Potential role of gut microbiota, the proto-oncogene PIKE (Agap2) and cytochrome P450 CYP2W1 in promotion of liver cancer by alcoholic and nonalcoholic fatty liver disease and protection by dietary soy protein

Authors: RONIS, MARTIN - Louisiana State University Medical Center; MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC); SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC); PULLIAM, CASEY - Louisiana State University Medical Center; PEDERSEN, KIM - Louisiana State University Medical Center; INGELMAN-SUNDBERG, MAGNUS - Karolinska Institute; FRISO, SIMONETTA - University Of Verona; SAMUELSONA, DERRICK - Louisiana State University Medical Center; DEL VALLE, LUIS - Louisiana State University Medical Center; TAYLOR, CHRIS - Louisiana State University Medical Center; WELSH, DAVID - Louisiana State University Medical Center

Submitted to: Chemico Biological Interactions
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/6/2020
Publication Date: 7/1/2020
Citation: Ronis, M.J., Mercer, K.E., Shankar, K., Pulliam, C., Pedersen, K., Ingelman-Sundberg, M., Friso, S., Samuelsona, D., Del Valle, L., Taylor, C., Welsh, D.A. 2020. Potential role of gut microbiota, the proto-oncogene PIKE (Agap2) and cytochrome P450 CYP2W1 in promotion of liver cancer by alcoholic and nonalcoholic fatty liver disease and protection by dietary soy protein. Chemico Biological Interactions. 325:109131. https://doi.org/10.1016/j.cbi.2020.109131.
DOI: https://doi.org/10.1016/j.cbi.2020.109131

Interpretive Summary: Liver tumorigenesis has been shown to be enhanced after feeding diets high in fat or alcohol to male mice. Interestingly, change of dietary protein from casein to soy protein isolate significantly reduced tumor formation. In this study, we demonstrate that alcohol consumption is linked to microbial dysbiosis and soy protein isolate significantly changes gut bacteria in mice. Similarly, feeding soy infant formula to piglets resulted in significant changes in microbiota, the pattern of bile acid metabolites and in inhibition of the intestinal-hepatic pathway which has been linked to both steatosis and hepatocyte proliferation. Feeding studies with differing dietary fats demonstrated tumor promotion specific to the saturated fat, cocoa butter relative to diets containing olive oil or corn oil associated with microbial dysbiosis. Additional adoptive transfer experiments and studies in mice with gene deletion are required to determine the exact relationship between soy diets, the microbiota, expression of specific pathways that may yield to the prevention of tumorigenesis.

Technical Abstract: We have previously demonstrated promotion of diethylnitrosamine (DEN) initiated liver tumorigenesis after feeding diets high in fat or ethanol (EtOH) to male mice. This was accompanied by hepatic induction of the proto-oncogene PIKE (Agap2). Switch of dietary protein from casein to soy protein isolate (SPI) signifcantly reduced tumor formation in these models. We have linked EtOH consumption in mice to microbial dysbiosis. Adoptive transfer studies demonstrate that microbiota from mice fed ethanol can induce hepatic steatosis in the absence of ethanol suggesting that microbiota or the microbial metabolome play key roles in development of fatty liver disease. Feeding SPI signifcantly changed gut bacteria in mice increasing alpha diversity (P < 0.05) and levels of Clostidiales spp. Feeding soy formula to piglets also resulted in signifcant changes in microbiota, the pattern of bile acid metabolites and in inhibition of the intestinal-hepatic FXR/FGF19-SHP pathway which has been linked to both steatosis and hepatocyte proliferation. Moreover, feeding SPI also resulted in induction of hepatic PPARa signaling and inhibition of PIKE mRNA expression coincident with inhibition of steatosis and cancer prevention. Feeding studies in the DEN model with differing dietary fats demonstrated tumor promotion specific to the saturated fat, cocoa butter relative to diets containing olive oil or corn oil associated with microbial dysbiosis including dramatic increases in Lachnospiraceae particularly from the genus Coprococcus. Immunohistochemical analysis demonstrated that tumors from EtOH-fed mice and patients with alcohol-associated HCC also expressed high levels of a novel cytochrome P450 enzyme CYP2W1. Additional adoptive transfer experiments and studies in knockout mice are required to determine the exact relationship between soy effects on the microbiota, expression of PIKE, CYP2W1, PPARa activation and prevention of tumorigenesis.