Abstract
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.
Highlights
With the development of antibiotic-resistant bacteria pathogens, identification of a chemical or pharmacological drug that could influence human immune response and decrease the risks of pathogen infection has become a key goal of innate immunity research
To determine whether metformin promotes the innate immunity, worms were exposed to the human opportunistic pathogen Pseudomonas aeruginosa(PA14), and we found that wild-type animals treated with metformin (1 mM, 2 mM, 5 mM, 10 mM, 25 mM, 50 mM, and 100 mM) exhibited increased resistance to P. aeruginosa in dose-dependent manner (Figure 1(a); Table S2)
These results suggest that metformin enhances the innate immunity in C. elegans
Summary
With the development of antibiotic-resistant bacteria pathogens, identification of a chemical or pharmacological drug that could influence human immune response and decrease the risks of pathogen infection has become a key goal of innate immunity research. An antiglycemic biguanide drug and the first-line drug for the treatment of type 2 diabetes, has been proven to extend lifespan in Caenorhabditis elegans [1,2,3,4,5] and mice [6,7]. Metformin has been used in the treatment of metabolic syndrome and cancer [9,10]. Recent studies have shown that metformin has antimicrobial properties for the treatment of pathogen infection, including Trichinella spiralis [11], Staphylococcus aureus [12], Pseudomonasaeruginosa [13,14], hepatitis B virus [15], hepatitis C virus [16,17], and human immunodeficiency virus [18]. Calu-3 airway epithelial cocultured cells with metformin treatment inhibited the basolateral glucose-induced apical P
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