Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects.
Cell Proliferation
/ drug effects
Down-Regulation
/ drug effects
Healthy Volunteers
Host-Pathogen Interactions
/ drug effects
Humans
Hypoglycemic Agents
/ pharmacology
Leukocytes, Mononuclear
/ drug effects
Metformin
/ pharmacology
Monocytes
/ drug effects
Mycobacterium tuberculosis
/ pathogenicity
Myeloid Cells
/ drug effects
Phagocytosis
/ drug effects
Reactive Oxygen Species
/ metabolism
Signal Transduction
/ drug effects
Tuberculosis
/ metabolism
Up-Regulation
/ drug effects
Metformin
antimycobacterial mechanisms
gene transcription
host-directed therapy
tuberculosis
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
05 06 2019
05 06 2019
Historique:
received:
25
09
2018
accepted:
07
02
2019
pubmed:
13
2
2019
medline:
25
2
2020
entrez:
13
2
2019
Statut:
ppublish
Résumé
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. We investigated in vitro and in vivo effects of metformin in humans. 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. Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis.
Sections du résumé
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.
Identifiants
pubmed: 30753544
pii: 5316196
doi: 10.1093/infdis/jiz064
pmc: PMC6548897
doi:
Substances chimiques
Hypoglycemic Agents
0
Reactive Oxygen Species
0
Metformin
9100L32L2N
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
139-150Subventions
Organisme : Medical Research Council
ID : MR/P017568/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.
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