Metformin Attenuates Inflammatory Responses and Enhances Antibody Production in an Acute Pneumonia Model of Streptococcus pneumoniae

Abstract

Metformin may potentially reverse various age-related conditions; however, it is unclear whether metformin can also mitigate or delay the deterioration of immunological resilience that occurs in the context of infections that are commonly observed in older persons. We examined whether metformin promotes the preservation of immunological resilience in an acute S. pneumoniae (SPN) infection challenge in young adult mice. Mice were fed metformin (MET-alone) or standard chow (controls-alone) for 10 weeks prior to receiving intratracheal inoculation of SPN. A subset of each diet group received pneumococcal conjugate vaccine at week 6 (MET + PCV and control + PCV). Compared to controls-alone, MET-alone had significantly less infection-associated morbidity and attenuated inflammatory responses during acute SPN infection. Metformin lowered the expression of genes in the lungs related to inflammation as well as shorter lifespan in humans. This was accompanied by significantly lower levels of pro-inflammatory cytokines (e.g., IL6). MET + PCV vs. control + PCV manifested enhanced SPN anticapsular IgM and IgG levels. The levels of SPN IgM production negatively correlated with expression levels of genes linked to intestinal epithelial structure among MET + PCV vs. control + PCV groups. Correspondingly, the gut microbial composition of metformin-fed mice had a significantly higher abundance in the Verrucomicrobia, Akkermansia muciniphila, a species previously associated with beneficial effects on intestinal integrity and longevity. Together, these findings indicate metformin’s immunoprotective potential to protect against infection-associated declines in immunologic resilience.

Causal relationship between type 2 diabetes and common respiratory system diseases: a two-sample Mendelian randomization analysis

“…Metformin is the first-line therapy for T2D and most of the diabetes patients might have taken metformin. Metformin has been shown to reduce the risk of many bacterial and viral infections including zika virus ( 21 ), dengue virus ( 21 ), Hepatitis C virus ( 22 ), Streptococcus pneumoniae ( 23 ) and PTB ( 24 ). The use of metformin in many of the patients with T2D might have modified and attenuated the positive association between T2D and PTB.…”

Dementia, stroke, age, use of medical devices and antipsychotic drugs may increase the risk of nosocomial infections among elderly patients hospitalized at Neurology Clinics

“…Other studies reported that diabetes mellitus is a protective factor against acute respiratory distress syndrome (ARDS), probably due to a lowering effect on cytokine storm produced by diabetes in this context 48 , 49 . Furthermore, a recent pre-clinical study suggests a potential protective effect of metformin, the most used oral antidiabetic drug, against severe forms of pneumonia due to Streptococcus pneumoniae 50 . Taken together, the above-mentioned findings might furnish a possible interpretative key of the negative association between diabetes mellitus and the incidence of nosocomial pneumonia found in our study.…”

Old drug, new tricks: the utility of metformin in infection and vaccination responses to influenza and SARS-CoV-2 in older adults

“…Metformin has direct anti-inflammatory action via inhibition of nuclear factor κB (NFκB) via AMPK-dependent and independent pathways ( Saisho, 2015 ) and has been shown to suppress pro-inflammatory cytokines ( Zhou et al, 2016 ; Giusti et al, 2022 ). Studies have also shown that metformin can improve metabolic parameters such as hyperglycemia, insulin resistance, and atherogenic dyslipidemia ( Lee et al, 2022 ) that contribute to inflammatory processes. In addition, metformin can modulate the gut microbiome ( Cabreiro et al, 2013 ; Sun et al, 2018 ; Pryor et al, 2019 ), further reducing inflammation and improving metabolism.…”