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

Abstract

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 β-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 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.

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.

• Authors: Klara Klimesova, Miloslav Kverka, Zuzana Zakostelska, Tomas Hudcovic, Tomas Hrncir, Renata Stepankova, Pavel Rossmann, Jakub Ridl, Martin Kostovcik, Jakub Mrazek, Jan Kopecny, Koichi S Kobayashi, Helena Tlaskalova-Hogenova
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 19 Issue 6 Pg. 1266-77 (May 2013) ISSN: 1536-4844 [Electronic] England
• PMID: 23567778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Cytokines
• RNA, Messenger
• Receptors, Interleukin-1
• Toll-Like Receptors
• Dextran Sulfate
• Interleukin-1 Receptor-Associated Kinases
• Irak3 protein, mouse
• Azoxymethane

Topics

• Animals
• Azoxymethane (toxicity)
• Blotting, Western
• Carcinogens (toxicity)
• Colitis (chemically induced, complications)
• Colonic Neoplasms (etiology, metabolism, pathology)
• Cytokines (genetics, metabolism)
• Dextran Sulfate (toxicity)
• Female
• Flow Cytometry
• Gastrointestinal Tract (microbiology)
• Interleukin-1 Receptor-Associated Kinases (physiology)
• Male
• Metagenome
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Interleukin-1 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• T-Lymphocytes, Regulatory (immunology, metabolism, pathology)
• Toll-Like Receptors (genetics, metabolism)