Role of DUOX in gut inflammation: lessons from Drosophila model of gut-microbiota interactions

Abstract

It is well-known that certain bacterial species can colonize the gut epithelium and induce inflammation in the mucosa, whereas other species are either benign or beneficial to the host. Deregulation of the gut-microbe interactions may lead to a pathogenic condition in the host, such as chronic inflammation, tissue injuries, and even cancer. However, our current understanding of the molecular mechanisms that underlie gut-microbe homeostasis and pathogenesis remains limited. Recent studies have used Drosophila as a genetic model to provide novel insights into the causes and consequences of bacterial-induced colitis in the intestinal mucosa. The present review discusses the interactions that occur between gut-associated bacteria and host gut immunity, particularly the bacterial-induced intestinal dual oxidase (DUOX) system. Several lines of evidence showed that the bacterial-modulated DUOX system is involved in microbial clearance, intestinal epithelial cell renewal (ECR), redox-dependent modulation of signaling pathways, cross-linking of biomolecules, and discrimination between symbionts and pathogens. Further genetic studies on the Drosophila DUOX system and on gut-associated bacteria with a distinct ability to activate DUOX may provide critical information related to the homeostatic inflammation as well as etiology of chronic inflammatory diseases, which will enhance our understanding on the mucosal inflammatory diseases frequently observed in the microbe-contacting epithelia of humans.

Keywords: dual oxidase; epithelial cell renewal; gut immunity; gut microbiota; gut-microbe interactions; reactive oxygen species; uracil.

Figure 1

DUOX as a mucosal antimicrobial system in Drosophila and human. (A) Similar domains of DUOX enzymes between Drosophila and human are shown. In Drosophila, peroxidase homology domain of DUOX converts H₂O₂ into HOCl in the presence of chloride. DUOX-dependent H₂O₂ molecules are eliminated by immune-regulated catalase (IRC) activity. In human, DUOX-dependent H₂O₂ is used for the oxidative conversion of SCN⁻ to OSCN⁻ by the enzymatic action of lactoperoxidase in the mucosal fluids. (B) Modification of gut commensal community members in flies carrying reduced DUOX activity. Midgut of control flies and that of DUOX-knockdown flies are dissected and the homogenates of midguts are spread on Mannitol agar plate. Representative images are shown.

Figure 2

Role of DUOX in gut-microbe interactions. (A) Different gut physiologies depending different uracil-releasing states (Uracil⁻ and Uracil⁺ for uracil non-releasing and releasing state, respectively) and different gut-colonizing ability (resident vs. non-resident) of each bacterium in a Drosophila gut environment. (B) DUOX regulatory mechanism in conventional and infectious conditions. See text for more details.

Figure 3

Role of DUOX in diverse biological activities. In addition to its original function in redox-dependent antimicrobial defense in mucosa described in Figures 1, 2. DUOX system is also involved in cross-linking of biomolecules, intestinal epithelial cell renewal, redox-dependent modulation of signaling pathways, and wound healing in different metazoans. See text for more details.