Colitis-induced inflammation induces the expansion of bacteria that promote tumorigenesis.
Major finding: Colitis-induced inflammation induces the expansion of bacteria that promote tumorigenesis.
Concept: Abnormal expansion of genotoxic E. coli leads to increased DNA damage in colon epithelial cells.
Impact: Chronic inflammation creates a tumorigenic environment by affecting both the host and microbiota.
Chronic intestinal inflammation is a risk factor for colorectal cancer, but the underlying mechanism is unclear. Given previous evidence implicating the intestinal microbiota in the development of colitis-associated colorectal cancer in mice, Arthur and colleagues sequenced the bacterial 16S rRNA gene in mucosal biopsies and stool samples to compare the microbial composition of wild-type mice with that of colitis-susceptible interleukin-10 (Il10)-deficient mice that selectively develop colorectal cancer following carcinogen exposure. Microbial diversity was significantly reduced in Il10-deficient mice compared with wild-type controls but was not affected by treatment with the colon-specific carcinogen azoxymethane (AOM), suggesting that inflammation, not cancer, causes a shift in the composition of the intestinal microbiota. Specifically, the abundance of Escherichia coli was increased 100-fold in Il10-deficient mice. The fact that colonization of germ-free Il10-deficient mice with commensal E. coli, but not commensal Enterococcus faecalis, led to invasive mucinous adenocarcinoma in 80% of mice despite a similar host inflammatory response in both groups suggested a selective role of the microbiota on colorectal cancer development. Unlike E. faecalis, E. coli harbors a pathogenicity island that encodes genotoxic polyketide synthases (pks). Notably, pks was detected in 40% of patients with inflammatory bowel disease and 66.7% of patients with colorectal cancer, compared with only 20.8% of healthy controls, and was sufficient to induce DNA damage in a rat intestinal epithelial cell line. In vivo, the absence of pks did not affect E. coli-induced colitis or AOM-dependent tumor initiation in Il10-deficient mice but led to a significant reduction in tumor burden and invasive carcinomas that was associated with a significant decrease in DNA damage foci in colon epithelial cells. Collectively, these findings provide evidence that host inflammation and expansion of genotoxic bacteria create a favorable microenvironment for the development of colorectal cancer.
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