Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells

Abstract

<p id="P1">Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using <i>Apc ^Min </i> mice colonized with the human pathobiont enterotoxigenic <i>Bacteroides fragilis</i> (ETBF) as a model of microbial-induced colon tumorigenesis, we show that the <i>Bacteroides fragilis</i> 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. </p>