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) significantly 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 significantly changed gut bacteria in mice increasing alpha diversity (P < 0.05) and levels of Clostidiales spp. Feeding soy formula to piglets also resulted in significant 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 PPARα 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, PPARα activation and prevention of tumorigenesis.

中文翻译：

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肠道微生物群、原癌基因 PIKE (Agap2) 和细胞色素 P450 CYP2W1 在酒精性和非酒精性脂肪性肝病促进肝癌和膳食大豆蛋白保护中的潜在作用。

我们之前已经证明，在给雄性小鼠喂食高脂肪或乙醇 (EtOH) 的饮食后，二乙基亚硝胺 (DEN) 会引发肝脏肿瘤发生。这伴随着原癌基因 PIKE (Agap2) 的肝脏诱导。在这些模型中，将膳食蛋白质从酪蛋白转换为大豆分离蛋白 (SPI) 显着减少了肿瘤的形成。我们已将小鼠的 EtOH 消耗与微生物生态失调联系起来。过继转移研究表明，在没有乙醇的情况下，来自喂食乙醇的小鼠的微生物群可诱导肝脏脂肪变性，这表明微生物群或微生物代谢组在脂肪肝疾病的发展中起关键作用。喂食 SPI 显着改变了小鼠的肠道细菌，增加了 α 多样性 (P < 0.05) 和梭菌属的水平。给仔猪喂食大豆配方食品还导致微生物群、胆汁酸代谢物模式的显着变化，以及与脂肪变性和肝细胞增殖有关的肠-肝 FXR/FGF19-SHP 通路的抑制。此外，喂食 SPI 还导致肝 PPARα 信号传导的诱导和 PIKE mRNA 表达的抑制与抑制脂肪变性和癌症预防相一致。在 DEN 模型中使用不同膳食脂肪进行的喂养研究表明，相对于含有橄榄油或玉米油的饮食，饱和脂肪、可可脂对肿瘤的促进作用与微生物失调相关，包括毛螺菌科的显着增加，特别是来自 Coprococcus 的。免疫组织化学分析表明，来自 EtOH 喂养的小鼠和酒精相关 HCC 患者的肿瘤也表达高水平的新型细胞色素 P450 酶 CYP2W1。需要在敲除小鼠中进行额外的过继转移实验和研究，以确定大豆对微生物群的影响、PIKE、CYP2W1、PPARα 激活和预防肿瘤发生之间的确切关系。