State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, 100050, China.
J Ethnopharmacol. 2023 Sep 15;313:116555. doi: 10.1016/j.jep.2023.116555. Epub 2023 Apr 25.
Traditional Chinese medicines (TCMs) are often prepared in oral dosage forms, making TCMs interact with gut microbiota after oral administration, which could affect the therapeutic effect of TCM. Xiaoyao Pills (XYPs) are a commonly used TCM in China to treat depression. The biological underpinnings, however, are still in its infancy due to its complex chemical composition.
The study aims to explore XYPs' underlying antidepressant mechanism from both in vivo and in vitro.
XYPs were composed of 8 herbs, including the root of Bupleurum chinense DC., the root of Angelica sinensis (Oliv.) Diels, the root of Paeonia lactiflora Pall., the sclerotia of Poria cocos (Schw.) Wolf, the rhizome of Glycyrrhiza uralensis Fisch., the leaves of Mentha haplocalyx Briq., the rhizome of Atractylis lancea var. chinensis (Bunge) Kitam., and the rhizome of Zingiber officinale Roscoe, in a ratio of 5:5:5:5:4:1:5:5. The chronic unpredictable mild stress (CUMS) rat models were established. After that, the sucrose preference test (SPT) was carried out to evaluate if the rats were depressed. After 28 days of treatment, the forced swimming test and SPT were carried out to evaluate the antidepressant efficacy of XYPs. The feces, brain and plasma were taken out for 16SrRNA gene sequencing analysis, untargeted metabolomics and gut microbiota transformation analysis.
The results revealed multiple pathways affected by XYPs. Among them, the hydrolysis of fatty acids amide in brain decreased most significant via XYPs treatment. Moreover, the XYPs' metabolites which mainly derived from gut microbiota (benzoic acid, liquiritigenin, glycyrrhetinic acid and saikogenin D) were found in plasma and brain of CUMS rats and could inhibit the levels of FAAH in brain, which contributed to XYPs' antidepressant effect.
The potential antidepressant mechanism of XYPs by untargeted metabolomics combined with gut microbiota-transformation analysis was revealed, which further support the theory of gut-brain axis and provide valuable evidence of the drug discovery.
中药（TCM）通常以口服剂型制备，口服后与肠道微生物群相互作用，这可能会影响 TCM 的治疗效果。逍遥丸（XYPs）是中国常用的治疗抑郁症的 TCM。然而，由于其复杂的化学成分，其生物学基础仍处于起步阶段。
本研究旨在从体内和体外两个方面探索 XYPs 的潜在抗抑郁机制。
XYPs 由 8 种草药组成，包括柴胡、当归、白芍、茯苓、甘草、薄荷、白术和生姜，比例为 5:5:5:5:4:1:5:5。建立慢性不可预测轻度应激（CUMS）大鼠模型。然后进行蔗糖偏好测试（SPT）以评估大鼠是否抑郁。治疗 28 天后，进行强迫游泳测试和 SPT 以评估 XYPs 的抗抑郁功效。取出粪便、大脑和血浆进行 16SrRNA 基因测序分析、非靶向代谢组学和肠道微生物转化分析。
结果揭示了多个受 XYPs 影响的途径。其中，通过 XYPs 治疗，大脑中脂肪酸酰胺的水解减少最为明显。此外，在 CUMS 大鼠的血浆和大脑中发现了主要来源于肠道微生物群的 XYPs 代谢物（苯甲酸、甘草素、甘草酸和 saikogenin D），它们可以抑制大脑中 FAAH 的水平，这有助于 XYPs 的抗抑郁作用。
通过非靶向代谢组学结合肠道微生物转化分析揭示了 XYPs 的潜在抗抑郁机制，进一步支持了肠道-大脑轴的理论，并为药物发现提供了有价值的证据。
