ABSTRACT

Metformin, as the first-line oral drug for type 2 diabetes, has proven benefits against aging, cancer and cardiovascular diseases. But the influence of metformin to the immune response and its molecular mechanisms remain obscure. Metformin increases resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Meanwhile, metformin protects the animals from the infection by enhancing the tolerance to the pathogen infection rather than by reducing the bacterial burden. Through the screening of classical immune pathways in C. elegans, we find metformin enhances innate immunity through p38 MAPK pathway. Furthermore, activated p38/PMK-1 by metformin acts on the intestine for innate immune response. In addition, metformin-treated mice have increased resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Therefore, promoted p38/PMK-1-mediated innate immunity by metformin is conserved from worms to mammals. Our work provides a conserved mechanism by which metformin enhances immune response and boosts its therapeutic application in the treatment of pathogen infection.

摘要

二甲双胍作为2型糖尿病的一线口服药物，已证明对衰老，癌症和心血管疾病具有益处。但是二甲双胍对免疫应答及其分子机制的影响仍然不清楚。二甲双胍不仅增加了对革兰氏阴性病菌铜绿假单胞菌和小肠沙门氏菌的抵抗力，而且还增强了对革兰氏阳性病原菌的粪肠球菌和金黄色葡萄球菌的抵抗力。同时，二甲双胍通过增强对病原体感染的耐受性而不是通过减轻细菌负担来保护动物免受感染。通过线虫中经典免疫途径的筛选，我们发现二甲双胍可通过p38 MAPK途径增强先天免疫。此外，二甲双胍激活的p38 / PMK-1对肠道产生先天免疫反应。此外，用二甲双胍治疗的小鼠对铜绿假单胞菌PA14感染的抵抗力增强，并显着提高了活性PMK-1的水平。因此，由二甲双胍促进的p38 / PMK-1介导的先天免疫力从蠕虫到哺乳动物都是保守的。我们的工作提供了一种保守的机制，通过该机制，二甲双胍可增强免疫应答并增强其在病原体感染治疗中的治疗应用。