TY - JOUR
T1 - Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation
AU - Nayak, Renuka R.
AU - Alexander, Margaret
AU - Deshpande, Ishani
AU - Stapleton-Gray, Kye
AU - Rimal, Bipin
AU - Patterson, Andrew D.
AU - Ubeda, Carles
AU - Scher, Jose U.
AU - Turnbaugh, Peter J.
N1 - Funding Information:
Special thanks to Lindsey Criswell, Kathy Lam, Mary Nakamura, and Katie Pollard for comments on the manuscript. We are indebted to Jessie Turnbaugh, Gregory Ostolaza, and the UCSF Gnotobiotics Core Facility (gnotobiotics.ucsf.edu) for technical assistance as well as the Institute for Human Genetics for help with RNA sequencing and the CZ Biohub for DNA sequencing. We thank Jordan E. Bisanz and Elizabeth N. Bess for their assistance with development of sequencing methods. We thank Dr. Philip B. Smith from the Metabolomics Core Facility at the Pennsylvania State University. This work was funded by the National Institutes of Health: R01HL122593, 1R21CA227232 (P.J.T.); 5T32AR007304-37, TR001871, 1K08AR073930 (R.R.N.); R03AR072182 (J.U.S.); S10OD021750 (A.D.P); and R01AR074500 P.J.T./J.U.S.). Additional support was provided by the Searle Scholars Program (SSP-2016-1352), MINECO (SAF2017-90083-R), and the Rheumatology Research Foundation (AWD00003947). P.J.T. was a Chan Zuckerberg Biohub investigator and a Nadia's Gift Foundation Innovator supported, in part, by the Damon Runyon Cancer Research Foundation (DRR-42-16). J.U.S. was further supported by the NYU Colton Center for Autoimmunity, the Riley Family Foundation, and the Snyder Family Foundation. This work was supported by the UCSF Breakthrough Program for Rheumatoid Arthritis-related Research (BPRAR; partially funded by the Sandler Foundation), MedImmune, and the Arthritis Foundation Center for Excellence. Conceptualization, R.R.N. and P.J.T.; Investigation, R.R.N. M.A. K.S.G, I.D. and B.R.; Data Analysis, R.R.N. M.A. B.R, and A.D.P.; Clinical Samples Acquisition and Sequencing, J.S. and C.U.; Writing, R.R.N. and P.J.T.; Funding Acquisition, R.R.N. and P.J.T. 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.
Funding Information:
Special thanks to Lindsey Criswell, Kathy Lam, Mary Nakamura, and Katie Pollard for comments on the manuscript. We are indebted to Jessie Turnbaugh, Gregory Ostolaza, and the UCSF Gnotobiotics Core Facility ( gnotobiotics.ucsf.edu ) for technical assistance as well as the Institute for Human Genetics for help with RNA sequencing and the CZ Biohub for DNA sequencing. We thank Jordan E. Bisanz and Elizabeth N. Bess for their assistance with development of sequencing methods. We thank Dr. Philip B. Smith from the Metabolomics Core Facility at the Pennsylvania State University . This work was funded by the National Institutes of Health : R01HL122593 , 1R21CA227232 (P.J.T.); 5T32AR007304-37 , TR001871 , 1K08AR073930 (R.R.N.); R03AR072182 (J.U.S.); S10OD021750 (A.D.P); and R01AR074500 P.J.T./J.U.S.). Additional support was provided by the Searle Scholars Program ( SSP-2016-1352 ), MINECO ( SAF2017-90083-R ), and the Rheumatology Research Foundation ( AWD00003947 ). P.J.T. was a Chan Zuckerberg Biohub investigator and a Nadia’s Gift Foundation Innovator supported, in part, by the Damon Runyon Cancer Research Foundation ( DRR-42-16 ). J.U.S. was further supported by the NYU Colton Center for Autoimmunity , the Riley Family Foundation , and the Snyder Family Foundation . This work was supported by the UCSF Breakthrough Program for Rheumatoid Arthritis-related Research (BPRAR; partially funded by the Sandler Foundation ), MedImmune , and the Arthritis Foundation Center for Excellence .
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/3/10
Y1 - 2021/3/10
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85100052024&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2020.12.008
DO - 10.1016/j.chom.2020.12.008
M3 - Article
C2 - 33440172
AN - SCOPUS:85100052024
SN - 1931-3128
VL - 29
SP - 362-377.e11
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -