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Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation.
- Source :
-
Cell host & microbe [Cell Host Microbe] 2021 Mar 10; Vol. 29 (3), pp. 362-377.e11. Date of Electronic Publication: 2021 Jan 12. - Publication Year :
- 2021
-
Abstract
- Immunomodulatory drugs can inhibit bacterial growth, yet their mechanism of action, spectrum, and clinical relevance remain unknown. Methotrexate (MTX), a first-line rheumatoid arthritis (RA) treatment, inhibits mammalian dihydrofolate reductase (DHFR), but whether it directly impacts gut bacteria is unclear. We show that MTX broadly alters the human gut microbiota. Drug sensitivity varied across strains, but the mechanism of action against DHFR appears conserved between mammalian and bacterial cells. RA patient microbiotas were sensitive to MTX, and changes in gut bacterial taxa and gene family abundance were distinct between responders and non-responders. Transplantation of post-treatment samples into germ-free mice given an inflammatory trigger led to reduced immune activation relative to pre-treatment controls, enabling identification of MTX-modulated bacterial taxa associated with intestinal and splenic immune cells. Thus, conservation in cellular pathways across domains of life can result in broad off-target drug effects on the human gut microbiota with consequences for immune function.<br />Competing Interests: Declaration of interests P.J.T is on the scientific advisory board for Kaleido, Pendulum, Seres, and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. R.R.N., J.U.S., and P.J.T. are listed as inventors on a patent application (33167/55261P1) related to this work.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Arthritis, Rheumatoid immunology
Autoimmune Diseases
Bacteria classification
Bacteria genetics
Bacteria isolation & purification
Female
Gastrointestinal Microbiome immunology
Humans
Metabolomics
Mice
Mice, Inbred C57BL
Phylogeny
Purines metabolism
Pyrimidines metabolism
RNA, Ribosomal, 16S genetics
Tetrahydrofolate Dehydrogenase
Transcriptome
Bacteria metabolism
Gastrointestinal Microbiome drug effects
Gastrointestinal Tract immunology
Methotrexate metabolism
Methotrexate pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1934-6069
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell host & microbe
- Publication Type :
- Academic Journal
- Accession number :
- 33440172
- Full Text :
- https://doi.org/10.1016/j.chom.2020.12.008