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Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects

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...

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Autores principales: Lachmandas, Ekta, Eckold, Clare, Böhme, Julia, Koeken, Valerie A C M, Marzuki, Mardiana Binte, Blok, Bastiaan, Arts, Rob J W, Chen, Jinmiao, Teng, Karen W W, Ratter, Jacqueline, Smolders, Elise J, Van den Heuvel, Corina, Stienstra, Rinke, Dockrell, Hazel M, Newell, Evan, Netea, Mihai G, Singhal, Amit, Cliff, Jacqueline M, Van Crevel, Reinout
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548897/
https://www.ncbi.nlm.nih.gov/pubmed/30753544
http://dx.doi.org/10.1093/infdis/jiz064
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author Lachmandas, Ekta
Eckold, Clare
Böhme, Julia
Koeken, Valerie A C M
Marzuki, Mardiana Binte
Blok, Bastiaan
Arts, Rob J W
Chen, Jinmiao
Teng, Karen W W
Ratter, Jacqueline
Smolders, Elise J
Van den Heuvel, Corina
Stienstra, Rinke
Dockrell, Hazel M
Newell, Evan
Netea, Mihai G
Singhal, Amit
Cliff, Jacqueline M
Van Crevel, Reinout
author_facet Lachmandas, Ekta
Eckold, Clare
Böhme, Julia
Koeken, Valerie A C M
Marzuki, Mardiana Binte
Blok, Bastiaan
Arts, Rob J W
Chen, Jinmiao
Teng, Karen W W
Ratter, Jacqueline
Smolders, Elise J
Van den Heuvel, Corina
Stienstra, Rinke
Dockrell, Hazel M
Newell, Evan
Netea, Mihai G
Singhal, Amit
Cliff, Jacqueline M
Van Crevel, Reinout
author_sort Lachmandas, Ekta
collection PubMed
description 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 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.
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spelling pubmed-65488972019-06-13 Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects Lachmandas, Ekta Eckold, Clare Böhme, Julia Koeken, Valerie A C M Marzuki, Mardiana Binte Blok, Bastiaan Arts, Rob J W Chen, Jinmiao Teng, Karen W W Ratter, Jacqueline Smolders, Elise J Van den Heuvel, Corina Stienstra, Rinke Dockrell, Hazel M Newell, Evan Netea, Mihai G Singhal, Amit Cliff, Jacqueline M Van Crevel, Reinout J Infect Dis Major Articles and Brief Reports 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 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. Oxford University Press 2019-07-01 2019-02-12 /pmc/articles/PMC6548897/ /pubmed/30753544 http://dx.doi.org/10.1093/infdis/jiz064 Text en © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Major Articles and Brief Reports
Lachmandas, Ekta
Eckold, Clare
Böhme, Julia
Koeken, Valerie A C M
Marzuki, Mardiana Binte
Blok, Bastiaan
Arts, Rob J W
Chen, Jinmiao
Teng, Karen W W
Ratter, Jacqueline
Smolders, Elise J
Van den Heuvel, Corina
Stienstra, Rinke
Dockrell, Hazel M
Newell, Evan
Netea, Mihai G
Singhal, Amit
Cliff, Jacqueline M
Van Crevel, Reinout
Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
title Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
title_full Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
title_fullStr Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
title_full_unstemmed Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
title_short Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
title_sort metformin alters human host responses to mycobacterium tuberculosis in healthy subjects
topic Major Articles and Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548897/
https://www.ncbi.nlm.nih.gov/pubmed/30753544
http://dx.doi.org/10.1093/infdis/jiz064
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