Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens
Name
Fox-2009-Gut microbes define.pdf
Size
4.94 MB
Format
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Checksum (MD5)
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Author(s)
Rogers, Arlin B.
Fry, Rebecca C.
Dedon, Peter C.
Tannenbaum, Steven Robert
Schauer, David B.
Essigmann, John M.
McFaline, Jose Luis
Williams, Michelle V.
Doernte, A. L.
Fiala, Jeannette Louise Allen
Date Issued
October 2009
Journal
Gut
Publisher
British Society of Gastroenterology
Citation
Fox, J G et al. “Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens.” Gut 59.01 (2010): 88-97. © 2010 BMJ Publishing Group Ltd & British Society of Gastroenterology
Version
Final published version
Abstract
Background and aims: Hepatocellular carcinoma (HCC) frequently results from synergism between chemical and infectious liver carcinogens. Worldwide, the highest incidence of HCC is in regions endemic for the foodborne contaminant aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection. Recently, gut microbes have been implicated in multisystemic diseases including obesity and diabetes. Here, the hypothesis that specific intestinal bacteria promote liver cancer was tested in chemical and viral transgenic mouse models.
Methods: Helicobacter-free C3H/HeN mice were inoculated with AFB1 and/or Helicobacter hepaticus. The incidence, multiplicity and surface area of liver tumours were quantitated at 40 weeks. Molecular pathways involved in tumourigenesis were analysed by microarray, quantitative real-time PCR, liquid chromatography/mass spectrometry, ELISA, western blot and immunohistochemistry. In a separate experiment, C57BL/6 FL-N/35 mice harbouring a full-length hepatitis C virus (HCV) transgene were crossed with C3H/HeN mice and cancer rates compared between offspring with and without H hepaticus.
Results: Intestinal colonisation by H hepaticus was sufficient to promote aflatoxin- and HCV transgene-induced HCC. Neither bacterial translocation to the liver nor induction of hepatitis was necessary. From its preferred niche in the intestinal mucus layer, H hepaticus activated nuclear factor-κB (NF-κB)-regulated networks associated with innate and T helper 1 (Th1)-type adaptive immunity both in the lower bowel and liver. Biomarkers indicative of tumour progression included hepatocyte turnover, Wnt/β-catenin activation and oxidative injury with decreased phagocytic clearance of damaged cells.
Conclusions: Enteric microbiota define HCC risk in mice exposed to carcinogenic chemicals or hepatitis virus transgenes. These results have implications for human liver cancer risk assessment and prevention.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
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DOI of Published Version
http://dx.doi.org/10.1136/gut.2009.183749
