4.7 Article

A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague-Dawley Rats

期刊

JOURNAL OF PROTEOME RESEARCH
卷 19, 期 8, 页码 3326-3339

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.0c00230

关键词

methotrexate; gastrointestinal toxicity; gut microbiome; metabolic phenotyping mass spectrometry; amplicon sequencing

资金

  1. Servier Technologies through the STRATiGRAD Program of Imperial College London
  2. Medical Research Council [MR/L01632X/1]
  3. National Institute for Health Research [MC_PC_12025]
  4. United States National Institutes of Health [AI083927, ES007091, ES006694]
  5. MRC [MR/P028225/1, MC_PC_12025, MR/L01632X/1] Funding Source: UKRI

向作者/读者索取更多资源

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.

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