State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
Cell Stem Cell. 2022 Sep 1;29(9):1366-1381.e9. doi: 10.1016/j.stem.2022.08.008.
Although disrupted bile acid (BA) homeostasis is implicated in inflammatory bowel disease (IBD), the role of hepatic BA metabolism in the pathogenesis of colitis is poorly understood. Here, we found that cholic acid (CA) levels were increased in patients and mice. Cytochrome P450 8B1 (CYP8B1), which synthesizes CA, was induced in livers of colitic mice. CA-treated or liver Cyp8b1-overexpressing mice developed more severe colitis with compromised repair of the mucosal barrier, whereas Cyp8b1-knockout mice were resistant to colitis. Mechanistically, CA inhibited peroxisome proliferator-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 CYP8B1 expression and ameliorated colitis in mice. This study reveals a connection between the hepatic CYP8B1-CA axis and colitis via regulating intestinal epithelial regeneration, suggesting that BA-based strategies might be beneficial in IBD treatment.
尽管胆汁酸（BA）稳态紊乱与炎症性肠病（IBD）有关，但肝 BA 代谢在结肠炎发病机制中的作用仍知之甚少。在这里，我们发现 CA 水平在患者和小鼠中增加。在结肠炎小鼠的肝脏中，合成 CA 的细胞色素 P450 8B1（CYP8B1）被诱导。CA 处理或肝 Cyp8b1 过表达的小鼠发生更严重的结肠炎，黏膜屏障修复受损，而 Cyp8b1 敲除小鼠则对结肠炎具有抗性。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）受损和 Lgr5 肠干细胞（ISC）更新受损。PPARα 激动剂恢复 FAO 并改善 Lgr5 ISC 功能。法尼醇 X 受体（FXR）的激活抑制肝 CYP8B1 表达并改善小鼠结肠炎。这项研究揭示了肝 CYP8B1-CA 轴通过调节肠上皮细胞再生与结肠炎之间的联系，表明基于 BA 的策略可能有益于 IBD 的治疗。
