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Metformin promotes innate immunity through a conserved PMK-1/p38 MAPK pathway

Yi Xiao1,2, Fang Liu3, Sanhua Li1,2

  • 1Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.

Virulence
|December 19, 2019
PubMed

Insights

Metformin enhances innate immunity and protects against bacterial infections by activating the p38 MAPK pathway. This conserved mechanism boosts therapeutic potential for treating infections.

Area of Science:

  • Immunology
  • Microbiology
  • Pharmacology

Background:

  • Metformin is a first-line type 2 diabetes drug with known benefits against aging, cancer, and cardiovascular diseases.
  • The influence of metformin on immune response and its underlying molecular mechanisms are not well understood.
  • Metformin's impact on resistance to both Gram-negative and Gram-positive bacterial pathogens requires further investigation.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which metformin influences the immune response.
  • To investigate metformin's role in innate immunity and its effects on pathogen resistance.
  • To determine if metformin's immune-enhancing effects are conserved across species.

Main Methods:

  • Screening of classical immune pathways in *C. elegans* to identify metformin's targets.
  • Assessing metformin's effect on bacterial burden and host tolerance during infection.
  • Investigating the role of the p38 MAPK pathway in metformin-mediated immunity.
  • Evaluating metformin's efficacy and mechanism in a mouse model of *Pseudomonas aeruginosa* infection.

Main Results:

  • Metformin enhances resistance to Gram-negative (*Pseudomonas aeruginosa*, *Salmonella enterica*) and Gram-positive (*Enterococcus faecalis*, *Staphylococcus aureus*) pathogens.
  • Metformin promotes host tolerance to infection rather than reducing bacterial load.
  • Metformin activates the p38 MAPK pathway (PMK-1 in *C. elegans*), which mediates innate immune responses in the intestine.
  • Metformin treatment increases resistance to *P. aeruginosa* infection in mice, correlating with elevated active PMK-1 levels.

Conclusions:

  • Metformin enhances innate immunity through the conserved p38/PMK-1 pathway, acting on the intestine.
  • This mechanism of immune enhancement by metformin is conserved from invertebrates to mammals.
  • Metformin's ability to boost innate immunity offers a conserved therapeutic strategy for combating pathogen infections.
Keywords:
C. elegansMetformininnate immunityp38 MAPK pathway

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