Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice
Abstract 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 stres...
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Nature Publishing Group
2025-04-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03326-2 |
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| author | Hongrui Li Ping Liu Tingfang Sun Yifan Li Jing Wu Yu Huang Jie Yang Minghao Yuan Jianping Zhang Jian Yang Ma-Li Wong Julio Licinio Peng Zheng |
| author_facet | Hongrui Li Ping Liu Tingfang Sun Yifan Li Jing Wu Yu Huang Jie Yang Minghao Yuan Jianping Zhang Jian Yang Ma-Li Wong Julio Licinio Peng Zheng |
| author_sort | Hongrui Li |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-e9bd7e7d3e6c4db2b97acdef64b5b564 |
| institution | OA Journals |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-e9bd7e7d3e6c4db2b97acdef64b5b5642025-08-20T01:54:30ZengNature Publishing GroupTranslational Psychiatry2158-31882025-04-0115111210.1038/s41398-025-03326-2Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress miceHongrui Li0Ping Liu1Tingfang Sun2Yifan Li3Jing Wu4Yu Huang5Jie Yang6Minghao Yuan7Jianping Zhang8Jian Yang9Ma-Li Wong10Julio Licinio11Peng Zheng12Department of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityBeijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical UniversityDepartment of Psychiatry, College of Medicine, SUNY Upstate Medical UniversityDepartment of Psychiatry, College of Medicine, SUNY Upstate Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityAbstract 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.https://doi.org/10.1038/s41398-025-03326-2 |
| spellingShingle | Hongrui Li Ping Liu Tingfang Sun Yifan Li Jing Wu Yu Huang Jie Yang Minghao Yuan Jianping Zhang Jian Yang Ma-Li Wong Julio Licinio Peng Zheng Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice Translational Psychiatry |
| title | Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice |
| title_full | Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice |
| title_fullStr | Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice |
| title_full_unstemmed | Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice |
| title_short | Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice |
| title_sort | dynamic alterations of depressive like behaviors gut microbiome and fecal metabolome in social defeat stress mice |
| url | https://doi.org/10.1038/s41398-025-03326-2 |
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