2. Academic Validation
  3. Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal

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.
Li Chen 1,  Tingying Jiao 2,  Weiwei Liu 3,  Yuhong Luo 4,  Jue Wang 5,  Xiaozhen Guo 2,  Xiao Tong 1,  Zemin Lin 2,  Chuying Sun 6,  Kanglong Wang 2,  Yifan He 1,  Yuwei Zhang 7,  Hualing Xu 6,  Jiawen Wang 8,  Jianping Zuo 1,  Qiurong Ding 7,  Shijun He 9,  Frank J Gonzalez 10,  Cen Xie 11
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
  • 3 Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China; Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China.
  • 4 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210029, P.R. China.
  • 7 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
  • 8 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China.
  • 9 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. Electronic address: heshijun@simm.ac.cn.
  • 10 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gonzalef@mail.nih.gov.
  • 11 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. Electronic address: xiecen@simm.ac.cn.
PMID: 36055192 DOI: 10.1016/j.stem.2022.08.008
Abstract

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.

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