Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice

• Published in: Inflammatory bowel diseases 2013-05, Vol.19 (6), p.1266-1277
• Main Authors: Klimesova, Klara, Kverka, Miloslav, Zakostelska, Zuzana, Hudcovic, Tomas, Hrncir, Tomas, Stepankova, Renata, Rossmann, Pavel, Ridl, Jakub, Kostovcik, Martin, Mrazek, Jakub, Kopecny, Jan, Kobayashi, Koichi S, Tlaskalova-Hogenova, Helena
• Format: Article
• Language: English
• Subjects: Animals; Azoxymethane - toxicity; Blotting, Western; Carcinogens - toxicity; Colitis - chemically induced; Colitis - complications; Colonic Neoplasms - etiology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Cytokines - genetics; Cytokines - metabolism; Dextran Sulfate - toxicity; Female; Flow Cytometry; Gastrointestinal Tract - microbiology; Interleukin-1 Receptor-Associated Kinases - physiology; Male; Metagenome; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptors, Interleukin-1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism
• ISSN: 1078-0998; 1536-4844
• 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.