Cholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells

Abstract Cholesterol sulfate, produced by hydroxysteroid sulfotransferase 2B1 (SULT2B1), is highly abundant in the intestine. Herein, we study the functional role and underlying intestinal epithelial repair mechanisms of cholesterol sulfate in ulcerative colitis. The levels of cholesterol and cholesterol sulfate, as well as the expression of Sult2b1 and genes involved in cholesterol biosynthesis, are significantly higher in inflamed tissues from patients with ulcerative colitis than in intestinal mucosa from healthy controls. Cholesterol sulfate in the gut and circulation is mainly catalyzed by intestinal epithelial SULT2B1. Specific deletion of the Sult2b1 gene in the intestinal epithelial cells aggravates dextran sulfate sodium-induced colitis; however, dietary supplementation with cholesterol sulfate ameliorates this effect in acute and chronic ulcerative colitis in mice. Cholesterol sulfate promotes cholesterol biosynthesis by binding to Niemann-Pick type C2 protein and activating sterol regulatory element binding protein 2 in colonic epithelial cells, thereby alleviates ulcerative colitis. In conclusion, cholesterol sulfate contributes to the healing of the mucosal barrier and exhibits therapeutic efficacy against ulcerative colitis in mice.