Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice.
Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice.
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DOI：
10.1097/mib.0b013e318281330a
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发表时间：
2013-05
影响因子：
4.9
通讯作者：
Tlaskalova-Hogenova H
中科院分区：
文献类型：
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作者：
Klimesova K;Kverka M;Zakostelska Z;Hudcovic T;Hrncir T;Stepankova R;Rossmann P;Ridl J;Kostovcik M;Mrazek J;Kopecny J;Kobayashi KS;Tlaskalova-Hogenova H
toll样受体（Toll-like receptors， TLR）的微生物感知及其负调控在炎症相关癌症的发病机制中具有重要作用。在本研究中，我们在小鼠模型中研究了TLR信号和肠道微生物群的负调控在结肠炎相关癌症发展中的作用。偶氮甲烷和右旋糖酐硫酸钠诱导野生型和白细胞介素-1受体相关激酶- m （IRAK-M）缺陷小鼠结肠炎相关癌症。用多重细胞因子试验或ELISA分析局部细胞因子的产生，用流式细胞术分析调节性T细胞。用焦磷酸测序法分析肿瘤发生过程中微生物群组成的变化，用荧光法测定肠道内容物中β-葡萄糖醛酸酶活性。野生型小鼠的ATB治疗降低了肿瘤的发生率和严重程度。与未处理的小鼠相比，atb处理的小鼠结肠中调节性T细胞数量明显减少，肠道微生物群组成改变，β-葡萄糖醛酸酶活性降低。然而，β-葡萄糖醛酸酶活性并不像无菌小鼠那么低。IRAK-M缺陷小鼠不仅发展为侵袭性肿瘤，而且atb诱导的β-葡萄糖醛酸酶活性降低并不能使它们摆脱严重的致癌表型。此外，IRAK-M缺陷小鼠肿瘤组织中促炎细胞因子水平显著升高。我们得出结论，肠道微生物群通过增加肠道上皮对致癌物的暴露来促进肿瘤的发生，即使在微生物群改变的条件下，IRAK-M的负调控对结肠癌耐药性也是必不可少的。因此，肠道菌群及其代谢活性可能是结肠炎相关癌症治疗的潜在靶点。
Microbial sensing by Toll-like receptors (TLR) and its negative regulation have important role in the pathogenesis of inflammation-related cancer. In this study, we investigated the role of negative regulation of TLR signaling and gut microbiota in the development of colitis-associated cancer in mouse model. Colitis-associated cancer was induced by azoxymethane and dextran sodium sulfate in wild-type and in Interleukin-1 receptor associated kinase-M (IRAK-M) deficient mice with or without antibiotic (ATB) treatment. Local cytokine production was analyzed by multiplex cytokine assay or ELISA, and regulatory T cells were analyzed by flow cytometry. Changes in microbiota composition during tumorigenesis were analyzed by pyrosequencing, and β-glucuronidase activity was measured in intestinal content by fluorescence assay. ATB treatment of wild-type mice reduced the incidence and severity of tumors. As compared with non-treated mice, ATB-treated mice had significantly lower numbers of regulatory T cells in colon, altered gut microbiota composition, and decreased β-glucuronidase activity. However, the β-glucuronidase activity was not as low as in germ-free mice. IRAK-M deficient mice not only developed invasive tumors, but ATB-induced decrease in β-glucuronidase activity did not rescue them from severe carcinogenesis phenotype. Furthermore, IRAK-M deficient mice had significantly increased levels of pro-inflammatory cytokines in the tumor tissue. We conclude that gut microbiota promotes tumorigenesis by increasing the exposure of gut epithelium to carcinogens and that IRAK-M negative regulation is essential for colon cancer resistance even in conditions of altered microbiota. Therefore, gut microbiota and its metabolic activity could be potential targets for colitis-associated cancer therapy.