ArticleCell host & microbe2021
Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation.
Article in Cell host & microbe, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
99 citing papers in PubMed, 135 citations in OpenAlex.
- Gut microbiome modulates the outcome in primary central nervous system lymphoma patients undergoing chemotherapy: An ancillary study from the BLOCAGE trial.Neuro-oncology · 2025Trial
- Oral and Intestinal Bacterial Substances Associated with Disease Activities in Patients with Rheumatoid Arthritis: A Cross-Sectional Clinical Study.Journal of immunology research · 2022Trial
- Sustained Drug Treatment Alters the Gut Microbiota in Rheumatoid Arthritis.Frontiers in immunology · 2021Trial
- Exploring the gut microbiome and metabolomic interactions of antimetabolite drugs to optimize therapy.Gut microbes · 2026Review
- Eggerthella lenta: metabolism, pathogenesis and therapeutic implications.Nature reviews. Microbiology · 2026Review
- Drug-microbiome-host interactions: antimicrobial effects of non-antibiotic compounds.Nature reviews. Gastroenterology & hepatology · 2026Review
- Recent advances in methotrexate pharmacology and potential therapeutic uses in age-related cardiometabolic and neurodegenerative diseases.Pharmacological reviews · 2026Review
- Gut Microbial Functional Ecology and Microbiota-Derived Metabolites in Rheumatoid Arthritis Autoimmunity.Cells · 2026Review
- Gallic Acid Attenuates Ifosfamide-Induced Gut Microbiota Dysbiosis: A Full-Length 16S rRNA Amplicon Sequencing Study.Microorganisms · 2026Article
- Microbial predictors of sustained clinical remission following the Crohn's disease exclusion diet in adults and microbiome shifts toward healthy pediatric controls.Crohn's & colitis 360 · 2026Article
- Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis.Signal transduction and targeted therapy · 2026Article
- Intestinal microbiota and arthritis.EULAR rheumatology open · 2026Review
- Probiotics mitigate non-antibiotic drug-induced dysbiosis via protein homology-driven competitive binding.Nature communications · 2026Article
- A drug-microbiome-drug interaction impacts co-prescribed medications for Parkinson's disease.Nature microbiology · 2026Article
- Emerging mechanistic trends and clinical efficacy for methotrexate: Applications to inflammatory bowel disease.Pharmacological reviews · 2026Review
- The microbial metabolome: remodeling the therapeutic landscape in hematologic malignancies.NPJ biofilms and microbiomes · 2026Review
- Multi-cohort Analysis Reveals Microbiome Signatures Associated with Drug Response in New-Onset Rheumatoid Arthritis.bioRxiv : the preprint server for biology · 2026Article
- Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.bioRxiv : the preprint server for biology · 2026Article
- Short-chain fatty acids and their gut microbial pathways distinguish rheumatoid arthritis in discordant monozygotic twins.Annals of the rheumatic diseases · 2026Article
- Clinical Significance of Gut Microbiota Community Types for Long-Term Response to Fecal Microbiota Transplantation in Patients With Psoriatic Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2026Article
39 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.