Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation
Por:
Nayak RR, Alexander M, Deshpande I, Stapleton-Gray K, Rimal B, Patterson AD, Ubeda C, Scher JU and Turnbaugh PJ
Publicada:
10 mar 2021
Ahead of Print:
1 mar 2021
Resumen:
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.
Filiaciones:
Nayak RR:
Rheumatology Division, Department of Medicine, University of California, San Francisco, CA 94143, USA
Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA
Alexander M:
Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA
Deshpande I:
Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA
Stapleton-Gray K:
Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA
Rimal B:
Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
Patterson AD:
Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
:
Centro Superior de Investigación en Salud Pública - FISABIO, Valencia, Spain
CIBER en Epidemiología y Salud Pública, Madrid, Spain
Scher JU:
Department of Medicine, New York University, New York, NY 10003, USA
Turnbaugh PJ:
Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA
Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:
Green Accepted, hybrid, Green Submitted
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