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 Wick; Drew M Pardoll; Fengyi Wan; Shaoguang Wu; Cynthia L Sears; Franck Housseau

doi:10.1016/j.chom.2018.01.007

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

Cell Host Microbe. 2018 Feb 14;23(2):203-214.e5. doi: 10.1016/j.chom.2018.01.007. Epub 2018 Feb 1.

Authors

Liam Chung¹, Erik Thiele Orberg², Abby L Geis², June L Chan³, Kai Fu⁴, Christina E DeStefano Shields², Christine M Dejea⁵, Payam Fathi⁵, Jie Chen³, Benjamin B Finard⁶, Ada J Tam⁶, Florencia McAllister², Hongni Fan⁶, Xinqun Wu⁵, Sudipto Ganguly⁶, Andriana Lebid⁶, Paul Metz⁷, Sara W Van Meerbeke⁵, David L Huso⁸, Elizabeth C Wick⁹, Drew M Pardoll⁶, Fengyi Wan¹⁰, Shaoguang Wu⁵, Cynthia L Sears¹¹, Franck Housseau¹²

Affiliations

¹ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA; Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21287, USA.
² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
³ Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁶ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
⁷ Department of Pathology, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, Netherlands.
⁸ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁹ Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁰ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
¹¹ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: csears@jhmi.edu.
¹² Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: fhousse1@jhmi.edu.

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.

Keywords: Nf-κB; STAT-3; colorectal cancer; inflammation; mucosal immunology; myeloid cells.

MeSH terms

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

Substances

Adenomatous Polyposis Coli Protein
Bacterial Toxins
Il17a protein, mouse
Il17ra protein, mouse
Interleukin-17
Receptors, Interleukin-17
Receptors, Interleukin-8B
Rela protein, mouse
STAT3 Transcription Factor
Stat3 protein, mouse
Transcription Factor RelA
Bacteroides fragilis toxin
Metalloendopeptidases

Abstract

MeSH terms

Substances

Grants and funding