Dietary tomato powder inhibits high fat diet-promoted hepatocellular carcinoma with alteration of gut microbiota in mice lacking carotenoid cleavage enzymes

Authors: XIA, HUI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LI, CHENG-CHUNG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FU, MAOBIN - Kagome Co, Ltd; TAKAHASHI, SHINGO - Kagome Co, Ltd; HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; AIZAWA, KOICHI - Kagome Co, Ltd; HIROYUKI, SUGANUMA - Kagome Co, Ltd; WU, GUOJUN - Rutgers University; ZHAO, LIPING - Rutgers University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2018
Publication Date: 11/16/2018
Citation: Xia, H., Liu, C., Li, C., Fu, M., Takahashi, S., Hu, K., Aizawa, K., Hiroyuki, S., Wu, G., Zhao, L., Wang, X. 2018. Dietary tomato powder inhibits high fat diet-promoted hepatocellular carcinoma with alteration of gut microbiota in mice lacking carotenoid cleavage enzymes. Cancer Prevention Research. https://doi.org/10.1158/1940-6207.CAPR-18-0188.
DOI: https://doi.org/10.1158/1940-6207.CAPR-18-0188

Interpretive Summary: Recently, both incidence and death rate of liver cancer have increased in the United States, which has paralleled the epidemic of nonalcoholic fatty liver disease and obesity. Discovering a diet rich in effective cancer-preventive agents is important. In this report, for the first time we demonstrated that dietary tomato powder rich in lycopene, as a whole food, can effectively inhibit high fat diet (HFD)-promoted hepatic inflammation and liver cancer (hepatocellular carcinoma) development. The mechanisms could be due to the inhibition of inflammatory responses by inducing an enzyme called sirtuin 1 deacetylase, and restored HFD-disrupted circadian rhythm (a daily cycle for sleeping and being awake) by tomato powder feeding. Additionally, tomato powder feeding increased microbial richness and diversity and caused a decrease in relative abundance of the genus Clostridium and Mucispirillum as compared with the HFD feeding alone group, indicating that the protective effects of tomato feeding may involve improving gut microbial richness and diversity. The results in this study could provide valuable insights into the mechanisms underlying the beneficial effect of tomato and tomato products against liver cancer development.

Technical Abstract: Both incidence and death rate due to liver cancer has increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. Beta-Carotene-15, 15'-oxygenase (BCO1) and beta-carotene-9', 10'-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 knock out mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to a 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%, 95% reduction in incidence, multiplicity, tumor volume, respectively, P < 0.05). Protective effects of TP feeding were associated with 1) decreased hepatic inflammatory foci development and mRNA expression of pro-inflammatory biomarkers (IL-1beta, IL-6, IL-12alpha, MCP1, and iNOS); 2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD+ 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.