Gut barrier defects, increased intestinal innate immune response, and enhanced lipid catabolism drive lethality inN-glycanase 1 deficientDrosophila

Abstract

AbstractIntestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of infectious versus non-infectious mechanisms on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss ofDrosophila N-glycanase 1 (Pngl) leads to gut barrier defects, which cause starvation and increased JNK activity. These defects result in Foxo overactivation, which induces a hyperactive innate immune response and lipid catabolism, thereby contributing to lethality associated with loss ofPngl. Notably, germ-free rearing ofPnglmutants did not rescue lethality. In contrast, raisingPnglmutants on isocaloric, fat-rich diets improved animal survival in a dosage-dependent manner. Our data indicate that Pngl functions inDrosophilalarvae to establish the gut barrier, and that the immune and metabolic consequences of loss ofPnglare primarily mediated through non-infectious mechanisms.