基于TLR4-NFκB/NLRP3和Wnt/β-Catenin信号通路的crosstalk调控“肠道菌群-肠-脑”轴探讨酸枣仁汤改善抑郁症的药效物质基础和作用机制

抑郁症是一种常见精神障碍，其发生与“肠道菌群-肠-脑”轴紊乱密切相关，而免疫炎症通路是其关键调控途径。研究发现外周TLR4-NFκB/NLRP3和Wnt/β-Catenin通路与炎症反应关系密切，但在抑郁等精神疾病中交互作用机制未明。申请人前期研究表明酸枣仁汤抗抑郁作用以及对炎症因子的调节与上述通路有较大相关性。鉴此本课题提出假设：酸枣仁汤通过调节TLR4-NFκB/NLRP3和Wnt/β-Catenin通路crosstalk交联作用参与“肠道菌群-肠-脑”轴，进而改善抑郁行为。本项目拟建立化学物质组学，以活性追踪为导向解析机体代谢网络；从分子水平探究酸枣仁汤对炎症通路crosstalk，以及相关HPA轴和神经递质的调节机制；借助网络药理学等方法建立“成分-靶标-通路”整合研究，分析酸枣仁汤药效成分与通路各环节靶标变化相关性，揭示酸枣仁汤抗抑郁作用机制及药效物质基础，为临床运用提供依据。

Depression is a common emotional disorder. It is closely associated with microbiota-gut-brain axis. The immune-inflammatory signal pathway is a vital pathway to the regulation of microbiota-gut-brain axis. It has been discovered that TLR4-NFκB/NLRP3 and Wnt/β-Catenin immune-inflammatory signal pathway had the crosslinked action in the peripheral system, but the action mechanism was unclear in depression and other mental diseases. Our previous research has implied that the antidepressant effect of Suan-Zao-Ren decoction (SZRD) and the regulation of the inflammatory factors, which had relativity with above immune-inflammatory signal pathway. Therefore, we propose a scientific hypothesis: SZRD regulate the crosstalk action of TLR4-NFκB/NLRP3 and Wnt/β-Catenin signal pathway to participate microbiota-gut-brain axis pathway, and then improve the depression behavior. The project intends to establish the Chemonics association analysis strategy to analysis the global metabolic network in vitro and in vivo. On this basis, we explored the global regulation mechanism of immune functions, together with its associated HPA axis and neurotransmitter by the above two immune-inflammatory signal pathways which involved in the microbiota-gut-brain axis on the cellular level to speculate the molecule mechanism of SZRD. Thus, the crosslinked action mechanism of these two immune-inflammatory signal pathways could be verified. The associated components and the Components-Targets-Pathway integration study is established based on network pharmacology and other bioinformatic methods. Therefore, the correlations between the effective components of SZRD and changes in each target element of TLR4-NFκB/NLRP3 and Wnt/β-Catenin pathways. We hope the results of the study can reveal the therapeutic material basis and action mechanism of SZRD, and provide theoretical basis for the utilization of SZRD.