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

Abstract

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.

Cholestasis alters brain lipid and bile acid composition and compromises motor function in neonatal piglets

“…One explanation for this may be related to the reported antagonistic effects of HCA species on FXR activation (Zheng et al, 2021) which could account for reduced secretion of FGF-19 from hepatocytes and low levels of circulating FGF-19 in BDL piglets (Johansson et al, 2020;Song et al, 2009). Targeting this pathway has recently shown promising results for prevention of liver pathology in cholestatic piglets, although the translatability to humans and implications for brain function have yet to be determined (Xiao et al, 2021).…”

Review article: therapeutic aspects of bile acid signalling in the gut‐liver axis

“… 141 A recent study in piglets subjected to BDL confirmed the beneficial effects of the FXR agonist tropifexor on intestinal inflammation and the gut barrier and indicated significant changes of the microbiome. 142 …”

Lactobacillus plantarum supplementation alleviates liver and intestinal injury in parenteral nutrition‐fed piglets

“…Immunofluorescence was performed using the chromogen diaminobenzidine as described previously. 18 Briefly, the slides were hydrated and blocked with 5% bovine serum albumin in PBS. The antibodies of cholesterol 7α-hydroxylase (CYP7A1) (Millipore, dilution, 1:100) were applied in a wet chamber overnight at 4°C.…”

“…The composition of bile acids (BAs) in the livers, serum, and colonic contents was measured according to the previously described method. [18][19][20] The BA quantification was performed using the Waters Xevo TQ-S mass spectrometer coupled to the Waters ACQUITY ultraperformance liquid chromatography system.…”

“…The gut microbial communities were amplified and sequenced using the 16S rRNA gene amplicon sequencing as described previously. 13,14,18 Briefly, total microbial genomic DNA samples from the samples of luminal contents were extracted using the DNeasy Power Soil Kit (QIAGEN, Inc) following the manufacturer's instructions. The bacterial 16S rRNA gene V4-V5 region was amplified using the forward primer 515F (5′-GTGCCAGCMGCCGCGGTAA-3′) and the reverse primer 907R (5′-CCGTCAATTCMTTTRAGTTT-3′).…”