Depression is associated with intestinal dysbiosis. Venlafaxine is a commonly used antidepressant in clinical practice as a serotonin and noradrenaline reuptake inhibitor. However, its effects on gut bacteria in depression remain unclear. Here, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and investigated the alterations of venlafaxine on the gut microbiota and potential key bacteria. Our data show that venlafaxine exerts antidepressant effects by restoring the serotonin (5-HT) system and glutamate (Glu) levels in CUMS mice. Moreover, we revealed that venlafaxine altered the diversity of gut bacteria in CUMS mice, and at genus level, Blautia, Oscillibacter, Tyzzerella, Butyricicoccus, and Enterorhabdus are the key bacteria responsible for venlafaxine-ameliorated depression in mice. Among these potential key bacteria, Blautia, Oscillibacter, and Butyricicoccus are correlated significantly with the 5-HT and 5-hydroxyindoleacetic acid levels; while Tyzzerella is correlated markedly with Glu levels. We further show that venlafaxine affected multiple functional metabolic pathways of gut bacteria in mice with CUMS-induced depression. Our results suggest that venlafaxine possibly ameliorates depression via modulating gut bacteria, and found the potential targets of its antidepressant effects.

抑郁症与肠道菌群失调有关。文拉法辛是临床实践中常用的抗抑郁药，作为血清素和去甲肾上腺素再摄取抑制剂。然而，它对抑郁症肠道细菌的影响仍不清楚。在这里，我们建立了慢性不可预测的轻度应激（CUMS）诱导的抑郁症小鼠模型，并研究了文拉法辛对肠道微生物群和潜在关键细菌的改变。我们的数据表明，文拉法辛通过恢复 CUMS 小鼠的血清素 (5-HT) 系统和谷氨酸 (Glu) 水平来发挥抗抑郁作用。此外，我们发现文拉法辛改变了 CUMS 小鼠肠道细菌的多样性，在属水平上，布氏菌属、颤杆菌属、泰泽氏菌属、丁酸球菌属和肠杆菌属是文拉法辛改善小鼠抑郁症的关键细菌。在这些潜在的关键细菌中， Blautia 、 Oscillibacter和Butyricicoccus与 5-HT 和 5-羟基吲哚乙酸水平显着相关；而Tyzzerella与 Glu 水平显着相关。我们进一步表明，文拉法辛影响 CUMS 诱导抑郁小鼠肠道细菌的多种功能代谢途径。我们的结果表明文拉法辛可能通过调节肠道细菌来改善抑郁症，并找到了其抗抑郁作用的潜在目标。