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

Nature Medicine volume 15, pages 1016–1022 (2009)Cite this article

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 (TH17) response distributed between CD4+ T cell receptor-αβ (TCRαβ)+ and CD4–8–TCRγδ+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying TH17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and TH17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.

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Figure 1: ETBF stimulates colonic inflammation and enhances colonic tumor formation in Min mice.
Figure 2: ETBF specifically activates Stat3 in the colons of Min mice.
Figure 3: ETBF, but not NTBF, induces IL-17–producing CD3+CD4+ T lymphocytes and γδ T lymphocytes in the colon lamina propria of Min and WT mice 1 week after NTBF or ETBF inoculation.
Figure 4: Blockade of IL-17 and IL-23R, but not IFN-γ, inhibits ETBF-induced colonic tumor formation in Min mice.
Figure 5: CD4+, but not γδ+, T cell depletion inhibits tumor formation in ETBF-colonized Min mice.

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Acknowledgements

This work was supported by the Crohn's and Colitis Foundation through a Senior Investigator Award (to C.L.S.) and a Research Fellowship Award (to K.-J.R.), RO1 DK45496 (to C.L.S.), RO1 DK080817 (to C.L.S.), US National Institutes of Health grants (to D.M.P.), Special Projects of Research Excellence grant CA62924, R24 DK64388 (to M. Donowitz, the principal investigator of this grant that provided resource support to this project), RR00171 grant (to D.L.H.), Institutional Training for Pediatricians 5 T32 HD44355 (to G. Dover, the principal investigator of this grant that provided partial salary support to S.R.), Clinical Pharmacology Training Program 2 T32GM066691 (to T. Shapiro, the principal investigator of this grant that provided salary support to F.M.) and F32 DK079509 (to S.R.). This work was also supported by gifts from B. Schwartz, W. and B. Topercer, D. Needle, B. Swartz and the Commonwealth Foundation. D.M.P. is a Januey scholar and holds the Abeloff Chair in Oncology at Johns Hopkins University. We thank J. Wolfe for her assistance with some experiments; L. Myers (formerly Montana State University) for ETBF strain 86-5443-2-2; B. Vogelstein and K. Kinzler (Johns Hopkins University School of Medicine) for Min mice and E. Jaffee (Johns Hopkins University School of Medicine) for GK1.5 antibody.

Author information

Author notes

  1. Ki-Jong Rhee

    Present address: Present addresses: Department of Medicine, University of Illinois, Chicago, Illinois, USA (K.-J.R.) and Cedars Sinai Medical Center, Los Angeles, California, USA (S.R.).,

  2. Shaoguang Wu, Ki-Jong Rhee and Shervin Rabizadeh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Shaoguang Wu, Ki-Jong Rhee, Xinqun Wu, Frederick L Brancati, Florencia McAllister, Drew M Pardoll & Cynthia L Sears

  2. Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Emilia Albesiano, Xinqun Wu, Hung-Rong Yen, Florencia McAllister, Franck Housseau, Drew M Pardoll & Cynthia L Sears

  3. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Shervin Rabizadeh

  4. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University and Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Hung-Rong Yen

  5. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    David L Huso

  6. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Elizabeth Wick

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Contributions

S.W. and K.-J.R. performed the majority of tumorigenesis experiments. E.A., S.R. and E.W. performed Stat experiments. X.W. did most of the mouse breeding and assisted with experiments. H.-R.Y. assisted with conditional CD4 Stat3-KO mouse experiments. D.L.H. evaluated and interpreted the histopathology. F.L.B. contributed the statistical analyses. F.M. performed qRT-PCR experiments. F.H. provided oversight and strategic planning for colonic immunology analyses. D.M.P. and C.L.S. designed the study, reviewed and discussed experiments and wrote the manuscript with input from co-authors.

Corresponding authors

Correspondence to Franck Housseau or Cynthia L Sears.

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Wu, S., Rhee, KJ., Albesiano, E. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15, 1016–1022 (2009). https://doi.org/10.1038/nm.2015

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