Wu Shaoguang, Rhee Ki-Jong, 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
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nat Med. 2009 Sep;15(9):1016-22. doi: 10.1038/nm.2015. Epub 2009 Aug 23.
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.
肠道菌群可能促进结肠癌的形成。在此，我们通过一种人类结肠细菌——产肠毒素脆弱拟杆菌（ETBF）来探索结肠癌发生的免疫机制。分泌脆弱拟杆菌毒素（BFT）的ETBF可导致人类炎症性腹泻，但也能在一部分人群中无症状地定植。我们的结果表明，虽然ETBF和无毒脆弱拟杆菌（NTBF）都能长期定植于小鼠体内，但只有ETBF会引发结肠炎，并在多发性肠道肿瘤（Min）小鼠中强烈诱导结肠肿瘤。ETBF诱导强大的、选择性的结肠信号转导及转录激活因子3（Stat3）激活，其结肠炎的特征是在CD4 + T细胞受体αβ（TCRαβ）+和CD4 - 8 - TCRγδ + T细胞之间分布有选择性的17型辅助性T细胞（Th17）反应。抗体介导的白细胞介素17（IL - 17）以及IL - 23受体（IL - 23是放大Th17反应 的关键细胞因子）的阻断，可抑制ETBF诱导的结肠炎、结肠增生和肿瘤形成。这些结果显示了一种由常见的人类共生细菌通过Stat3和Th17依赖途径引发炎症诱导癌症的机制，为人类结肠癌发生提供了新的机制性见解。
