Department of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
PLoS One. 2012;7(7):e39764. doi: 10.1371/journal.pone.0039764. Epub 2012 Jul 26.
Intestinal microbiota mediate toxicity of irinotecan (CPT-11) cancer therapies and cause systemic infection after CPT-11-induced loss of barrier function. The intestinal microbiota and their functions are thus potential targets for treatment to mitigate CPT-11 toxicity. However, microbiota changes during CPT-11 therapy remain poorly described. This study analysed changes in intestinal microbiota induced by CPT-11 chemotherapy. Qualitative and quantitative taxonomic analyses, and functional analyses were combined to characterize intestinal microbiota during CPT-11-based chemotherapy, and in presence or absence of oral glutamine, a treatment known to reduce CPT-11 toxicity. In the first set of experiments tumour-bearing rats received a dose-intensive CPT-11 regimen (125 mg kg(-1)×3 days), with or without oral glutamine bolus (0.75 g kg(-1)). In a subsequent more clinically-oriented chemotherapy regimen, rats received two cycles of CPT-11 (50 mg kg(-1)) followed by 5-flurouracil (50 mg kg(-1)). The analysis of fecal samples over time demonstrated that tumours changed the composition of intestinal microbiota, increasing the abundance of clostrridial clusters I, XI, and Enterobacteriaceae. CPT-11 chemotherapy increased cecal Clostridium cluster XI and Enterobacteriaceae, particularly after the dose-intensive therapy. Glutamine treatment prevented the reduced abundance of major bacterial groups after CPT-11 administration; i.e. total bacteria, Clostridium cluster VI, and the Bacteroides-group. Virulence factor/toxin genes of pathogenic Escherichia coli and Clostridium difficile were not detected in the cecal microbiota. In conclusion, both colon cancer implantation and CPT-11-based chemotherapies disrupted the intestinal microbiota. Oral glutamine partially mitigated CPT-11 toxicity and induced temporary changes of the intestinal microbiota.
肠道微生物群介导伊立替康（CPT-11）癌症疗法的毒性，并在 CPT-11 诱导的屏障功能丧失后引起全身感染。因此，肠道微生物群及其功能是减轻 CPT-11 毒性的潜在治疗靶点。然而，CPT-11 治疗期间的微生物群变化仍描述不足。本研究分析了 CPT-11 化疗引起的肠道微生物群变化。定性和定量分类分析以及功能分析相结合，以描述 CPT-11 化疗期间以及存在或不存在口服谷氨酰胺时的肠道微生物群，口服谷氨酰胺是一种已知可降低 CPT-11 毒性的治疗方法。在第一组实验中，荷瘤大鼠接受了剂量密集型 CPT-11 方案（125 mg kg(-1)×3 天），同时或不给予口服谷氨酰胺冲击（0.75 g kg(-1)）。在随后更具临床导向的化疗方案中，大鼠接受了两个周期的 CPT-11（50 mg kg(-1)），随后是 5-氟尿嘧啶（50 mg kg(-1)）。随时间分析粪便样本表明，肿瘤改变了肠道微生物群的组成，增加了梭菌簇 I、XI 和肠杆菌科的丰度。CPT-11 化疗增加了盲肠中的 Clostridium cluster XI 和肠杆菌科，特别是在剂量密集型治疗后。谷氨酰胺治疗防止了 CPT-11 给药后主要细菌群丰度的降低，即总细菌、梭菌簇 VI 和拟杆菌群。盲肠微生物群中未检测到致病性大肠杆菌和艰难梭菌的毒力因子/毒素基因。总之，结直肠癌植入和 CPT-11 为基础的化疗均破坏了肠道微生物群。口服谷氨酰胺部分减轻了 CPT-11 的毒性，并诱导了肠道微生物群的暂时变化。
