title: 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.affiliation: Department of Immunology and Gnotobiology, Institute of Microbiology, v.v.i., Academy of Sciences of the Czech Republic, Prague and Novy Hradek, Czech Republic. klimesov@biomed.cas.cz
authors.forename: Klara
authors.initials: K
authors.lastname: Klimesova
authors.forename: Miloslav
authors.initials: M
authors.lastname: Kverka
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zakostelska
authors.forename: Tomas
authors.initials: T
authors.lastname: Hudcovic
authors.forename: Tomas
authors.initials: T
authors.lastname: Hrncir
authors.forename: Renata
authors.initials: R
authors.lastname: Stepankova
authors.forename: Pavel
authors.initials: P
authors.lastname: Rossmann
authors.forename: Jakub
authors.initials: J
authors.lastname: Ridl
authors.forename: Martin
authors.initials: M
authors.lastname: Kostovcik
authors.forename: Jakub
authors.initials: J
authors.lastname: Mrazek
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecny
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
authors.forename: Helena
authors.initials: H
authors.lastname: Tlaskalova-Hogenova
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000382:microbiology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000502:physiology*; D008297:Male; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D016207:Cytokines; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D016264:Dextran Sulfate; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D001397:Azoxymethane