Department of Immunology and Gnotobiology, Institute of Microbiology, v.v.i., Academy of Sciences of the Czech Republic, Prague and Novy Hradek, Czech Republic.
Inflamm Bowel Dis. 2013 May;19(6):1266-77. doi: 10.1097/MIB.0b013e318281330a.
Microbial sensing by Toll-like receptors (TLR) and its negative regulation have an important role in the pathogenesis of inflammation-related cancer. In this study, we investigated the role of negative regulation of Toll-like receptors 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 enzyme-linked immunosorbent assay, 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. Compared with nontreated 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 proinflammatory 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.
Toll 样受体（TLR）的微生物感应及其负调控在炎症相关癌症的发病机制中具有重要作用。在这项研究中，我们研究了 TLR 信号负调控和肠道微生物群在小鼠模型中炎症相关癌症发展中的作用。
在野生型和白细胞介素-1 受体相关激酶 M（IRAK-M）缺陷型小鼠中，通过氧化偶氮甲烷和葡聚糖硫酸钠诱导结肠炎相关癌症，并进行或不进行抗生素（ATB）治疗。通过多重细胞因子分析或酶联免疫吸附试验分析局部细胞因子产生，通过流式细胞术分析调节性 T 细胞。通过焦磷酸测序分析肿瘤发生过程中微生物群组成的变化，并通过荧光测定法测量肠道内容物中的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。与未治疗的小鼠相比，ATB 治疗的小鼠结肠中的调节性 T 细胞数量明显减少，肠道微生物群组成发生改变，β-葡萄糖醛酸酶活性降低。然而，β-葡萄糖醛酸酶活性并未像在无菌小鼠中那样低。IRAK-M 缺陷型小鼠不仅发生侵袭性肿瘤，而且 ATB 诱导的β-葡萄糖醛酸酶活性降低并不能使它们从严重的致癌表型中恢复。此外，IRAK-M 缺陷型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细胞暴露于致癌物质来促进肿瘤发生，而 IRAK-M 的负调控对于结肠癌的抵抗是至关重要的，即使在微生物群改变的情况下也是如此。因此，肠道微生物群及其代谢活性可能是炎症相关癌症治疗的潜在靶点。
