Collectively, this study utilizing mice with fibroblast-specific OTUD3 deficiency or with UC-associated Otud3 SNP knock-in provided evidence that cGAS-STING-mediated type I IFN responses exacerbate the development of DSS-induced colitis in the absence of OTUD3 or presence of UC-associated Otud3 SNP. Here, CGAS is linked to colitis.