Both incidence and death rate due to liver cancer have increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. b-Carotene-15, 15 0 -oxygenase (BCO1), and b-carotene-9 0 , 10 0 -oxygenase (BCO2) cleave lycopene to produce bioactive apo-lycopenoids. Although BCO1/BCO2 polymorphisms affect human and animal lycopene levels, whether dietary tomato consumption can inhibit high-fat diet (HFD)-promoted hepatocellular carcinoma (HCC) development and affect gut microbiota in the absence of BCO1/BCO2 is unclear. BCO1/BCO2 double knockout mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to an HFD (60% of energy as fat) with or without tomato powder (TP) feeding for 24 weeks. Results showed that TP feeding significantly decreased HCC development (67%, 83%, and 95% reduction in incidence, multiplicity, and tumor volume, respectively, P < 0.05). Protective effects of TP feeding were associated with (1) decreased hepatic inflammatory foci development and mRNA expression of proinflammatory biomarkers (IL1b, IL6, IL12a, monocyte chemoattractant protein-1, and inducible NO synthase); (2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD þ production; and (3) increased hepatic circadian clock genes (circadian locomotor output cycles kaput, period 2, and cryptochrome-2, Wee1). Furthermore, TP feeding increased gut microbial richness and diversity, and significantly decreased the relative abundance of the genus Clostridium and Mucispirillum, respectively. The present study demonstrates that dietary tomato feeding independent of carotenoid cleavage enzymes prevents HFD-induced inflammation with potential modulating gut microbiota and inhibits HFD-promoted HCC development. Cancer Prev Res; 11(12); 797-810. Ó2018 AACR. Effects of TP feeding on microbiota richness and distribution at phylum, genus, and species levels in DENþHFD-fed BCO1 À/À BCO2 À/À double KO mice. A, Observed OTUs, Chao1, and ACE, representing community richness. B, Shannon index, representing community evenness. C, Relative abundance of gram-positive bacteria or gram-negative bacteria. D, Relative abundance of major bacteria at phylum level. E and F, Relative abundance of major bacteria at genus, species levels. Ã Significantly different from the DENþHFD, P < 0.05. Xia et al. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): H. Xia, C. Liu, S. TakahashiAnalysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):
