Tumorigenic Colonic Bacteria May Promote Early Neoplasia

In the colon a dense mucus layer separates the colonic epithelium from the gut microbiome. However, in patients with sporadic colorectal cancer, gut microbiome abnormalities can develop including the formation of biofilms in the normal mucus layer, which is linked to a pro-oncogenic state. This suggests that biofilm formation may promote colon cancer progression, but this has not yet been investigated in hereditary colon cancer. Dejea and colleagues studied the colonic mucosal bacteria in patients with familial adenomatous polyposis (FAP), a hereditary condition caused by germline APC mutations that results in benign precursor lesions that can progress to colorectal cancer. In patients with FAP, bacterial invasion through the mucus layer was observed, with patchy biofilms comprised primarily of E. coli and B. fragilis scattered along the entire length of the colon. Mucosal bacterial enrichment was also observed in a mouse model of FAP driven by mutant APC, indicating that Apc mutations may promote mucosal bacterial adherence. E. coli containing the polyketide synthase (pks) genotoxic island produce the colibactin (clbB) genotoxin, which induces DNA damage and colon tumorigenesis, and enterotoxigenic B. fragilis (termed ETBF) produce the B. fragilis toxin (bft), which is linked to sporadic colorectal cancer. Cultures of mucosal tissues from 25 patients with FAP revealed that 68% had pks⁺E. coli, compared with 22% of healthy controls, and 60% had ETBF, compared with 30% of healthy controls, and bft and clbB were present in the mucus layer of FAP biofilms in direct contact with the FAP epithelium. In two mouse models of FAP, cocolonization with pks⁺E. coli and ETBF accelerated colon tumorigenesis and reduced survival. Cocolonization was associated with an IL17-mediated increase in colon inflammation that was necessary, but not sufficient, for tumorigenesis. Further, cocolonization enhanced DNA damage in the colonic epithelium. Collectively, these findings indicate that tumorigenic bacteria in the colon may promote early tumorigenesis in patients with FAP.

Dejea CM, Fathi P, Craig JM, Boleji A, Taddese R, Geis AL, et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 2018;359:592–7.

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