Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, USA.
Department of Biosciences, University of Milan, Milan, Italy.
Nat Commun. 2023 Sep 13;14(1):5667. doi: 10.1038/s41467-023-40910-w.
Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of Pngl in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of Pngl mutants rescued their developmental delay but not lethality. However, raising Pngl mutants on isocaloric, fat-rich diets partially rescued lethality. Our data indicate that Pngl functions in Drosophila larvae to establish the gut barrier, and that the lethality caused by loss of Pngl is primarily mediated through non-bacterial induction of immune and metabolic abnormalities.
肠道屏障功能障碍会导致炎症和相关代谢变化。然而，在屏障功能障碍的情况下，肠道细菌与非细菌损伤对动物健康的相对影响尚不清楚。在这里，我们证实果蝇 N-糖基酶 1（Pngl）在特定肠细胞类型中的缺失会导致肠道屏障缺陷，导致饥饿和 JNK 过度激活。这些异常，以及肠细胞和脂肪体中 Pngl 的缺失，导致 Foxo 过度激活，导致先天免疫反应和脂质分解代谢过度活跃，从而导致致死性。无菌饲养 Pngl 突变体可挽救其发育迟缓，但不能挽救其致死性。然而，在等热量、高脂肪饮食上饲养 Pngl 突变体可部分挽救致死性。我们的数据表明，Pngl 在果蝇幼虫中发挥作用以建立肠道屏障，并且 Pngl 的缺失引起的致死性主要是通过非细菌诱导的免疫和代谢异常介导的。
