中国科学院上海药物研究所谢岑和何世君研究组合作发现，肝细胞色素P450 8B1和胆酸通过抑制肠干细胞更新增强结肠炎肠上皮损伤。该项研究成果发表在2022年9月1日出版的《细胞—干细胞》上。

他们发现患者和小鼠的胆酸(CA)水平升高。在结肠炎小鼠的肝脏中诱导了合成CA的细胞色素P450 8B1 (CYP8B1)。CA 治疗或肝脏Cyp8b1过表达小鼠发展为更严重的结肠炎，粘膜屏障修复受损，而Cyp8b1敲除小鼠对结肠炎有抵抗力。从机制上讲CA抑制过氧化物酶体增殖物激活受体α (PPARα)，导致脂肪酸氧化(FAO)受阻和Lgr5+肠道干细胞(ISC)更新受损。 PPARα激动剂恢复FA并改善Lgr5+ IS功能。

法尼醇X受体(FXR)的激活抑制了小鼠肝脏 CYP8B1的表达并改善了结肠炎。该研究通过调节肠上皮再生揭示了肝脏CYP8B1-CA轴与结肠炎之间的联系，表明基于胆汁酸(BA)的策略可能对炎症性肠病 (IBD)治疗有益。

研究人员表示，尽管破坏的BA稳态与IBD相关，但肝脏BA代谢在结肠炎发病机制中的作用却知之甚少。

附：英文原文

Title: Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal

Author: Li Chen, Tingying Jiao, Weiwei Liu, Yuhong Luo, Jue Wang, Xiaozhen Guo, Xiao Tong, Zemin Lin, Chuying Sun, Kanglong Wang, Yifan He, Yuwei Zhang, Hualing Xu, Jiawen Wang, Jianping Zuo, Qiurong Ding, Shijun He, Frank J. Gonzalez, Cen Xie

Issue&Volume: 2022/09/01

Abstract: Although disrupted bile acid (BA) homeostasis is implicated in inflammatory boweldisease (IBD), the role of hepatic BA metabolism in the pathogenesis of colitis ispoorly understood. Here, we found that cholic acid (CA) levels were increased in patientsand mice. Cytochrome P450 8B1 (CYP8B1), which synthesizes CA, was induced in liversof colitic mice. CA-treated or liver Cyp8b1-overexpressing mice developed more severe colitis with compromised repair of themucosal barrier, whereas Cyp8b1-knockout mice were resistant to colitis. Mechanistically, CA inhibited peroxisomeproliferator-activated receptor alpha (PPARα), resulting in impeded fatty acid oxidation(FAO) and impaired Lgr5+ intestinal stem cell (ISC) renewal. A PPARα agonist restored FAO and improved Lgr5+ ISC function. Activation of the farnesoid X receptor (FXR) suppressed liver CYP8B1expression and ameliorated colitis in mice. This study reveals a connection betweenthe hepatic CYP8B1-CA axis and colitis via regulating intestinal epithelial regeneration,suggesting that BA-based strategies might be beneficial in IBD treatment.

DOI: 10.1016/j.stem.2022.08.008

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00344-7