Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats.
Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats.
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DOI：
10.1007/s00280-017-3364-z
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发表时间：
2017-08
影响因子：
3
通讯作者：
Österlund P
中科院分区：
文献类型：
--
作者：
Forsgård RA;Marrachelli VG;Korpela K;Frias R;Collado MC;Korpela R;Monleon D;Spillmann T;Österlund P
化疗诱导的胃肠道毒性（CIGT）是一个涉及多种病理生理机制的复杂过程。我们之前已经证明常用的化疗药物5-氟尿嘧啶、奥沙利铂和伊立替康会损伤肠粘膜并增加肠对碘海醇的渗透性。我们假设CIGT与粪便微生物群和代谢组的改变有关。我们的目的是描述这些变化，并研究它们如何与CIGT的严重程度。共向48只雄性Sprague-Dawley大鼠腹腔注射5-氟尿嘧啶（150 mg/kg）、奥沙利铂（15 mg/kg）或伊立替康（200 mg/kg）。给药后每天测量体重变化，72小时后对动物实施安乐死。在基线和实验结束时收集血液、尿液和粪便样品。用16S rRNA基因测序分析粪便微生物群组成的变化。用1mm质子核磁共振（1H-NMR）测量血清和尿液代谢物组的代谢变化。伊立替康增加了梭菌和变形菌的相对丰度，而5-FU和奥沙利铂仅引起粪便微生物群组成的微小变化。所有化疗药物均增加血清脂肪酸和N（CH3）3部分的水平，降低克雷布斯循环代谢物和游离氨基酸的水平。化疗药物5-氟尿嘧啶、奥沙利铂和伊立替康可诱导几种微生物和代谢变化，这些变化可能在CIGT的病理生理学中发挥作用。观察到的肠道通透性、粪便微生物群和代谢组的变化表明炎症过程的激活。本文的在线版本（doi：10.1007/s00280 - 017 - 3364-z）包含补充材料，可供授权用户使用。
Chemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT. A total of 48 male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR). Irinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)3 moieties and decreased the levels of Krebs cycle metabolites and free amino acids. Chemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes. The online version of this article (doi:10.1007/s00280-017-3364-z) contains supplementary material, which is available to authorized users.
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影响因子：
5.4
作者：
Han YW
通讯作者：
Han YW
DOI：
10.1124/dmd.116.070615
发表时间：
2016-11
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Fennema D;Phillips IR;Shephard EA
通讯作者：
Shephard EA
影响因子：
4.9
作者：
Gupta, Nitin K.;Thaker, Ameet I.;Kanuri, Navya;Riehl, Terrence E.;Rowley, Christopher W.;Stenson, William F.;Ciorba, Matthew A.
通讯作者：
Ciorba, Matthew A.
影响因子：
8.8
作者：
Hardman, WE;Moyer, MP;Cameron, IL
通讯作者：
Cameron, IL
DOI：
10.1073/pnas.1215689109
发表时间：
2012-12-26
影响因子：
11.1
作者：
Craciun, Smaranda;Balskus, Emily P.
通讯作者：
Balskus, Emily P.