当前位置: X-MOL 学术J. Proteome Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague-Dawley Rats.
Journal of Proteome Research ( IF 4.4 ) Pub Date : 2020-06-16 , DOI: 10.1021/acs.jproteome.0c00230
Marine P M Letertre 1 , Nyasha Munjoma 2 , Kate Wolfer 1 , Alexandros Pechlivanis 1, 3, 4 , Julie A K McDonald 1 , Rhiannon N Hardwick 5 , Nathan J Cherrington 5 , Muireann Coen 1, 6 , Jeremy K Nicholson 7 , Lesley Hoyles 1, 8 , Jonathan R Swann 1 , Ian D Wilson 1
Affiliation  

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.

中文翻译:

甲氨蝶呤与雄性 Sprague-Dawley 大鼠肠道微生物群之间的双向相互作用。

甲氨蝶呤 (MTX) 是一种化疗药物,可引起一系列毒副作用,包括胃肠道损伤、肝毒性、骨髓抑制和肾毒性,并可能与肠道微生物组发生复杂的相互作用。在对以 0、10、40 或 100 mg/kg MTX 给药的雄性 Sprague-Dawley 大鼠的尿液和粪便样本进行非靶向 UPLC-qtof-MS 分析后,检测到内源性代谢物谱的剂量依赖性变化。半定量靶向 UPLC-MS 检测到尿液中排泄的 MTX 以及 MTX 和两种代谢物 2,4-二氨基-N-10-甲基蝶酸 (DAMPA) 和 7-羟基-MTX,在粪便中。DAMPA 由肠道中的细菌酶羧肽酶谷氨酸 2 (CPDG2) 产生。粪便样本的微生物群分析(16S rRNA 基因扩增子测序)显示,在低剂量 MTX 下,厚壁菌门相对于拟杆菌门的相对丰度增加,但在高剂量下则相反。厚壁菌的相对丰度与 48 小时粪便中 DAMPA 的排泄呈正相关,与 40 mg/kg 相比,在 100 mg/kg 时两者均较低。总体而言,长期接触 MTX 似乎会诱导肠道微生物群的群落和功能发生变化,从而导致 CPDG2 活性的下游扰动,因此可能会延迟 MTX 对 DAMPA 的解毒。这种代谢清除率的降低可能与胃肠道毒性增加有关。
更新日期:2020-08-08
down
wechat
bug