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

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 (PPAR alpha), resulting in impeded fatty acid oxidation (FAO) and impaired Lgr5(+) intestinal stem cell (ISC) renewal. A PPAR alpha 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.

Automated summary

This study reveals that disrupted bile acid (BA) homeostasis, specifically increased cholic acid (CA) levels and induced cytochrome P450 8B1 (CYP8B1) synthesis, plays a significant role in the pathogenesis of colitis. CA inhibits peroxisome proliferator-activated receptor alpha (PPAR alpha), resulting in impaired fatty acid oxidation (FAO) and intestinal stem cell (ISC) renewal, leading to more severe colitis. Activation of the farnesoid X receptor (FXR) suppresses CYP8B1 expression and ameliorates colitis. These findings suggest that targeting the hepatic CYP8B1-CA axis may be a beneficial strategy for treating inflammatory bowel disease (IBD).