Targeting bile salt homeostasis in biliary diseases.

Abstract

Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed. Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na + -taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes. Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.