The gut–brain axis, which includes gut microbiota and microbiome-derived metabolites, might be implicated in depression. We reported the sustained prophylactic effects of a new antidepressant arketamine in chronic restrain stress (CRS) model of depression. In this study, we investigated the role of gut–brain axis on the prophylactic effects of arketamine in the CRS (7 days) model. Pretreatment with arketamine (10 mg/kg, 1 day prior to the CRS onset) significantly prevented CRS-induced body weight loss, increased immobility time of forced swimming test, decreased sucrose preference of sucrose preference test, and reduced expressions of synaptic proteins (GluA1 and PSD-95) in the prefrontal cortex (PFC) in the male mice. Gut microbiota analysis showed that pretreatment with arketamine might restore altered abundance of gut microbiota in CRS-exposed mice. An untargeted metabolomics analysis revealed four metabolites (e.g., L-leucine, -acetyl--glutamine, 2-(2,4-dichlorophenyl)-3-[4-(dimethylamino)phenyl]acrylonitrile, L-threonine amide) that were altered between control and CRS group; however, there were found to be altered between the saline + CRS group and the arketamine + CRS group. Network analysis demonstrated correlations among synaptic proteins in the PFC and certain microbiota, and blood metabolites. These findings suggest that gut–brain axis, including its metabolites, might partially contribute to the persistent prophylactic effects of arketamine in the CRS model.

中文翻译：

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肠-脑轴对慢性束缚应激雄性小鼠阿氯胺酮预防作用的作用

肠-脑轴，包括肠道微生物群和微生物组衍生的代谢物，可能与抑郁症有关。我们报告了一种新型抗抑郁药阿氯胺酮在抑郁症慢性束缚应激（CRS）模型中的持续预防作用。在这项研究中，我们在 CRS（7 天）模型中研究了肠-脑轴对阿氯酮胺预防作用的作用。用阿氯胺酮预处理（10 mg/kg，CRS 发病前 1 天）可显着预防 CRS 引起的体重减轻、强迫游泳测试的不动时间增加、蔗糖偏好测试的蔗糖偏好降低以及突触蛋白 (GluA1) 的表达减少和 PSD-95）在雄性小鼠的前额皮质（PFC）中。肠道微生物群分析表明，用阿酮胺预处理可能会恢复 CRS 暴露小鼠肠道微生物群丰度的改变。非靶向代谢组学分析显示四种代谢物（例如，L-亮氨酸、-乙酰基-谷氨酰胺、2-(2,4-二氯苯基)-3-[4-(二甲氨基)苯基]丙烯腈、L-苏氨酸酰胺）发生了改变对照组和 CRS 组之间；然而，发现盐水+CRS组和阿氯胺酮+CRS组之间存在改变。网络分析证明了 PFC 中的突触蛋白与某些微生物群和血液代谢物之间的相关性。这些发现表明，肠-脑轴，包括其代谢物，可能在一定程度上促进了阿氯胺酮在 CRS 模型中的持久预防作用。