells. In the terminal ileum, 95% of BAs are reabsorbed into ileal epithelial cells via the apical sodium-dependent bile acid transporter (ASBT). A basolateral organic solute transporter alpha and beta (OSTα/β) heterodimer mediates the efflux of BA from ileal epithelial cells into the portal blood for circulation back to the liver. In the ileum, BAs and FXR agonist activate FXR and induce FGF19, which circulates to the liver and binds to FGFR4. Thus, the enterohepatic circulation associated with BAs is formed. (3) Microbial BA metabolism in the gut. In the lumen of the distal ileum and colon, gut microbial bile salt hydrolase (BSH) deconjugates glycine and taurine conjugated BAs, and microbial 7α-dehydroxylase removes the 7α-hydroxyl group to covert the primary BAs, CA and CDCA, to the secondary bile acids, DCA and LCA. (4) Role of BAs in gut integrity. BAs affect intestinal microbiota and effect epithelial barrier integrity via FXR stimulation. The activated FXR regulates the tight junction (TJ), mucin production, and gut-vascular barrier. BAs also have anti-inflammatory and immunomodulatory effects on both innate and adaptive immune cells, preventing inflammatory reactions that would damage intestinal integrity. ASBT, apical sodium-dependent bile acid transporter; BA, bile acid; BSEP, bile salt export pump; BSH, bile salt hydrolase; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol-7α-hydroxylase; DCA, deoxycholic acid; FGF19, fibroblast growth factor 19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; LCA, lithocholic acid; NTCP, sodium/taurocholate cotransporting polypeptide; OSTα/β, organic solute transporter alpha and beta; TJ, tight junction