Epithelial Dual Oxidase 2 shapes the mucosal microbiome and contributes to inflammatory susceptibility. DUOX2 shapes the mucosal microbiome and contributes to inflammatory susceptibility

Reactive oxygen species (ROS) are highly reactive molecules formed from diatomic oxygen. They act as cellular signals and exert antibiotic activity towards invading microorganisms but also inflict damage on host cells. Dual oxidase 2 (DUOX2) is the main ROS-producing enzyme in the intestine, regulated by cues of the commensal microbiota and functions in pathogen defense. DUOX2 plays multiple roles in different organs and cell types complicating the functional analysis using systemic deletion models. Here, we report the generation of conditional DUOX2∆IEC mice lacking DUOX2 specifically in intestinal epithelial cells, which allow to elucidate the precise role of epithelial DUOX2 for intestinal homeostasis and host-microbiome interactions. Under unchallenged conditions we did not observe any obvious phenotype, although intestinal epithelial ROS production was drastically decreased, and the mucosal microbiome composition was altered. When challenged with dextran sodium sulfate (DSS), DUOX2∆IEC mice were protected from colitis, possibly by inhibiting ROS mediated damage and fostering epithelial regenerative responses. Finally, by analyzing paired DUOX2 expression and microbiome data of patients with intestinal inflammation, we found that DUOX2 expression was increased in inflamed tissue and high DUOX2 levels were linked to a dysbiotic microbiome. Our findings demonstrate that bidirectional DUOX2-microbiome interactions contribute to mucosal homeostasis and their dysregulation may drive disease development, thus highlighting this axis as therapeutic target to treat intestinal inflammation.