Journal article
A Two-Way interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats
Journal of Proteome Research, Vol.19(8), pp.3326-3339
2020
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.
Details
- Title
- A Two-Way interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats
- Authors/Creators
- M.P.M. Letertre (Author/Creator) - Imperial College LondonN. Munjoma (Author/Creator) - Waters (United States)K. Wolfer (Author/Creator) - Imperial College LondonA. Pechlivanis (Author/Creator)J.A.K. McDonald (Author/Creator) - Imperial College LondonR.N. Hardwick (Author/Creator) - University of ArizonaN.J. Cherrington (Author/Creator) - University of ArizonaM. Coen (Author/Creator) - Imperial College LondonJ.K. Nicholson (Author/Creator) - Murdoch UniversityL. Hoyles (Author/Creator) - Nottingham Trent UniversityJ.R. Swann (Author/Creator) - Imperial College LondonI.D. Wilson (Author/Creator) - Imperial College London
- Publication Details
- Journal of Proteome Research, Vol.19(8), pp.3326-3339
- Publisher
- American Chemical Society
- Identifiers
- 991005543245807891
- Copyright
- © 2020 American Chemical Society
- Murdoch Affiliation
- Health Futures Institute
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.231 Vitamin Metabolism
- 1.231.1535 Methotrexate
- Web Of Science research areas
- Biochemical Research Methods
- ESI research areas
- Biology & Biochemistry