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

Liam Chung, Erik Thiele Orberg, Abby L. Geis, June L. Chan, Kai Fu, Christina E. DeStefano Shields, Christine M. Dejea, Payam Fathi, Jie Chen, Benjamin B. Finard, Ada J. Tam, Florencia McAllister, Hongni Fan, Xinqun Wu, Sudipto Ganguly, Andriana Lebid, Paul Metz, Sara W. Van Meerbeke, David L. Huso, Elizabeth C. WickDrew M. Pardoll, Fengyi Wan, Shaoguang Wu, Cynthia L. Sears, Franck Housseau

Research output: Contribution to journalArticlepeer-review

Abstract

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 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. Chung et al. uncover a complex, microbe-driven carcinogenic mechanism whereby the Bacteroides fragilis toxin targets the colonic epithelium to trigger an IL-17 mucosal immune response that relays back to epithelial cells, inciting pro-tumoral myeloid cell infiltration, principally to the distal colon, corresponding to the region of tumorigenesis in ApcMin/− mice.

Original languageEnglish (US)
Pages (from-to)203-214.e5
JournalCell Host and Microbe
Volume23
Issue number2
DOIs
StatePublished - Feb 14 2018

Keywords

  • Nf-κB
  • STAT-3
  • colorectal cancer
  • inflammation
  • mucosal immunology
  • myeloid cells

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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