Dietary Tomato Powder Inhibits High-Fat Diet–Promoted Hepatocellular Carcinoma with Alteration of Gut Microbiota in Mice Lacking Carotenoid Cleavage Enzymes

Abstract

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):

Extraction and Analysis by HPLC-DAD of Carotenoids in Human Faeces from Spanish Adults

“…Intestinal microbiota plays a major role in the breakdown, absorption and metabolism of key dietary constituents contributing, for example, to the transformation of compounds to bioactive components [43] as is the case with the metabolization of 9-Z-β-carotene to its respective retinoic acid. It has also been shown that some foods, owing to their content in certain nutrients including carotenoids, are able to regulate intestinal microbiota and lower the risk of several chronic diseases [44][45][46].…”

Identification of Potential Key Genes for Pathogenesis and Prognosis in Prostate Cancer by Integrated Analysis of Gene Expression Profiles and the Cancer Genome Atlas

“…The enzyme β-carotene oxygenase 1 (BCO1) is a carotenoid lyase that was reported to be associated with a high consumption of tomato and tomato products rich in lycopene. BCO1 can cleave lycopene to produce carotenoids (39). However, there was also evidence that BCO1 is stably expressed in NB cells, and the expression of this gene inhibits the self-renewal and labeling of neuroblastoma CSC by regulating related miRNA (40).…”

Association between Dietary Tomato Intake and the Risk of Hepatocellular Carcinoma: The Singapore Chinese Health Study

“…Tomato intake may also decrease risk of HCC through increased gut microbial diversity, as NASH is related to gut dysbiosis and progression to HCC 28,29 . In β-carotene-15, 15'-oxygenase (BCO1) and β-carotene-9', 10'oxygenase (BCO2) knockout mice assigned to high-fat diet with or without tomato powder for 24 weeks, tomato powder significantly reduced the incidence of HCC by 67% along with decreased hepatic inflammatory foci 30 . Taken together, these experimental data suggested that tomato rather than lycopene offered protective effect against the promoting effect of alcohol and high-fat diet on chemical carcinogen induced carcinogenesis.…”