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

Shaoguang Wu, Kijong 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

793 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

Fingerprint

Th17 Cells
Bacteroides fragilis
T-cells
Tumors
STAT3 Transcription Factor
Colon
Carcinogenesis
Chemical activation
T-Cell Antigen Receptor
Bacteria
Interleukin-17 Receptors
Colitis
Interleukin-23
Neoplasms
Cytokines
Antibodies
Interleukin-17
Transcriptional Activation
Hyperplasia
Diarrhea

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wu, Shaoguang ; Rhee, Kijong ; Albesiano, Emilia ; Rabizadeh, Shervin ; Wu, Xinqun ; Yen, Hung Rong ; Huso, David L. ; Brancati, Frederick L. ; Wick, Elizabeth ; McAllister, Florencia ; Housseau, Franck ; Pardoll, Drew M. ; Sears, Cynthia L. / A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. In: Nature Medicine. 2009 ; Vol. 15, No. 9. pp. 1016-1022.
@article{c205ab383b5948a3959a274f97598ad1,
title = "A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses",
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.",
author = "Shaoguang Wu and Kijong Rhee and Emilia Albesiano and Shervin Rabizadeh and Xinqun Wu and Yen, {Hung Rong} and Huso, {David L.} and Brancati, {Frederick L.} and Elizabeth Wick and Florencia McAllister and Franck Housseau and Pardoll, {Drew M.} and Sears, {Cynthia L.}",
year = "2009",
month = "9",
day = "1",
doi = "10.1038/nm.2015",
language = "English",
volume = "15",
pages = "1016--1022",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "9",

}

Wu, S, Rhee, K, Albesiano, E, Rabizadeh, S, Wu, X, Yen, HR, Huso, DL, Brancati, FL, Wick, E, McAllister, F, Housseau, F, Pardoll, DM & Sears, CL 2009, 'A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses', Nature Medicine, vol. 15, no. 9, pp. 1016-1022. https://doi.org/10.1038/nm.2015

A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. / Wu, Shaoguang; Rhee, Kijong; Albesiano, Emilia; Rabizadeh, Shervin; Wu, Xinqun; Yen, Hung Rong; Huso, David L.; Brancati, Frederick L.; Wick, Elizabeth; McAllister, Florencia; Housseau, Franck; Pardoll, Drew M.; Sears, Cynthia L.

In: Nature Medicine, Vol. 15, No. 9, 01.09.2009, p. 1016-1022.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses

AU - Wu, Shaoguang

AU - Rhee, Kijong

AU - Albesiano, Emilia

AU - Rabizadeh, Shervin

AU - Wu, Xinqun

AU - Yen, Hung Rong

AU - Huso, David L.

AU - Brancati, Frederick L.

AU - Wick, Elizabeth

AU - McAllister, Florencia

AU - Housseau, Franck

AU - Pardoll, Drew M.

AU - Sears, Cynthia L.

PY - 2009/9/1

Y1 - 2009/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=69949120571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69949120571&partnerID=8YFLogxK

U2 - 10.1038/nm.2015

DO - 10.1038/nm.2015

M3 - Article

C2 - 19701202

AN - SCOPUS:69949120571

VL - 15

SP - 1016

EP - 1022

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 9

ER -