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

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-weekold 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. Abbreviations 25-HC 25-Hydroxycholesterol IBD Inflammatory bowel disease DSS Dextran sulfate sodium CD Corhn's disease UC Ulcerative colitis WT Wild type CH25H Cholesterol 25-hydroxylase EAE Experimental autoimmune encephalomyelitis HβCD 2-Hydroxypropyl-β-cyclodextrin BMDMs Bone marrow-derived macrophages Inflammatory bowel disease (IBD), which encompasses Corhn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder with increasing incidence and prevalence in many countries 1. Many genetic and

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High cholesterol diet, oxysterols and their impact on the gut–brain axis

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