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

Liam Chung, Erik Thiele Orberg, Abby Geis, June L. Chan, Kai Fu, Christina E.De Stefano Shields, Christine M. Dejea, Payam Fathi, Jie Chen, Benjamin B. Finard, Ada J. Tam, Florencia M. McAllister, Hongni Fan, Xinqun Wu, Sudipto Ganguly, Andriana Lebid, Paul Metz, Sara W. Van Meerbeke, David L. Huso, Elizabeth C. Wick & 5 others Andrew Mark Pardoll, Fengyi Wan, Shaoguang Wu, Cynthia Louise Sears, Franck Housseau

Research output: Contribution to journalArticle

Abstract

Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc Min 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 Apc Min/- mice.

Original languageEnglish (US)
JournalCell Host and Microbe
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Colon
Epithelial Cells
Carcinogenesis
Bacteroides fragilis
Myeloid Cells
Interleukin-17
Chemokine CXCL1
CXC Chemokines
Mucosal Immunity
Colonic Neoplasms
Bacteroides fragilis toxin
Epithelium
Bacteria

Keywords

  • Colorectal cancer
  • Inflammation
  • Mucosal immunology
  • Myeloid cells
  • Nf-κB
  • STAT-3

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Cite this

Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells. / Chung, Liam; Orberg, Erik Thiele; Geis, Abby; Chan, June L.; Fu, Kai; Shields, Christina E.De Stefano; Dejea, Christine M.; Fathi, Payam; Chen, Jie; Finard, Benjamin B.; Tam, Ada J.; McAllister, Florencia M.; Fan, Hongni; Wu, Xinqun; Ganguly, Sudipto; Lebid, Andriana; Metz, Paul; Van Meerbeke, Sara W.; Huso, David L.; Wick, Elizabeth C.; Pardoll, Andrew Mark; Wan, Fengyi; Wu, Shaoguang; Sears, Cynthia Louise; Housseau, Franck.

In: Cell Host and Microbe, 01.01.2018.

Research output: Contribution to journalArticle

Chung, L, Orberg, ET, Geis, A, Chan, JL, Fu, K, Shields, CEDS, Dejea, CM, Fathi, P, Chen, J, Finard, BB, Tam, AJ, McAllister, FM, Fan, H, Wu, X, Ganguly, S, Lebid, A, Metz, P, Van Meerbeke, SW, Huso, DL, Wick, EC, Pardoll, AM, Wan, F, Wu, S, Sears, CL & Housseau, F 2018, 'Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells', Cell Host and Microbe. https://doi.org/10.1016/j.chom.2018.01.007
Chung, Liam ; Orberg, Erik Thiele ; Geis, Abby ; Chan, June L. ; Fu, Kai ; Shields, Christina E.De Stefano ; Dejea, Christine M. ; Fathi, Payam ; Chen, Jie ; Finard, Benjamin B. ; Tam, Ada J. ; McAllister, Florencia M. ; Fan, Hongni ; Wu, Xinqun ; Ganguly, Sudipto ; Lebid, Andriana ; Metz, Paul ; Van Meerbeke, Sara W. ; Huso, David L. ; Wick, Elizabeth C. ; Pardoll, Andrew Mark ; Wan, Fengyi ; Wu, Shaoguang ; Sears, Cynthia Louise ; Housseau, Franck. / Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells. In: Cell Host and Microbe. 2018.
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abstract = "Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc Min 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 Apc Min/- mice.",
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T1 - Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells

AU - Chung, Liam

AU - Orberg, Erik Thiele

AU - Geis, Abby

AU - Chan, June L.

AU - Fu, Kai

AU - Shields, Christina E.De Stefano

AU - Dejea, Christine M.

AU - Fathi, Payam

AU - Chen, Jie

AU - Finard, Benjamin B.

AU - Tam, Ada J.

AU - McAllister, Florencia M.

AU - Fan, Hongni

AU - Wu, Xinqun

AU - Ganguly, Sudipto

AU - Lebid, Andriana

AU - Metz, Paul

AU - Van Meerbeke, Sara W.

AU - Huso, David L.

AU - Wick, Elizabeth C.

AU - Pardoll, Andrew Mark

AU - Wan, Fengyi

AU - Wu, Shaoguang

AU - Sears, Cynthia Louise

AU - Housseau, Franck

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc Min 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 Apc Min/- mice.

AB - Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc Min 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 Apc Min/- mice.

KW - Colorectal cancer

KW - Inflammation

KW - Mucosal immunology

KW - Myeloid cells

KW - Nf-κB

KW - STAT-3

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