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The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli ( Apc ) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma—caused by either chromosomal (  C DX2 P  9.5-NLS  C re;Apc +/flox  , abbreviated to  CPC;Apc ) or microsatellite ( CDX2P9.5-G19Cre;Apc flox/flox  and CDX2P9.5-G22Cre;Apc flox/flox  ) instability, respectively—were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In  CPC;Apc  mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of  CDX2P9.5-G19Cre;Apc flox/flox  and CDX2P9.5-G22Cre;Apc flox/flox   mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the  Apc  gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes  Clostridium perfringens  and  C .  difficile , as well as species belonging to the  Atopobium  cluster, including  Enterobacteriaceae  and  Staphylococcus  sp., which was associated with colon tumorigenesis in  CPC;Apc  mice. These results suggest that differences in tumorigenesis among  CPC;Apc  mice consuming chlorinated versus tap water may be due to differences in gastrointestinal commensal populations.

Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice