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

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.

Keywords: CYP8B1; FXR; Lgr5; PPARα; bile acid; cholic acid; colitis; epithelial mucosal barrier; intestinal stem cell; liver-gut axis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bile Acids and Salts
  • Cell Self Renewal
  • Cholic Acid / metabolism
  • Cholic Acid / pharmacology
  • Colitis* / metabolism
  • Inflammatory Bowel Diseases*
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Steroid 12-alpha-Hydroxylase / genetics
  • Steroid 12-alpha-Hydroxylase / metabolism


  • Bile Acids and Salts
  • PPAR alpha
  • Receptors, Cytoplasmic and Nuclear
  • Steroid 12-alpha-Hydroxylase
  • Cholic Acid