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Methotrexate-Induced Shifts in the Human Gut Microbiome Decrease Immune Activation

63 Pages Posted: 30 Apr 2020 Sneak Peek Status: Under Review

See all articles by Renuka R. Nayak

Renuka R. Nayak

University of California, San Francisco (UCSF)

Margaret Alexander

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

Ishani Deshpande

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

Kye Stapleton-Grey

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

Carles Ubeda

CIBER de Epidemiología y Salud Pública (CIBERESP)

Jose U. Scher

New York University (NYU)

Peter Turnbaugh

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology; Stanford University - Chan Zuckerberg Biohub

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Abstract

Emerging evidence suggests that the use of non-antibiotic drugs can alter the human gut microbiota with unknown consequences for treatment outcomes. Here, we use a combination of in vitro, in vivo, and ex vivo methods to demonstrate that the first-line therapy for rheumatoid arthritis (RA), methotrexate (MTX), has off-target effects on the human gut microbiota, resulting in decreases in Bacteroidetes, which tend to be more sensitive. Longitudinal analyses of the gut microbiotas of RA patients revealed that MTX-induced shifts in bacterial relative abundance are associated with improved drug response and transplant experiments in gnotobiotic mice show that these shifts lead to reduced inflammation. Specific MTX-modulated taxa are associated with immune activation. Together, these results suggest that the mechanism-of-action of non-antibiotic drugs may be due in part to off-target effects on the gut microbiota, while providing a critical first step towards explaining long-standing differences in drug response between patients.

Keywords: rheumatoid arthritis, human gut microbiome, off-target effects, immune activation, methotrexate

Suggested Citation

Nayak, Renuka R. and Alexander, Margaret and Deshpande, Ishani and Stapleton-Grey, Kye and Ubeda, Carles and Scher, Jose U. and Turnbaugh, Peter, Methotrexate-Induced Shifts in the Human Gut Microbiome Decrease Immune Activation. CELL-D-20-01066. Available at SSRN: https://ssrn.com/abstract=3578147 or http://dx.doi.org/10.2139/ssrn.3578147
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Renuka R. Nayak

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Margaret Alexander

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

San Francisco, CA 94143
United States

Ishani Deshpande

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

San Francisco, CA 94143
United States

Kye Stapleton-Grey

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

San Francisco, CA 94143
United States

Carles Ubeda

CIBER de Epidemiología y Salud Pública (CIBERESP)

Monforte de Lemos 5
Madrid
Spain

Jose U. Scher

New York University (NYU)

Bobst Library, E-resource Acquisitions
20 Cooper Square 3rd Floor
New York, NY 10003-711
United States

Peter Turnbaugh (Contact Author)

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology ( email )

San Francisco, CA 94143
United States

Stanford University - Chan Zuckerberg Biohub ( email )

499 Illinois Street
San Francisco, CA 94158
United States

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