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-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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Wu
authors.forename: Ki-Jong
authors.initials: KJ
authors.lastname: Rhee
authors.forename: Emilia
authors.initials: E
authors.lastname: Albesiano
authors.forename: Shervin
authors.initials: S
authors.lastname: Rabizadeh
authors.forename: Xinqun
authors.initials: X
authors.lastname: Wu
authors.forename: Hung-Rong
authors.initials: HR
authors.lastname: Yen
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Brancati
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wick
authors.forename: Florencia
authors.initials: F
authors.lastname: McAllister
authors.forename: Franck
authors.initials: F
authors.lastname: Housseau
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
mesh_terms: 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*
chemical_list: 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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