Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis. Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients’ colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.

Summary Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbial-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1 that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a procarcinogenic signaling relay from the CEC to a mucosal Th17 response that results in NFκB activation selectively in distal colon CECs, that collectively triggers myeloid cell-dependent distal colon tumorigenesis.

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Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are pro-carcinogenic are not fully understood. Tregs typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL-17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote ETBF. Depletion of Tregs in ETBF-colonized C57BL/6 Foxp3DTR mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL-17 to IFN-γ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL-17 inflammation and IFN-γ-independent. Treg enhancement of IL-17 production is cell-extrinsic. IL-2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL-2 in the local microenvironment, allowing Th17 development necessary to promote ETBF-triggered neoplasia and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis.