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

• Published in: Cell host & microbe Vol. 23; no. 2; pp. 203 - 214.e5
• Main Authors: Chung, Liam, Thiele Orberg, Erik, Geis, Abby L., Chan, June L., Fu, Kai, DeStefano Shields, Christina E., Dejea, Christine M., Fathi, Payam, Chen, Jie, Finard, Benjamin B., Tam, Ada J., McAllister, Florencia, Fan, Hongni, Wu, Xinqun, Ganguly, Sudipto, Lebid, Andriana, Metz, Paul, Van Meerbeke, Sara W., Huso, David L., Wick, Elizabeth C., Pardoll, Drew M., Wan, Fengyi, Wu, Shaoguang, Sears, Cynthia L., Housseau, Franck
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2018
• Subjects: 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 cancer; Colorectal Neoplasms - etiology; Colorectal Neoplasms - microbiology; Colorectal Neoplasms - pathology; Enzyme Activation - immunology; Epithelial Cells - immunology; Female; Gene Deletion; HT29 Cells; Humans; inflammation; Inflammation - immunology; Inflammation - microbiology; Interleukin-17 - genetics; Interleukin-17 - immunology; Male; Metalloendopeptidases - immunology; Metalloendopeptidases - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; mucosal immunology; myeloid cells; Myeloid Cells - immunology; Nf-κB; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - immunology; Receptors, Interleukin-8B - genetics; STAT-3; STAT3 Transcription Factor - metabolism; Transcription Factor RelA - metabolism; mucosal immunology; STAT-3; colorectal cancer; myeloid cells; inflammation; Nf-κB
• ISSN: 1931-3128; 1934-6069; 1934-6069
• 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 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. [Display omitted] •B. fragilis toxin-induced tumorigenesis requires epithelial IL17 and Stat3 signaling•IL17 targets colonic epithelial cells (CECs) to promote ETBF-mediated carcinogenesis•IL17-activated NF-κb signaling in CECs triggers C-X-C chemokine expression•NF-κB-induced chemokines direct pro-tumoral myeloid infiltration to distal colon 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.