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Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects

Lachmandas, E., Eckold, C., Böhme, J. et al.

BACKGROUND:
Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis.

METHODS:
We investigated in-vitro and in-vivo effects of metformin in humans.

RESULTS:
Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in-vitro cellular metabolism whilst inhibiting the mammalian target of rapamycin (mTOR) targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation, and increased phagocytosis. Metformin administered to healthy human volunteers led to significant down-regulation of genes involved in oxidative phosphorylation, mTOR signaling and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species (ROS) production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to non-classical monocytes. At a functional level, metformin lowered ex vivo production of TNF-α, IFN-γ and IL-1β but increased phagocytosis and ROS production. Conclusion Metformin has a range of potentially beneficial effects on cellular metabolism, immune function and gene-transcription involved in innate host responses to M. tuberculosis.

Citation

Lachmandas, E., Eckold, C., Böhme, J. et al. "Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects" Journal of Infectious Diseases (2019): doi: 10.1093/infdis/jiz064