A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis
A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis
复制标题
非胆汁酸法尼醇 X 受体激动剂 tropifexor 通过调节肠肝轴有效抑制胆汁淤积性肝损伤和纤维化
DOI：
10.1111/liv.14906
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发表时间：
2021
影响因子：
6.7
通讯作者：
Cai Wei
中科院分区：
文献类型：
--
作者：
Xiao Yongtao;Wang Ying;Liu Yang;Wang Weipeng;Tian Xinbei;Chen Shanshan;Lu Ying;Du Jun;Cai Wei
背景& AimsTropifexor （TXR）是一种新型的非胆汁酸，可作为farnesoid X受体（FXR）的激动剂。TXR目前正处于治疗非酒精性脂肪性肝炎（NASH）的2期临床试验中。在此，我们报告了TXR对由胆管结扎（BDL）引起的胆汁淤积性肝损伤和纤维化的仔猪模型的影响。方法连续2周给予BDL和TXR治疗。分析肝脏、门静脉和结肠胆汁酸和氨基酸分布及肠道微生物组。采用酶联免疫吸附试验（ELISA）测定门脉成纤维细胞生长因子（FGF） 19的水平。结果我们首次发现胆道闭锁患者胆汁酸代谢和信号传导功能紊乱。接下来，我们观察到TXR能有效抑制BDL诱导的仔猪肝损伤、纤维化和小管反应。在回肠内，TXR可增强FGF19的表达，进而提高门脉FGF19的水平。在肝脏中，TXR促进小异源二聚体伴侣（SHP）的表达，抑制胆固醇7α‐羟化酶（CYP7A1）。此外，TXR增加了回肠远端胆汁酸生物转化细菌的丰度，并改变了结肠中氨基酸的组成。最后，TXR可改善BDL仔猪肠道屏障损伤。结论txr通过调节肠-肝轴对仔猪胆汁淤积性肝损伤及纤维化有明显改善作用。它支持TXR作为胆汁淤积性肝病（如胆道闭锁）治疗策略的临床评价。
Background & AimsTropifexor (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).MethodsThe 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).ResultsWe 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.ConclusionTXR 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.