Colonic Methane Production Modifies Gastrointestinal Toxicity Associated With Adjuvant 5-Fluorouracil Chemotherapy for Colorectal Cancer

Goals: To investigate the association of colonic methane, formed by methanogenic achaea, and pH with gastrointestinal symptoms during colorectal cancer chemotherapy. Background: Adjuvant 5-fluorouracil chemotherapy reduces recurrences in colorectal cancer, but causes severe gastrointestinal toxicity, partly related to disturbed intestinal microbiota. Study: Resected colorectal cancer patients (n=143) were analyzed for colonic methanogenesis and pH before and during the 24 weeks of 5-fluorouracil chemotherapy and for gastrointestinal symptoms during chemotherapy. This study was performed within the setting of an intervention study on the effects of Lactobacillus on chemotherapy-related gastrointestinal toxicity. The site of resected cancer, resection type, stoma, chemotherapy regimen, hypolactasia, and Lactobacillus intervention were considered as possible confounding factors, and multivariate models were constructed. Results: Baseline methane producers had less frequent diarrhea (more than or equal to moderate) during chemotherapy than nonproducers [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.20 to 0.88; P=0.022] and more frequent constipation (OR, 4.56; 95% CI, 2.01 to 10.32; P<0.001). Baseline fecal pH was also associated with symptoms during chemotherapy; higher the pH, the lower the risk of diarrhea (OR, 0.56; 95% CI, 0.31 to 1.02; P=0.058) and higher the risk of constipation (OR, 2.23; 95% CI, 1.35 to 3.68; P=0.002). In multivariate stepwise models, methanogenesis was a significant explaining factor with inverse association with diarrhea and positive association with constipation. Fecal pH, which was significantly associated with methane production, was no longer a significant explaining factor when methanogensis was included in the model. Conclusions: Methane producer status has a role in determining fluorouracil therapy. This underscores the importance of intestinal microbiota in the development of intestinal toxicity during 5-fluorouracil therapy.