DUOX2-Driven Oxidative Stress Alters the Gut Redox Niche and Promotes Microbial Dysbiosis in Crohn’s Disease

Crohn's disease (CD) is characterized by chronic intestinal inflammation accompanied by gut dysbiosis and redox imbalance. We investigated the role of dual oxidase-2 (DUOX2), a major epithelial source of reactive oxygen species (ROS), in linking oxidative stress to microbe-host crosstalk. DUOX2 expression was upregulated in human intestinal samples and was positively associated with inflammatory readouts, oxidative stress indices, and dysbiosis. Intestinal epithelial cell-specific <i>Duox2</i> knockout (KO) mice exhibited reduced mucosal ROS, preserved barrier integrity, and attenuated dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Cohousing and fecal microbiota transplantation demonstrated that this protective phenotype was microbiota-dependent. Multi-omics profiling identified enrichment of <i>Parabacteroides</i>, particularly <i>P. distasonis</i>, in <i>Duox2</i> KO mice, and oral supplementation with <i>P. distasonis</i> enhanced resistance to colitis. Mechanistically, DUOX2-derived oxidative stress constrained <i>Parabacteroides</i> growth, as <i>P. distasonis</i> displayed marked susceptibility to hydrogen peroxide, with excessive intracellular ROS accumulation and an absence of key antioxidant defenses-including peroxide reductase C (AhpC) and superoxide dismutase B (SodB)-indicating that epithelial DUOX2 shapes a hostile luminal redox niche unfavorable to these beneficial microbes. Pharmacological inhibition of DUOX2 with Compound 521 reduced oxidative stress, ameliorated colitis, and partially restored microbial balance. These findings establish a DUOX2-ROS-microbiota axis in which epithelial DUOX2 amplifies oxidative stress, remodels the gut ecosystem, and promotes inflammation, and highlights DUOX2 suppression or ROS-sensitive <i>Parabacteroides</i> as potential redox-centric therapeutic strategies for CD.