DUOX2 and colitis: Here we show that (1) unchallenged Duox2∆IEC mice did not display any obvious intestinal phenotype but harbored an altered mucosal microbiome, that (2) loss of epithelial DUOX2 protected from dextran sodium sulfate (DSS)-induced colitis associated with enhanced epithelial regenerative responses and fecal microbiome changes, and that (3) dysregulated DUOX2 expression in the mucosa of IBD patients coincided with an altered microbiome.