Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

Sci Rep. 2020 Aug 28;10(1):14246. doi: 10.1038/s41598-020-71198-1.

Abstract

Cholesterol 25-hydroxylase (CH25H) encodes the enzyme that converts cholesterol to 25-hydroxycholesterol (25-HC). 25-HC has been demonstrated to be involved in the pathogenesis of inflammatory bowel disease. However, the role of CH25H in experimental colitis remains unknown. Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Ch25h-/- mice in 8-week-old male for 7 days by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. The function of CH25H was investigated using loss-of-function and gain-of-function such as Ch25h-deficient mice, supplementation with exogenous 25-HC and treatment of 25-HC into Caco2 and HCT116 colonic epithelial cells. Ch25h-/- mice with DSS-induced colitis exhibited aggravated injury, including higher clinical colitis scores, severe injury of the epithelial barrier, lower tight junction protein levels and higher levels of IL-6. Supplementation with exogenous 25-HC ameliorated disease symptoms and reduced the extent of damage in DSS-induced colitis, which was characterized by lower colon damage, higher tight junction protein expression, significantly decreased local and systemic production of pro-inflammatory cytokines IL-6. In Caco2 and HCT116 cells, 25-HC induced tight junction genes expression in colon cancer epithelial cells. These effects of CH25H were obtained by promoting ATF3 expression. Taken together, our findings reveal a protective role for 25-HC in DSS-induced colitis and the ability of CH25H to maintain epithelial gut barrier function through ATF3 expression. Supplementation with exogenous 25-HC ameliorates disease symptoms, which provides a new therapeutic strategy for ulcerative colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / physiopathology
  • Colitis, Ulcerative / pathology
  • Colon / metabolism
  • Colonic Neoplasms / pathology
  • Cytokines / metabolism
  • Dextran Sulfate / pharmacology
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Gastrointestinal Microbiome / drug effects
  • HCT116 Cells
  • Humans
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Intestines / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Permeability / drug effects
  • Steroid Hydroxylases / metabolism
  • Steroid Hydroxylases / pharmacology*
  • Tight Junction Proteins / metabolism
  • Tight Junctions / metabolism

Substances

  • Cytokines
  • Tight Junction Proteins
  • Dextran Sulfate
  • Steroid Hydroxylases
  • cholesterol 25-hydroxylase