Epithelial barrier DUOX2 serves as early immune defense in intestinal pathogen control

Epithelial barriers constitute the first line of immune defense, preventing pathogen adherence, growth and entry through physical and chemical mechanisms. Essential to chemical defense are reactive oxygen species, usually provided by the phagocyte NADPH oxidase. DUOX2, a related oxidase, functions as sensor of the gut environment, and its dysregulation has been associated with inflammatory bowel disease. Here, we combine cell-based approaches with newly developed transgenic mice to explore how altering epithelial DUOX2 activity shapes host responses to intestinal bacteria including IBD-associated pathogens and to chemical colitis inducers. Although the pathogenic mechanisms of these bacteria differ, each triggered DUOX2 recruitment and transient H₂O₂ bursts in the vicinity of the pathogen during early, but not late, stages of infection. In vivo, epithelial DUOX2 acted as universal immune defense system without inducing or perpetuating intestinal inflammation. Our findings show that epithelial DUOX2 chemically undermines pathogen-induced niches, decreasing bacterial virulence and strengthening the barrier.