Journal
INFLAMMATORY BOWEL DISEASES
Volume 19, Issue 6, Pages 1266-1277Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/MIB.0b013e318281330a
Keywords
cancer in IBD; mucosal immunity; colorectal cancer; microbiota; germ-free
Categories
Funding
- Czech Science Foundation [P304/11/1252, P303/08/0367, P303/12/0535]
- Academy of Sciences of the Czech Republic [M200201207]
- NIH [R01DK074738, R03TW006833]
- Institutional Research Concept [RVO: 61388971]
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Background: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.Methods: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 -glucuronidase activity was measured in intestinal content by fluorescence assay.Results: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 -glucuronidase activity. However, the -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 -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.Conclusions: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.
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