A two-way interaction between methotrexate and the gut microbiota of male Sprague Dawley rats

Letertre, M.P.M., Munjoma, N., Wolfer, K., Pechlivanis, A., McDonald, J.A.K., Hardwick, R., Cherrington, N.J., Coen, M., Nicholson, J.K., Hoyles, L. ORCID: 0000-0002-6418-342X, Swann, J.R. and Wilson, I.D., 2020. A two-way interaction between methotrexate and the gut microbiota of male Sprague Dawley rats. Journal of Proteome Research. ISSN 1535-3893

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Abstract

Methotrexate (MTX) is a chemotherapeutic agent that can cause a range of toxic side effects including gastrointestinal damage, hepatotoxicity, myelosuppression, and nephrotoxicity and has potentially complex interactions with the gut microbiome. Following untargeted UPLC-qtof-MS analysis of urine and fecal samples from male Sprague–Dawley rats administered at either 0, 10, 40, or 100 mg/kg of MTX, dose-dependent changes in the endogenous metabolite profiles were detected. Semiquantitative targeted UPLC-MS detected MTX excreted in urine as well as MTX and two metabolites, 2,4-diamino-N-10-methylpteroic acid (DAMPA) and 7-hydroxy-MTX, in the feces. DAMPA is produced by the bacterial enzyme carboxypeptidase glutamate 2 (CPDG2) in the gut. Microbiota profiling (16S rRNA gene amplicon sequencing) of fecal samples showed an increase in the relative abundance of Firmicutes over the Bacteroidetes at low doses of MTX but the reverse at high doses. Firmicutes relative abundance was positively correlated with DAMPA excretion in feces at 48 h, which were both lower at 100 mg/kg compared to that seen at 40 mg/kg. Overall, chronic exposure to MTX appears to induce community and functionality changes in the intestinal microbiota, inducing downstream perturbations in CPDG2 activity, and thus may delay MTX detoxication to DAMPA. This reduction in metabolic clearance might be associated with increased gastrointestinal toxicity.

Item Type: Journal article
Publication Title: Journal of Proteome Research
Creators: Letertre, M.P.M., Munjoma, N., Wolfer, K., Pechlivanis, A., McDonald, J.A.K., Hardwick, R., Cherrington, N.J., Coen, M., Nicholson, J.K., Hoyles, L., Swann, J.R. and Wilson, I.D.
Publisher: American Chemical Society (ACS)
Date: 16 June 2020
ISSN: 1535-3893
Identifiers:
NumberType
10.1021/acs.jproteome.0c00230DOI
1334550Other
Rights: Copyright © 2020 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Divisions: Schools > School of Science and Technology
Record created by: Linda Sullivan
Date Added: 19 Jun 2020 15:30
Last Modified: 17 Jul 2020 14:59
URI: http://irep.ntu.ac.uk/id/eprint/40069

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