Abstract
CPT-11 is a drug used as chemotherapy for colorectal cancer. CPT-11 causes toxic side-effects in patients. CPT-11 toxicity has been attributed to the activity of intestinal microbiota, however, intestinal microbiota may also have protective effects in CP!-11 chemotherapy. This study aimed to elucidate mechanisms through which microbiota and dietary fibres could modify host health. Rats bearing a Ward colon carcinoma were treated with a two-cycle CPT-11/5-fluorouracil therapy recapitulating clinical therapy of colorectal cancer. Animals were fed with a semi-purified diet or a semi-purified diet was supplemented with non-digestible carbohydrates (isomalto-oligosaccharides, resistant starch, fructo-oligosaccharides, or inulin) in 3 independent experiments. Changes in intestinal microbiota, bacteria translocating to mesenteric lymphnodes, cecal GUD activity, and cecal SCFA production, and the intestinal concentration of CPT-11 and its metabolites were analysed. Non-digestible carbohydrates significantly influenced feed intake, body weight and other indicators of animal health. The identification of translocating bacteria and their quantification in cecal microbiota indicated that overgrowth of the intestine by opportunistic pathogens was not a major contributor to CPT-11 toxicity. Remarkably, fecal GUD activity positively correlated to body weight and feed intake but negatively correlated to cecal SN-38 concentrations and IL1-β. The reduction in CPT-11 toxicity by non-digestible carbohydrates did not correlate to stimulation of specific bacterial taxa. However, cecal butyrate concentrations and feed intake were highly correlated. The protective role of intestinal butyrate production was substantiated by a positive correlation of the host expression of MCT1 (monocarboxylate transporter 1) with body weight as well as a positive correlation of the abundance of bacterial butyryl-CoA gene with cecal butyrate concentrations. These correlations support the interpretation that the influence of dietary fibre on CPT-11 toxicity is partially mediated by an increased cecal production of butyrate.
Highlights
CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin) is a drug commonly used as a first-line chemotherapy for colorectal cancer
All treatment groups displayed large intragroup variation indicating that factors other than the diet had a major influence on animal health
The six different fibres used in Exp 2 resulted in a range of outcomes in rats: animals fed on resistant starch (RS) and Synergy had a significantly lower weight loss and reduction in feed intake compared to those fed on starch and IMO [22]
Summary
CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin) is a drug commonly used as a first-line chemotherapy for colorectal cancer. Late onset diarrhea is one of the most common symptoms that limit the application and efficacy of CPT-11, and has been attributed to enzymatic activities of intestinal microbiota. Gastrointestinal symptoms were substantially reduced when antibiotics or inhibitors of bacterial glucuronidase were used in combination with CPT-11 [1,2]. Dietary fibres stimulate beneficial bacteria and to provide short chain fatty acids as an essential substrate for the colonic mucosa, and modulate activities of bacterial enzymes [4]. They may ameliorate or mitigate CPT-11 toxicity without causing pronounced side-effects
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