Elevated miR-124-3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T-synthase

The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin-typeO-glycosylation. We evaluated alterations in the colon mucus layer in 2-, 16-, and 24-month-old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. ThemiR-124-3pexpression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T-synthase, the rate-limiting enzyme inO-glycosylation, displayed an age-related decline in protein expression. Further experiments indicated thatmiR-124-3pmodulatedO-glycosylation by directly targeting T-synthase. Moreover, young mice overexpressingmiR-124-3pexhibited abnormal glycosylation, early-onset, and more severe colitis. These data suggest thatmiR-124-3ppredisposes to senile colitis by reducing T-synthase, and themiR-124-3p/T-synthase/O-glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis.