Bacteroides Fragilis Toxin Coordinates a Pro-Carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells

Abstract

Pro-carcinogenic bacteria have the potential to initiate and/or promote human colon cancer. However, the mechanism(s) by which a bacterium may trigger carcinogenesis remains unclear. Herein, we show Bacteroides fragilis toxin (BFT) secretion by the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) triggers in Min Apc /- mice a ETBF pro- carcinogenic inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CEC). This signaling promotes the chemokine-dependent recruitment of pro-tumoral myeloid cells. Although necessary, Stat3 activation in CEC upon ETBF colonization is not sufficient to trigger 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 CXCR2-expressing polymorphonuclear immature myeloid cell recruitment with parallel onset of ETBF tumorigenesis in the distal colon, explaining the restricted localization of ETBF tumorigenesis. Inhibitors of pathway drivers linking specific microbial mediators to early colon tumorigenesis could disrupt a myeloid/epithelial pro-tumoral loop.