Table_8_Antidepressants amitriptyline, fluoxetine, and traditional Chinese medicine Xiaoyaosan caused alterations in gut DNA virome composition and function in rats exposed chronic unpredictable mild stress.xlsx

BackgroundIn clinical practice, antidepressant drugs are widely used to treat depression. Previous studies have attention to the impact of antidepressants on the bacterial microbiome, while the role of these drugs in the gut virome is still unclear.
MethodsIn this study, we estimated the effects of antidepressant amitriptyline (Ami), fluoxetine (Flu), and traditional Chinese medicine Xiaoyaosan (XYS) administration on gut viral composition and function in a chronic unpredictable mild stress (CUMS)-induced depression rat model based on shotgun metagenomic sequencing.
ResultsThe results showed that treatment with Ami, Flu, and XYS significantly changed the gut viral composition compared with the CUMS-induced rats. At the family level, the abundance of f_unclassified_Caudovirales in CUMS rats was remarkably lower than in the HC rats, nevertheless, XYS significantly recovered the abundance of Caudovirales. Meanwhile, the abundance of Podoviridae was expanded in CUMS rats compared with the HC rats, and the profile was then significantly reduced after XYS treatment. Furthermore, both antidepressants and XYS increased the abundance of Siphoviridae compared with the CUMS rats, but only Ami treatments had significant differences. Subsequent function annotation further implied that Ami, Flu, and XYS showed to involve an alteration of the diverse viral functions, such as carbohydrate metabolism, xenobiotics biodegradation and metabolism, community-prokaryotes, translation, and neurodegenerative disease. Additionally, the co-occurrence network displayed that there are complex interactions between viral operational taxonomic units (vOTUs) represented by temperate phages and the majority of bacterial genera in the intestine ecosystem.
ConclusionOur study proved for the first time that depression is characterized by massive alterations and functional distortion of the gut viruses, and after oral administration of Ami, Flu, and XYS could affect disordered gut virome, which could be a novel target in depression.

背景
在临床实践中，抗抑郁药物被广泛用于抑郁症的治疗。既往研究多聚焦于抗抑郁药物对细菌微生物组的影响，而此类药物在肠道病毒组（gut virome）中的作用仍未阐明。
方法
本研究以慢性不可预见性温和应激（chronic unpredictable mild stress, CUMS）诱导的抑郁症大鼠模型为研究对象，基于鸟枪宏基因组测序（shotgun metagenomic sequencing）技术，评估了抗抑郁药物阿米替林（amitriptyline, Ami）、氟西汀（fluoxetine, Flu）以及中药逍遥散（Xiaoyaosan, XYS）干预对肠道病毒组成与功能的影响。
结果
研究结果表明，相较于CUMS造模大鼠，阿米替林、氟西汀及逍遥散干预均可显著重塑肠道病毒群落组成。在科分类水平上，CUMS造模大鼠体内未分类有尾噬菌体目科（f_unclassified_Caudovirales）的丰度显著低于健康对照（healthy control, HC）大鼠，而逍遥散干预可显著恢复有尾噬菌体目（Caudovirales）的丰度。与此同时，CUMS造模大鼠体内短尾噬菌体科（Podoviridae）的丰度相较于健康对照大鼠有所升高，经逍遥散干预后该类病毒的丰度则显著降低。此外，与CUMS造模大鼠相比，抗抑郁药物与逍遥散干预均提升了长尾噬菌体科（Siphoviridae）的丰度，但仅阿米替林干预组的提升效果具有统计学显著性。后续功能注释分析进一步揭示，阿米替林、氟西汀与逍遥散干预均可改变多种病毒相关功能，包括碳水化合物代谢、外源生物降解与代谢、原核生物群落、翻译过程以及神经退行性疾病相关功能。此外，共现关联网络分析显示，以温和噬菌体（temperate phages）为代表的病毒操作分类单元（viral operational taxonomic units, vOTUs）与肠道生态系统中的多数细菌属之间存在复杂的相互作用。
结论
本研究首次证实，抑郁症以肠道病毒的大规模改变与功能紊乱为特征，口服阿米替林、氟西汀与逍遥散可改善紊乱的肠道病毒组，这或许可成为抑郁症治疗的新型靶点。