丹栀逍遥散（DZXYS）是一种中药，在临床治疗抑郁症方面起着重要作用，但其在人体中的机制尚不清楚。为了研究其作为抑郁症辅助治疗药物的药理学效应和机制，我们进行了一项双盲安慰剂对照试验，试验对象为接受选择性5-羟色胺再摄取抑制剂（SSRIs）治疗的抑郁症患者。采集了血清和粪便样本，分别使用UHPLC-QTRAP-MS/MS和16S rRNA基因测序技术进行代谢组学和菌群分析。使用24项汉密尔顿抑郁量表评估抑郁症状。我们运用网络药理学、代谢组学和分子对接技术找出与DZXYS相关的潜在靶点。我们还检查了肠道微生物和代谢物之间的相关性，以了解DZXYS如何影响肠道菌群-肠道-脑轴。结果显示，DZXYS与SSRIs联合使用比单独使用SSRIs更有效地改善抑郁症。我们鉴定了与DZXYS治疗相关的39个差异代谢物，并发现了七个上调的代谢途径。活性成分槲皮素和芦丁与富集的途径“胰腺癌”和“磷脂酶D信号通路”中的靶点（AVPR2、EGFR、F2和CDK6）进行了对接，其中包括代谢物溶血磷脂酸[LPA（0：0/16：0）]。此外，我们还发现了32个与DZXYS治疗相关的肠道微生物菌种，其中拟杆菌属和蓟门类球菌与特定代谢物如L-2-氨基丁酸和LPA（0：0/16：0）呈负相关。我们的研究结果表明，DZXYS的抗抑郁机制涉及多个靶点、途径以及对LPA和肠道菌群-肠道-脑轴的调节。我们的系统药理学分析结果为理解DZXYS在抑郁症治疗中的潜在药理机制提供了重要见解。

Danzhi-xiaoyao-San (DZXYS), a Traditional Chinese Medicine, plays an essential role in the clinical treatment of depression, but its mechanisms in humans remain unclear. To investigate its pharmacological effects and mechanisms as an add-on therapy for depression, we conducted a double-blind, placebo-controlled trial with depressed patients receiving selective serotonin reuptake inhibitors (SSRIs). Serum and fecal samples were collected for metabolomic and microbiome analysis using UHPLC-QTRAP-MS/MS and 16S rRNA gene sequencing technologies, respectively. Depression symptoms were assessed using the 24-item Hamilton Depression Scale. We employed network pharmacology, metabolomics, and molecular docking to identify potential targets associated with DZXYS. We also examined the correlation between gut microbes and metabolites to understand how DZXYS affects the microbiota-gut-brain axis. The results showed that DZXYS combined with SSRIs was more effective than SSRIs alone in improving depression. We identified 39 differential metabolites associated with DZXYS treatment and found seven upregulated metabolic pathways. The active ingredients quercetin and luteolin were docked to targets (AVPR2, EGFR, F2, and CDK6) associated with the enriched pathways 'pancreatic cancer' and 'phospholipase D signaling pathway', which included the metabolite lysophosphatidic acid [LPA(0:0/16:0)]. Additionally, we identified 32 differential gut microbiota species related to DZXYS treatment, with Bacteroides coprophilus and Ruminococcus gnavus showing negative correlations with specific metabolites such as L-2-aminobutyric acid and LPA(0:0/16:0). Our findings indicate that DZXYS's antidepressant mechanisms involve multiple targets, pathways, and the regulation of LPA and the microbiota-gut-brain axis. These insights from our systems pharmacology analysis contribute to a better understanding of DZXYS's potential pharmacological mechanisms in depression treatment.Communicated by Ramaswamy H. Sarma.