茵陈蒿汤通过调控 AQPs 平衡肝癌胆汁酸代谢-肠道微生态对话失衡以稳定肝脏肿瘤微环境

Liver cancer is one of the malignant tumors with high incidence and mortality. The tumor microenvironment is the “soil” for its occurrence and development. How to effectively improve the microenvironment of liver cancer to reduce the mortality is an international problem. Aquaporins (AQPs) mediate bile acid metabolism, and bile acid metabolism disorders and intestinal microecological imbalances are involved in the microenvironment of liver cancer and they have interactions, combined with the lower expressions of AQP8 and AQP9 in rat liver cancer tissues than those in adjacent tissues and the effect of artemisia capillaris extracts promoting bile secretion in rats, we hypothesized: Yinchenhao decoction can improve microenvironment of liver tumor by regulating AQPs to balance bile acid metabolism-intestinal microecological dialogue in liver cancer. we plan to establish a mouse model of H22 liver cancer, and select AQP8 and AQP9 as therapeutic targets, to definite the relationship between AQPs expression and liver microenvironment, bile acid metabolism and intestinal flora spectrum, compare the compositional spectrum and dose-concentration relationship of Yinchenhao decoction in liver and intestinal tissues of healthy and model mice, and uncover the pharmacodynamics of Yinchenhao decoction regulating liver microenvironment- bile acid metabolism-intestinal microecological axis imbalance in the mice of liver cancer. Finally, it may help us to clarify the dose-concentration-effect of Yinchenhao decoction ameliorating the microenvironment of liver cancer, screen out the target of Yinchenhao decoction regulating the microenvironment of liver cancer, and provide experimental basis for clinical practice.

肝癌是发病率高、病死率高的恶性肿瘤，肿瘤微环境是其发生发展的“土壤”，如何有效改善肝癌微环境以降低其病死率是一个国际性难题。水通道蛋白（AQPs）介导胆汁酸代谢、胆汁酸代谢障碍和肠道微生态失衡参与调节肝癌微环境且相互影响的机理，结合大鼠肝癌组织中 AQP8、AQP9 特征性低表达于癌旁组织的进展和茵陈蒿提取物促进大鼠胆汁分泌的基础，假设：茵陈蒿汤通过调控 AQPs-平衡肝癌胆汁酸代谢-肠道微生态对话失衡以改善肝脏微环境。拟建立H22肝癌小鼠模型，AQP8、AQP9为调控靶点，明确AQPs表达与肝脏微环境、胆汁酸代谢异常、肠道菌群谱构成的关系；比较茵陈蒿汤在健康-模型小鼠的肝脏-肠道的成分谱及量效关系；明确茵陈蒿汤调控肝癌小鼠肝脏微环境-胆汁酸代谢-肠道微生态轴失衡的药效学。最终阐明茵陈蒿汤改善肝癌微环境的剂量-浓度-效应关系，筛选茵陈蒿汤调节肝癌肿瘤微环境的靶点，为临床提供实验依据。

肝癌是发病率高、病死率高的恶性肿瘤，肿瘤微环境是其发生发展的“土壤”，如何有效改善肝癌微环境以降低其病死率是一个国际性难题。水通道蛋白（AQPs）介导胆汁酸代谢、胆汁酸代谢障碍和肠道微生态失衡参与肝癌微环境且相互影响，结合大鼠肝癌组织中AQP8、AQP9特征性低表达于癌旁组织的进展和茵陈蒿提取物促进大鼠胆汁酸分泌的基础，我们提出了假设：茵陈蒿汤通过调控 AQPs -平衡肝癌胆汁酸代谢-肠道微生态对话失衡以改善肝脏微环境。我们成功建立了BABL/C小鼠肝癌原位移植瘤模型，选择肝脏高表达的AQP8、9为靶点，以肝脏微环境-胆汁酸代谢-肠道微生态为研究轴线，研究了AQPs表达与肝脏微环境、胆汁酸代谢及肠道菌群谱构成的关系，及茵陈蒿汤对该轴线的药效学。我们发现：茵陈蒿汤可能是通过调高肝癌小鼠肝脏中AQP8/9的蛋白表达，改变胆汁酸代谢谱，并减少厚壁菌门和norank_f__Lachnospiraceae的丰富度，增加拟杆菌门和norank_f__Muribaculaceae的丰富度，进而下调炎症因子表达以改善肝癌周围炎症微环境，减少肝细胞坏死，实现保护肝癌小鼠肝脏的目的；明确了茵陈蒿汤对肝癌小鼠胆汁酸代谢和肠道菌群的调控作用，且具有一定的剂量-效应关系，探索了中医药治疗肝癌可能的作用机制，并丰富了“肝胆相表里”中医理论的现代生物学认识。