KCTD10 Modulates DSS-induced Ulcerative Colitis via Regulating Intestinal Stem Cell Function.

Abstract

The incidence of inflammatory bowel disease (IBD) continues to rise annually, which severely threatens public health. While estimates indicate that current therapies cause a 30% IBD clinical treatment failure, the precise pathogenesis remains unclear. Here, we found that a key embryonic development regulator, KCTD10, is correlated with the severity of IBD. We observed enhanced KCTD10 expression during enterocolitis. Intestinal epithelial cell (IEC)-specific knockout of KCTD10 in mice impaired intestinal epithelial barrier function, activated intestinal adaptive immune response, and disrupted intestinal homeostasis. Furthermore, in a dextran sodium sulfate (DSS) -induced ulcerative colitis model, IEC deletion of KCTD10 exacerbated colonic inflammation and impaired post-injury repair. Mechanistically, KCTD10 deletion downregulated intestinal stem cell (ISC) marker genes and affected their function. Importantly, KCTD10 stabilizes the transcription factor ATOH1 by regulating its ubiquitination, thereby determining the fate of intestinal progenitor cells derived from Lgr5+ intestinal stem cells. Our data thus revealed a previously undescribed function of KCTD10 in modulating ulcerative colitis by regulating intestinal stem cell function.