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

Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F
Cell Host Microbe. 2018 23 (2): 203-214.e5

PMID: 29398651 · PMCID: PMC5954996 · DOI:10.1016/j.chom.2018.01.007

Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-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 pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (26)

Adenomatous Polyposis Coli Protein Animals Bacterial Toxins Bacteroides fragilis Carcinogenesis Cell Line, Tumor Colon Colorectal Neoplasms Enzyme Activation Epithelial Cells Female Gene Deletion HT29 Cells Humans Inflammation Interleukin-17 Male Metalloendopeptidases Mice Mice, Inbred C57BL Mice, Knockout Myeloid Cells Receptors, Interleukin-8B Receptors, Interleukin-17 STAT3 Transcription Factor Transcription Factor RelA

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