The study investigates the role of intestinal inflammation in promoting cancer through its impact on the gut microbiota. In colitis-susceptible interleukin-10-deficient (Il10−/−) mice, inflammation alters the gut microbial composition, leading to the expansion of genotoxic bacteria. Specifically, monocolonization with the commensal Escherichia coli NC101 promotes invasive carcinoma in azoxymethane (AOM)-treated Il10−/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 reduces tumor multiplicity and invasion without altering intestinal inflammation. Mucosa-associated pks+ E. coli are found in a significant percentage of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients, suggesting that colitis can promote tumorigenesis by altering microbial composition and expanding genotoxic bacteria. The study highlights the complex interplay between inflammation, the gut microbiota, and cancer progression.The study investigates the role of intestinal inflammation in promoting cancer through its impact on the gut microbiota. In colitis-susceptible interleukin-10-deficient (Il10−/−) mice, inflammation alters the gut microbial composition, leading to the expansion of genotoxic bacteria. Specifically, monocolonization with the commensal Escherichia coli NC101 promotes invasive carcinoma in azoxymethane (AOM)-treated Il10−/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 reduces tumor multiplicity and invasion without altering intestinal inflammation. Mucosa-associated pks+ E. coli are found in a significant percentage of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients, suggesting that colitis can promote tumorigenesis by altering microbial composition and expanding genotoxic bacteria. The study highlights the complex interplay between inflammation, the gut microbiota, and cancer progression.