Paper

Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens

James G Fox¹, Yan Feng¹, Elizabeth J Theve¹, Rebecca C Fry², Jeannette L A Fiala¹, Amy L Doernte¹, Michelle Williams¹, Arkadiusz R Raczynski¹, Jose L McFaline¹, John M Essigmann¹, David B Schauer¹, Steven R Tannenbaum¹, Peter C Dedon¹, Steven A Weinman³, Stanley M Lemon³, Arlin B Rogers^2,*

¹ Massachusetts Institute of Technology, United States;
² University of North Carolina at Chapel Hill, United States;
³ University of Texas Medical Branch, Galveston, United States

Correspondence to: Arlin B Rogers, Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7431, Chapel Hill, NC, 27599-7431, United States; abr{at}med.unc.edu

Accepted 22 August 2009

Background & 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 food-borne contaminant aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection. Recently, gut microbes have been implicated in multisystemic diseases including obesity and diabetes. Here, we tested in chemical and viral-transgenic mouse models the hypothesis that specific intestinal bacteria promote liver cancer.

Methods: Helicobacter-free C3H/HeN mice were inoculated with AFB1 and/or Helicobacter hepaticus. Incidence, multiplicity and surface area of liver tumors were quantitated at 40 weeks. Molecular pathways involved in tumorigenesis were analyzed by microarray, qRT-PCR, LC/MS, ELISA, Western blot and immunohistochemistry. In a separate experiment, C57BL/6 FL-N/35 mice harboring 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 colonization 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-B (NF-B)-regulated networks associated with innate and Th1-type adaptive immunity both in the lower bowel and liver. Biomarkers indicative of tumor 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.

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