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dc.contributor.authorLachmandas, Ektaen_US
dc.contributor.authorEckold, Clareen_US
dc.contributor.authorBöhme, Juliaen_US
dc.contributor.authorKoeken, Valerie A. C. M.en_US
dc.contributor.authorMardiana Marzukien_US
dc.contributor.authorBlok, Bastiaanen_US
dc.contributor.authorArts, Rob J. W.en_US
dc.contributor.authorChen, Jinmiaoen_US
dc.contributor.authorTeng, Karen W. W.en_US
dc.contributor.authorRatter, Jacquelineen_US
dc.contributor.authorSmolders, Elise J.en_US
dc.contributor.authorVan den Heuvel, Corinaen_US
dc.contributor.authorStienstra, Rinkeen_US
dc.contributor.authorDockrell, Hazel M.en_US
dc.contributor.authorNewell, Evanen_US
dc.contributor.authorNetea, Mihai G.en_US
dc.contributor.authorSinghal, Amiten_US
dc.contributor.authorCliff, Jacqueline M.en_US
dc.contributor.authorVan Crevel, Reinouten_US
dc.identifier.citationLachmandas, E., Eckold, C., Böhme, J., Koeken, V. A. C. M., Mardiana Marzuki, Blok, B., Arts, R. J. W., Chen, J., Teng, K. W. W., Ratter, J., Smolders, E. J., Van den Heuvel, C., Stienstra, R., Dockrell, H. M., Newell, E., Netea, M. G., Singhal, A., Cliff, J. M. & Van Crevel, R. (2019). Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects. Journal of Infectious Diseases, 220(1), 139-150.
dc.description.abstractBackground" 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 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. 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.en_US
dc.description.sponsorshipAgency for Science, Technology and Research (A*STAR)en_US
dc.relation.ispartofJournal of Infectious Diseasesen_US
dc.titleMetformin alters human host responses to Mycobacterium tuberculosis in healthy subjectsen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.contributor.organizationAgency for Science, Technology and Research (A∗STAR)en_US
dc.description.versionPublished versionen_US
dc.description.acknowledgementThis study was supported by the European Union’s Seventh Framework Programme (to the TANDEM Consortium, under grant agreement 305279); the Singapore Immunology Center, Agency of Science, Technology, and Research (A*STAR; to A. S.); the A*STAR Joint Council Office (career development award 15302FG151 to A. S.); the European Research Council (consolidator grant 310372 to M. G. N.); and the Netherlands Organization for Scientific Research (Spinoza grant to M. G. N.).en_US
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