Our key findings include (1) inactivation of Sec1 exacerbated symptoms of colitis in a mouse model of IBD, (2) Sec1 negatively regulated the secretion of key inflammatory factors in the intestinal environment, (3) Sec1 exerted its protective effect by supporting cell proliferation and regulating DR5 fucosylation and IEC apoptosis. Here, TNFRSF10B is linked to colitis.