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

Holma, Reetta PhD*; Korpela, Riitta PhD*; Sairanen, Ulla MSc; Blom, Mikko MSc; Rautio, Merja PhD§; Poussa, Tuija MSc; Saxelin, Maija PhD; Osterlund, Pia MD, PhD**

Journal of Clinical Gastroenterology: January 2013 - Volume 47 - Issue 1 - p 45–51
doi: 10.1097/MCG.0b013e3182680201
ALIMENTARY TRACT: Original Articles

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 whether patient experiences diarrhea or constipation during 5-fluorouracil therapy. This underscores the importance of intestinal microbiota in the development of intestinal toxicity during 5-fluorouracil therapy.

*Institute of Biomedicine, University of Helsinki

Department of Microbiology, National Public Health Institute

§Helsinki University Central Hospital Laboratory, Division of Clinical Microbiology, HUSLAB

**Department of Oncology, Helsinki University Central Hospital, HUS, Helsinki

Valio Research Centre, Helsinki, Finland

Orion Corporation, Orion Pharma, Kuopio

STAT-Consulting, Nokia, Finland

The sampling was funded in part by the Cancer Society of Finland, the Finnish Medical Association (Finska Läkaresällskapet), and Valio Research Centre.

During the last 2 years, P.O. has received research support, speaker fees (not exceeding €20,000) and/or served as an advisory board member for Roche, Amgen, MSD, Bayer, Eli-Lilly, and Sanofi-Aventis. R.H. and T.P. have received data analysis fees from Valio Research Centre. R.K., U.S., and M.S. are former employees of Valio Research Centre. U.S. is an employee of Orion Corporation. The remaining authors declare that they have nothing to disclose.

Reprints: Pia Osterlund, MD, PhD, Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HUS, Helsinki, Finland (e-mail:

Received February 6, 2012

Accepted July 3, 2012

© 2013 Lippincott Williams & Wilkins, Inc.