Role of bile acids in inflammatory liver diseases

Abstract

Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

Keywords: Bile acid signaling; Bile acids; Immune cells; Immunity; Inflammation; Liver; Liver disease; Microbiome; Non-alcoholic fatty liver disease; Primary biliary cholangitis; Primary sclerosing cholangitis.

Fig. 1

Generation of primary and secondary bile acids. Cholesterol is converted by a series of oxidative reactions to the primary bile acids, cholic acid (CA), and chenodeoxycholic acid (CDCA). In response to a meal, the conjugated forms of primary bile acids are released into the small intestine where they play an important role in digestion of dietary lipids. In the ileum of the intestine, approximately 95% of bile acids are reabsorbed and return to the liver via the enterohepatic circulation. In the colon, primary bile acids are deconjungated and converted by a number of bacterial enzymes to secondary bile acids such as deoxycholic acid (DCA) or lithocholic acid (LCA), which can be excreted or follow the enterohepatic circulation. As indicated in red, in mice bile acids are primarily conjugated to taurine (T), while human bile acids are conjugated to glycine (G). Notably, murine bile acids known as muricholic acids (MCA) are generated by CYP2C70, an enzyme expressed in murine but not in human liver explaining the difference in the composition of human and murine bile acid species