Forsgård Richard A, Marrachelli Vannina G, Korpela Katri, Frias Rafael, Collado Maria Carmen, Korpela Riitta, Monleon Daniel, Spillmann Thomas, Österlund Pia
Pharmacology, Faculty of Medicine, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
Metabolomics and Molecular Imaging Lab, Health Research Institute INCLIVA, Valencia, Spain.
Cancer Chemother Pharmacol. 2017 Aug;80(2):317-332. doi: 10.1007/s00280-017-3364-z. Epub 2017 Jun 23.
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 (H-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(CH) 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.
化疗引起的胃肠道毒性（CIGT）是一个复杂的过程，涉及多种病理生理机制。我们之前已经表明，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黏膜并增加肠道对碘海醇的通透性。我们推测CIGT与粪便微生物群和代谢组的改变有关。我们的目的是表征这些变化，并研究它们与CIGT严重程度的关系。
总共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采集血液、尿液和粪便样本。用16S rRNA基因测序分析粪便微生物群组成的变化。用1毫米质子核磁共振（H-NMR）测量血清和尿液代谢组的代谢变化。
伊立替康增加了梭杆菌属和变形菌门的相对丰度，而5-氟尿嘧啶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了血清脂肪酸和N(CH)基团的水平，并降低了三羧酸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会引起多种微生物和代谢变化，这些变化可能在CIGT的病理生理过程中起作用。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被激活。
