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 effe...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/149037 |
| _version_ | 1824454526742036480 |
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| author | Lachmandas, Ekta Eckold, Clare Böhme, Julia Koeken, Valerie A. C. M. Mardiana Marzuki 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 |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Lachmandas, Ekta Eckold, Clare Böhme, Julia Koeken, Valerie A. C. M. Mardiana Marzuki 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 | NTU |
| 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. |
| first_indexed | 2025-02-19T03:23:43Z |
| format | Journal Article |
| id | ntu-10356/149037 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:23:43Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1490372023-03-05T16:44:48Z Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects Lachmandas, Ekta Eckold, Clare Böhme, Julia Koeken, Valerie A. C. M. Mardiana Marzuki 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 Lee Kong Chian School of Medicine (LKCMedicine) Agency for Science, Technology and Research (A∗STAR) Science::Medicine Metformin Tuberculosis 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. Agency for Science, Technology and Research (A*STAR) Published version This 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.). 2021-05-11T05:37:59Z 2021-05-11T05:37:59Z 2019 Journal Article Lachmandas, 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. https://dx.doi.org/10.1093/infdis/jiz064 0022-1899 https://hdl.handle.net/10356/149037 10.1093/infdis/jiz064 30753544 2-s2.0-85066910114 1 220 139 150 en 15302FG151 Journal of Infectious Diseases application/pdf |
| spellingShingle | Science::Medicine Metformin Tuberculosis Lachmandas, Ekta Eckold, Clare Böhme, Julia Koeken, Valerie A. C. M. Mardiana Marzuki 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 | Science::Medicine Metformin Tuberculosis |
| url | https://hdl.handle.net/10356/149037 |
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