Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent helicobacter felis infection and inflammation in mice

Background & Aims Dual oxidases (DUOX) are conserved reduced nicotinamide adenine dinucleotide phosphate oxidases that produce H ₂O₂ at the epithelial cell surface. The DUOX enzyme comprises the DUOX and DUOX maturation factor (DUOXA) subunits. Mammalian genomes encode 2 DUOX isoenzymes (DUOX1/DUOXA1 and DUOX2/DUOXA2). Expression of these genes is up-regulated during bacterial infections and chronic inflammatory diseases of the luminal gastrointestinal tract. The roles of DUOX in cellular interactions with microbes have not been determined in higher vertebrates. Methods Mice with disruptions of Duoxa1 and Duoxa2 genes (Duoxa^-/- mice) and control mice were infected with Helicobacter felis to create a model of Helicobacter pylori infection - the most common human chronic infection. Results Infection with H felis induced expression of Duox2 and Duoxa2 in the stomachs of wild-type mice, and DUOX protein specifically localized to the apical surface of epithelial cells. H felis colonized the mucus layer in the stomachs of Duoxa^-/- mice to a greater extent than in control mice. The increased colonization persisted into the chronic phase of infection and correlated with an increased, yet ineffective, inflammatory response. H felis colonization also was increased in Duoxa^+/- mice, compared with controls. We observed reduced expression of the H₂O ₂-inducible katA gene in H felis that colonized Duoxa^-/- mice, compared with that found in controls (P =.0002), indicating that Duox causes oxidative stress in these bacteria. In vitro, induction of oxidative defense by H felis failed to prevent a direct bacteriostatic effect at sustained levels of H₂O₂ as low as 30 μmol/L. Conclusions Based on studies of Duoxa^-/- mice, the DUOX enzyme complex prevents gastric colonization by H felis and the inflammatory response. These findings indicate the nonredundant function of epithelial production of H₂O₂ in restricting microbial colonization.