Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats

Abstract

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.

Figure 1. Experimental design of chemotherapy treatment of cancer-bearing rats.

The dose-intensive CPT-11 regimen is shown in panel A; the CPT-11/5-FU regimen is shown in panel B, Black arrows represent chemotherapy treatment at different time points. Grey and white arrows represent the time points at which cecal and fecal samples were taken, respectively (n = 6/time point). For glutamine-treated rats in dose-intensive regimen, glutamine bolus was administered 30 min before each CPT-11 dose.

Figure 2. DGGE profiles of the cecal microbiota of sham- and glutamine-treated rats at day 0, day 3 (6

h after the third DPT-11/glutamine administration), and day 7 in the dose-intensive regimen. Cluster analysis was performed by UPGMA algorithm based on the dice correlation coefficient.