Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects.

Ekta Lachmandas,Corina Van Den Heuvel,Mihai G Netea,Karen W W Teng,Jacqueline Ratter,Jinmiao Chen,Valerie A C M Koeken,Elise J Smolders,Rob J W Arts,Evan Newell,Clare Eckold,Amit Singhal,Rinke Stienstra,Jacqueline M Cliff,Hazel M Dockrell,Reinout Van Crevel,Bastiaan Blok,Julia Böhme,Mardiana Binte Marzuki

doi:10.1093/infdis/jiz064

Abstract

BackgroundMetformin, 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.MethodsWe investigated in vitro and in vivo effects of metformin in humans.ResultsMetformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production.ConclusionMetformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis.

Highlights

Diabetes increases susceptibility to tuberculosis [1] and worsens tuberculosis outcome [2]
Proposed mechanisms for metformin’s beneficial effects include an increase in mitochondrial reactive oxygen species and enhanced killing of M. tuberculosis but none of these have been investigated in humans
The mechanism of action behind metformin’s effects are not clearly defined as metformin acts through several pathways including mitochondrial complex I inhibition, an increase in AMP/ATP levels leading to increased AMP activated kinase (AMPK) signaling, and decreased glucagon and mammalian target of rapamycin (mTOR) signaling [11]

Summary

Metformin has shown beneficial effects in a murine model of tuberculosis. Using in-vitro and in-vivo studies we show that metformin has beneficial effects on cellular metabolism, immune function and gene-transcription involved in innate host responses to M.

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