目的 整合脑组织代谢组学和肠道菌群测序分析研究酸枣仁汤（Suanzaoren Decoction，SZRD）抗抑郁的作用机制。方法 30只雄性SD大鼠随机分为对照组、模型组、文拉法辛（0.035 g/kg）组和SZRD低、高（12、24 g/kg）剂量组。除对照组外，其余各组大鼠均进行慢性不可预知温和应激（chronic unpredictable mild stress，CUMS）造模，同时ig相应药物，连续给药28 d。基于超高效液相色谱-串联质谱（ultra performance liquid chromatography-tandem mass spectrometry，UPLC-MS/MS）技术进行脑组织神经递质测定。基于超高效液相色谱-四极杆飞行时间质谱（ultra performance liquid chromatography-quadrupole time of flight mass spectrometry，UPLC-Q-TOF-MS）技术进行脑组织非靶向代谢组学研究，通过多元统计对代谢轮廓进行分析，以变量重要性投影值（variable importance in projection，VIP）＞1、P＜0.05筛选差异代谢物，并通过MetaboAnalyst进行通路分析。采用肠道菌群测序（16S ribosomal RNA，16S rRNA）技术对肠道菌群进行结构表征，并用气相色谱-质谱联用技术（gas chromatography-mass spectrometry，GC-MS）对短链脂肪酸含量进行测定。将差异菌群的相对丰度，短链脂肪酸含量和差异代谢物的相对含量与行为学结果进行Spearman分析。结果 SZRD可显著升高脑中的5-羟色胺（5-hydroxytryptamine，5-HT）和谷氨酸（glutamic acid，Glu）的含量（P＜0.01）。脑代谢组学结果显示，与对照组比较，模型组中共鉴定到43个差异代谢物，其中8个脂肪酸和3个氨基酸相对含量显著降低（P＜0.05），4个磷脂酰胆碱，4个磷脂酰乙醇胺和1个鞘脂相对含量显著升高（P＜0.05）；与模型组比较，SZRD低、高（12、24 g/kg）剂量组分别能显著回调15、11个差异代谢物（P＜0.05），共同显著回调了10个差异代谢物（P＜0.05），且共同作用于苯丙氨酸、酪氨酸和色氨酸生物合成，丙氨酸、天冬氨酸和谷氨酸代谢和三羧酸循环（tricarboxylic acid cycle，TCA）3条代谢通路。同时，SZRD可显著升高乳酸杆菌和粪球菌的丰度（P＜0.05）并显著增加丙酸，乙酸和丁酸的含量（P＜0.05）。Spearman分析表明，乳酸杆菌等差异菌的丰度及乙酸、丁酸、丙酸的含量与抑郁行为密切相关，差异代谢物的相对丰度与抑郁行为也显著相关。结论 SZRD发挥抗抑郁作用机制可能与回调乳酸杆菌、粪球菌、乙酸、丙酸、丁酸及丙氨酸、天冬氨酸和谷氨酸代谢等通路有关。

Objective To investigate the anti-depression mechanism of Suanzaoren Decoction (酸枣仁汤, SZRD) by integrated brain metabolomics and gut microbiota sequencing analysis. Methods A total of 30 male SD rats were randomly divided into control group, model group, venlafaxine (0.035 g/kg) group, SZRD low- and high-dose groups (12, 24 g/kg). Except control group, chronic unpredictable mild stress (CUMS) modeling was performed and drugs were ig administered for 28 d. Determination of neurotransmitters in brain tissue based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was conducted. Non-targeted metabolomic study of brain tissue was conducted based on ultra performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS) technology, metabolic profile was analyzed by multivariate statistics, differential metabolites were screened by variable importance in projection (VIP) > 1 and P < 0.05, and pathway analysis was performed by MetaboAnalyst. The gut microbiota was characterized by 16S ribosomal RNA (16S rRNA) and the content of short-chain fatty acids was determined by gas chromatography-mass spectrometry (GC-MS). The relative abundance, short-chain fatty acid content, and metabolite content of different bacteria were compared with behavioral results by Spearman analysis. Results SZRD could significantly increase the content of 5-hydroxytryptamine (5-HT) and glutamic acid (Glu) in brain (P < 0.01). Brain metabolomics results showed that compared with control group, a total of 43 differential metabolites were identified in model group, specifically, the relative contents of eight fatty acids and three amino acids were significantly reduced (P < 0.05), and the relative contents of four phosphatidylcholine, four phosphatidylethanolamine and one sphinspolipid were significantly increased (P < 0.05). SZRD low- and high-dose groups could significantly reduce 15 and 11 differential metabolites (P < 0.05), respectively. All of them significantly reversed ten different metabolites (P < 0.05), and together acted on three pathways of phenylalanine, tyrosine and tryptophan biosynthesis, alanine, aspartate and glutamate metabolism and tricarboxylic acid cycle (TCA). At the same time, SZRD could significantly increase the abundance of lactobacillus and faecalis (P < 0.05) and significantly increase the contents of propionic acid, acetic acid and butyric acid (P < 0.05). Spearman analysis showed that the abundance of Lactobacillus and other differential bacteria and the contents of acetic acid, butyric acid and propionic acid were closely correlated with depressive behavior, and the relative abundance of differential metabolites was also significantly correlated with depressive behavior. Conclusion SZRD can exert antidepressant effect. The mechanism of the antidepressant effect may be related to the regulation of lactobacillus, fecal bacteria, acetic acid, propionic acid, butyric acid, alanine, aspartate and glutamate metabolism pathway.

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山西省科学技术厅-地产中药功效物质研究与利用山西省重点实验室项目（201605D111004）;山西省科学技术厅山西省科技创新人才团队项目（202304051001020）;山西省科技成果转化引导专项计划项目（202204021301063）;山西省科学技术厅中央引导地方科技发展资金项目（YDZJSX2021C025）;山西中医药大学科技创新团队项目（2022TD2009）;山西中医药大学2024年科技创新能力培育计划项目（2024PY-JL-11-01，2024PY-JL-11-02）