EPITHELIAL DUOX2 ACTIVATION INCREASES GUT PERMEABILITY AND BACTERIAL TRANSLOCATION THAT IS RESCUED WITH BUTYRATE SUPPLEMENTATION

Abstract BACKGROUND Inflammatory bowel diseases (IBD) are chronic pathologies characterized by dysbiosis, defects in epithelial barrier function, and increased redox stress. Dysbiosis IBD involves an expansion of Proteobacteria a reduction Firmicutes, which produce metabolites important maintaining gut homeostasis. The NADPH oxidase dual 2 (DUOX2) catalyzes the production hydrogen peroxide (H2O2) is only gene consistently altered patients association with dysbiosis before onset disease. However, functional consequence DUOX2 activation not understood. Using models leading to activation, we aimed dissect contribution activity function observed IBD. METHODS villin-TLR4 (vTLR4) mice, express constitutively active form TLR4 colonic cells (CECs) have DUOX2, vTLR4-DUOX2-KO their wild-type (WT) littermates were euthanized. Livers collected for permeability assessment bacterial translocation. Colonic tissue was RNA-sequencing isolation CECs expression determinations qPCR. Separately, vTLR4 mice treated butyrate drinking water. Tissue harvested same measurement H2O2 via Amplex Red. Colonoids from WT stimulated IFN? or heat-killed adherent invasive Escherichia coli. Duox2 determined. RESULTS revealed that abrogation downregulated cytokine-mediated signaling cytokine pathways, including tumor necrosis factors key chemotactic proteins such as CXCL1 CXCL2. Similarly, Tnfa, Cxcl1, Cxcl2 significantly levels mice. had translocation, rescued deletion DUOX2. Butyrate treatment inhibited response stimuli vitro, accompanied transcripts. In vivo, reduced H2O2, translocation liver, led downregulation CONCLUSIONS Chronic leads resulting This increase proinflammatory cytokines chemokines. microbial metabolite blocked activity, rescuing intestinal reducing inflammatory expression. We posit therapies at controlling through microbiome metabolome-targeted approaches may be beneficial