title: Colonic methane production modifies gastrointestinal toxicity associated with adjuvant 5-fluorouracil chemotherapy for colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Holma
authors.forename: Riitta
authors.initials: R
authors.lastname: Korpela
authors.forename: Ulla
authors.initials: U
authors.lastname: Sairanen
authors.forename: Mikko
authors.initials: M
authors.lastname: Blom
authors.forename: Merja
authors.initials: M
authors.lastname: Rautio
authors.forename: Tuija
authors.initials: T
authors.lastname: Poussa
authors.forename: Maija
authors.initials: M
authors.lastname: Saxelin
authors.forename: Pia
authors.initials: P
authors.lastname: Osterlund
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D001944:Breath Tests; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000532:radiotherapy / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003106:Colon / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000532:radiotherapy / Q000601:surgery; D003248:Constipation / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D005243:Feces / Q000737:chemistry; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D054892:Metagenome / Q000187:drug effects; D008697:Methane / Q000096:biosynthesis* / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011446:Prospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D008697:Methane; D005472:Fluorouracil