Li Hongrui, Liu Ping, Sun Tingfang, Li Yifan, Wu Jing, Huang Yu, Yang Jie, Yuan Minghao, Zhang Jianping, Yang Jian, Wong Ma-Li, Licinio Julio, Zheng Peng
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
Transl Psychiatry. 2025 Apr 1;15(1):115. doi: 10.1038/s41398-025-03326-2.
Gut microbiome is implicated in the onset and progression of major depressive disorder (MDD), but the dynamic alterations of depressive symptoms, gut microbiome, and fecal metabolome across different stages of stress exposure remain unclear. Here, we modified the chronic social defeat stress (CSDS) model to evaluate mice subjected to social defeat stress for 1, 4, 7, and 10 days. Behavioral tests, 16S rRNA, metagenomics, and fecal metabolomics were conducted to investigate the impact of stress exposure on behaviors, gut microbiota and fecal metabolites. We observed that depressive-like behaviors, such as anhedonia and social avoidance, worsened significantly as stress exposure increased. The microbial composition, function, and fecal metabolites exhibited distinct separations across the different social defeat stress groups. Mediation analysis identified key bacteria, such as Lachnospiraceae_UCG-001 and Bacteroidetes, and fecal metabolites like valeric acid and N-acetylaspartate. In our clinical depression cohort, we confirmed that fecal valeric acid levels, were significantly lower in depressive-like mice and MDD patients, correlating closely with stress exposure and anhedonia in mice. Further analysis of serum and brain metabolites in mice revealed sustained changes of N-acetylaspartate abundance in fecal, serum, and cortical samples following increasing stress exposure. Together, this study elucidated the characteristics of depressive-like behaviors, gut microbiome, and fecal metabolome across various social defeat stress exposure, and identified key bacteria and fecal metabolites potentially involved in modulating social defeat stress response and depressive-like behaviors, providing new insights into the pathogenesis and intervention of depression.
肠道微生物群与重度抑郁症（MDD）的发病和进展有关，但在应激暴露的不同阶段，抑郁症状、肠道微生物群和粪便代谢组的动态变化仍不清楚。在此，我们改进了慢性社会挫败应激（CSDS）模型，以评估遭受1、4、7和10天社会挫败应激的小鼠。进行行为测试、16S rRNA、宏基因组学和粪便代谢组学研究，以调查应激暴露对行为、肠道微生物群和粪便代谢物的影响。我们观察到，随着应激暴露增加，诸如快感缺失和社交回避等类似抑郁的行为显著恶化。不同社会挫败应激组的微生物组成、功能和粪便代谢物表现出明显的差异。中介分析确定了关键细菌，如毛螺菌科_UCG-001和拟杆菌门，以及粪便代谢物，如戊酸和N-乙酰天门冬氨酸。在我们的临床抑郁症队列中，我们证实，类似抑郁的小鼠和MDD患者的粪便戊酸水平显著降低，与小鼠的应激暴露和快感缺失密切相关。对小鼠血清和脑代谢物的进一步分析显示，随着应激暴露增加，粪便、血清和皮质样本中N-乙酰天门冬氨酸丰度持续变化。总之，本研究阐明了不同社会挫败应激暴露下类似抑郁行为、肠道微生物群和粪便代谢组的特征，并确定了可能参与调节社会挫败应激反应和类似抑郁行为的关键细菌和粪便代谢物，为抑郁症的发病机制和干预提供了新的见解。
