A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses

Shaoguang Wu, Ki Jong Rhee, Emilia Albesiano, Shervin Rabizadeh, Xinqun Wu, Hung Rong Yen, David L. Huso, Frederick L. Brancati, Elizabeth Wick, Florencia McAllister, Franck Housseau, Drew M. Pardoll, Cynthia L. Sears

Research output: Contribution to journalArticle

833 Citations (Scopus)

Abstract

The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (T H 17) response distributed between CD4+ T cell receptor-αΒ (TCRαΒ)+ and CD4-8-TCRγ+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying T H 17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and T H 17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.

Original languageEnglish
Pages (from-to)1016-1022
Number of pages7
JournalNature Medicine
Volume15
Issue number9
DOIs
Publication statusPublished - 2009 Sep 1

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wu, S., Rhee, K. J., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H. R., Huso, D. L., Brancati, F. L., Wick, E., McAllister, F., Housseau, F., Pardoll, D. M., & Sears, C. L. (2009). A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Medicine, 15(9), 1016-1022. https://doi.org/10.1038/nm.2015