Gut barrier defects, increased intestinal innate immune response, and enhanced lipid catabolism drive lethality in N-glycanase 1 deficient Drosophila
Pandey, A.; Galeone, A.; Han, S. Y.; Story, B. A.; Consonni, G.; Mueller, W. F.; Steinmetz, L. M.; Vaccari, T.; Jafar-Nejad, H.
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Intestinal 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 of Drosophila 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 of Pngl. Notably, germ-free rearing of Pngl mutants did not rescue lethality. In contrast, raising Pngl mutants on isocaloric, fat-rich diets improved animal survival in a dosage-dependent manner. Our data indicate that Pngl functions in Drosophila larvae to establish the gut barrier, and that the immune and metabolic consequences of loss of Pngl are primarily mediated through non-infectious mechanisms.
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