Enterotoxigenic Bacteroides fragilis induces oncogenic regulatory T cells (TUM9P.1000)

Abstract

Abstract Enterotoxigenic Bacteroides fragilis (ETBF) is an occasional inducer of inflammatory diarrhea and acute colitis, and preliminary studies have recently demonstrated an association with inflammatory bowel disease and colorectal cancer in humans. The pathogenesis of ETBF can largely be attributed to the secretion of a toxin, BFT (B. fragilis toxin), which has a profound effect on the colonic microenvironment. BFT promotes cleavage of E-cadherin, activates NF-kB and Wnt/b-catenin signaling, and stimulates the secretion of pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-a. The inflammation associated with ETBF is characterized by robust IL-17 cytokine secretion, and in MinAPC/+ mice, ETBF induces IL-17-dependent distal colon tumorigenesis. In an attempt to elucidate the immunologic differences between the distal and proximal colon, we found ETBF induced a greater density of Foxp3+ Tregs in the distal colon. Furthermore, those Tregs initiate the oncogenic IL-17 response to ETBF. While investigating the Treg and IL-17 responses to ETBF, we found that depletion of Tregs in ETBF-colonized C57BL/6 Foxp3DTR-GFP MinAPC/+ mice mitigated intestinal IL-17 production as well as colonic neoplasia. Antibody blockade of IL-2, but not genetic ablation of IFN-γ, restored ETBF-induced microadenoma formation. These findings unveil a new mechanism of cancer-induced inflammation whereby an overt Treg response to intestinal bacteria promotes colon tumorigenesis.