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.
Bibliographical noteFunding Information:
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.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)