A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses.
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-alphabeta (TCRalphabeta)+ and CD4-8-TCRgammadelta+ 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.
Wu
Shaoguang
S
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Rhee
Ki-Jong
KJ
Albesiano
Emilia
E
Rabizadeh
Shervin
S
Wu
Xinqun
X
Yen
Hung-Rong
HR
Huso
David L
DL
Brancati
Frederick L
FL
Wick
Elizabeth
E
McAllister
Florencia
F
Housseau
Franck
F
Pardoll
Drew M
DM
Sears
Cynthia L
CL
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D001442:Bacteroides Infections / Q000276:immunology / Q000473:pathology; D001441:Bacteroides fragilis / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity*; D003092:Colitis / Q000209:etiology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004768:Enterotoxins / Q000633:toxicity; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008213:Lymphocyte Activation; D008666:Metalloendopeptidases / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009500:Neutralization Tests; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D001427:Bacterial Toxins; D004768:Enterotoxins; D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C405031:Bacteroides fragilis toxin; D008666:Metalloendopeptidases
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