肠道真菌及其代谢产物通过“肠-肝轴”调控MDSCs代谢和功能促进肝癌发生的作用机制

肠道微生物在哺乳动物中普遍存在且参与了肠道炎症反应。已有研究报道肠道细菌移位可通过释放内毒素参与了肝癌的恶性进程，然而尚不清楚肠道真菌是否参与肝癌的发生发展。我们前期实验发现肠道特异性敲除Dectin-3后肝脏肿瘤负荷加重，且Dectin-3 敲除鼠结肠中真菌清酒假丝酵母菌增多。进一步通过高通量检测发现敲除鼠门静脉血中代谢产物甲羟戊酸显著增多，且体外实验证实甲羟戊酸可以上调MDSCs的糖酵解通路。我们提出假说：Dectin-3/CARD9通路缺失导致肠道中清酒假丝酵母菌增多，其代谢产物甲羟戊酸经门静脉入肝，通过上调MDSCs的糖酵解通路促进MDSCs的免疫抑制功能，进而促进了肝癌的恶性进程。本课题拟通过体外细胞模型和活体动物模型分析肠道真菌通过“肠-肝轴”调控肝脏疾病的机制，明确真菌及其代谢产物介导的肠道局域免疫和肝脏免疫在肝癌发病中的作用，为临床探索肝癌诊治的新靶点提供理论依据。

Gut microbes are ubiquitous in mammals and are involved in intestinal inflammatory responses. Studies have reported that intestinal bacterial translocation can participate in the malignant process of liver cancer by releasing endotoxin, but it is unclear whether intestinal fungi participate in the occurrence and development of liver cancer. Our previous experiments found that liver tumor burden increased after intestinal-specific knockout of Dectin-3, and that the fungus Candida sake was increased in the colon of Dectin-3 knockout mice. Further high-throughput testing revealed that mevalonate was significantly increased in the portal vein blood of knockout mice, and in vitro experiments confirmed that mevalonate can up-regulate the glycolytic pathway of MDSCs. We therefore propose a hypothesis: the absence of the Dectin-3/CARD9 pathway leads to an increase in Candida sake in the intestinal tract, and its metabolite mevalonic acid enters the liver through the portal vein. It promotes the immunosuppressive function of MDSCs by upregulating the glycolytic pathway of MDSCs, and then The malignant process of liver cancer. This project intends to analyze the mechanism of intestinal fungi through "intestinal-liver axis" regulation of liver diseases through in vitro cell models and live animal models, and to clarify the role of fungal and its metabolites-mediated intestinal local immunity and liver immunity in the pathogenesis of liver cancer. Role, to provide theoretical basis for clinical exploration of new targets for diagnosis and treatment of liver cancer.