A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.

BACKGROUND & AIMS: Tropifexor (TXR) is a novel nonbile acid that acts as an agonist of farnesoid X receptor (FXR). TXR is currently in Phase 2 trials for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we report the impact of TXR on in a piglet model in which cholestatic liver damage and fibrosis where induced by bile duct ligation (BDL).

METHODS

The piglets received BDL and TXR for 2 wk. Hepatic, portal and colonic bile acid and amino acid profiles and gut microbiome were analysed. Portal fibroblast growth factor (FGF) 19 levels were measured using an enzyme-linked immunosorbent assay (ELISA).

RESULTS

We first showed that bile acid metabolism and signalling are dysfunctional in patients with biliary atresia. Next, we observed that TXR potently suppresses BDL-induced liver injury, fibrosis and ductular reaction in piglets. Within the ileum, TXR enhances FGF19 expression and subsequently increases portal FGF19 levels. In the liver, TXR promotes the expression of small heterodimer partner (SHP) and inhibits cholesterol 7α-hydroxylase (CYP7A1). Additionally, TXR increases the abundance of bile acid-biotransforming bacteria in the distal ileum and alters the composition of amino acids in the colon. Lastly, TXR ameliorates intestinal barrier injury in piglets subjected to BDL.

CONCLUSION

TXR potently ameliorated cholestatic liver injury and fibrosis by modulating the gut-liver axis in piglets. It supports the clinical evaluation of TXR as a therapeutic strategy for cholestatic liver diseases, such as biliary atresia.