Journal article
p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans
GeroScience
07/27/2026
DOI: 10.1007/s11357-026-02405-6
PMID: 42503569
Appears in UI Libraries Support Open Access
Abstract
Mitis group streptococci are opportunistic pathogens residing in the oral cavity, where they produce hydrogen peroxide (H2O2), a key virulence factor contributing to their pathogenesis. We previously demonstrated that these bacteria kill the nematode Caenorhabditis elegans through H2O2 production. Metformin, a widely used biguanide drug for managing blood glucose levels, has shown promising effects on aging by extending lifespan in worms and mice, and has also demonstrated potential cancer treatment. Additionally, pretreatment with metformin enhances the survival of worms and triggers an immune response via the p38 MAPK pathway against various pathogenic bacteria. Based on these observations, we investigated metformin's potential as a therapeutic agent against mitis group streptococcal infections and its underlying mechanisms in the current study. Pretreatment of worms with metformin provided significant dose-dependent protection from streptococcal-derived H2O2. This protective effect was attributed to the activation of the oxidative stress response transcription factor SKN-1/NRF2. Further analysis revealed that the p38 MAPK pathway and the transcription mediator complex protein MDT-15 are essential for the activation of SKN-1 by metformin. Interestingly, SKN-1 activity, mediated by MDT-15, was found to be independent of the p38 MAPK pathway. Our findings establish that metformin-mediated protection against mitis group streptococcal infections relies on the coordinated action of SKN-1, the p38 MAPK pathway, and MDT-15. These insights suggest that metformin could be a valuable therapeutic agent in combating these infections. Future research should focus on further elucidating the molecular mechanisms involved and exploring the potential clinical applications of metformin in treating these bacterial infections.
Details
- Title: Subtitle
- p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans
- Creators
- Ali Al Hatem - The University of Texas Health Science Center at HoustonBoopathi Balasubramaniam - University of IowaAlissa Villhauer - University of IowaAli K Naji - The University of Texas Health Science Center at HoustonRansome van der Hoeven - University of Iowa
- Resource Type
- Journal article
- Publication Details
- GeroScience
- DOI
- 10.1007/s11357-026-02405-6
- PMID
- 42503569
- ISSN
- 2509-2715
- eISSN
- 2509-2723
- Publisher
- Springer Nature
- Grant note
- University of Iowa, College of Dentistry and Dental Clinics National Institute of General Medical Sciences: R24GM137786 Division of Intramural Research, National Institute of Allergy and Infectious Diseases: R01 AI158429-6 University of Texas Health Science Center at Houston, School of Dentistry
Sections of this study were supported by R01 AI158429-6 from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Proteomic analysis of samples was supported by the IDeA National Resource for Quantitative Proteomics voucher program (R24GM137786) from the National Institute of General Medical Sciences. This manuscript is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH. This work was also supported by startup funding provided by the University of Texas, Health Science Center, School of Dentistry at Houston and the University of Iowa, College of Dentistry and Dental Clinics to R. van der Hoeven. Funding was also provided by the University of Iowa College of Dentistry seed grant program to R. van der Hoeven.
- Language
- English
- Electronic publication date
- 07/27/2026
- Academic Unit
- Dental Research; Periodontics
- Record Identifier
- 9985214915202771
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