Exploring the associations between gut microbiota and male depression: an integrated study of mendelian randomization and animal experiment

Physiol Behav. 2025 Aug 18:115070. doi: 10.1016/j.physbeh.2025.115070. Online ahead of print.

ABSTRACT

BACKGROUND: Depression is a major global health concern. Although multiple observational and Mendelian randomization (MR) studies have suggested an association between gut microbiota (GM) and depression, the causal relationship between specific GM taxa and male depression remains unclear.

METHODS: We conducted MR analysis to investigate the causal relationship between GM and male depression. The primary analysis employed the inverse variance weighted method, and additional MR and sensitivity analyses were performed to ensure the robustness of the results. To provide supportive evidence for the MR results, we evaluated changes in relevant microbial taxa using 16S rDNA sequencing in male rats subjected to chronic unpredictable mild stress. Taxa that showed significant differences in both the MR analysis and the animal model were selected for correlation analysis with depression-related behavioral indicators.

RESULTS: Through MR analysis, we identified potential positive causal relationships between Eubacterium oxidoreducens group, Anaerotruncus, Ruminiclostridium 9, and Streptococcus and male depression. Additional MR approaches and sensitivity analyses supported the robustness of these findings. Among the four taxa, only Ruminiclostridium 9 exhibited a significantly increased relative abundance in the depression model group compared to the control group. Correlation analysis further revealed that Ruminiclostridium 9 was negatively associated with sucrose preference test and total distance in the open field test, and positively associated with immobility time in the forced swim test.

CONCLUSION: Our study provides both genetic and biological evidence supporting Ruminiclostridium 9 as a potential risk factor for male depression, highlighting its potential as a therapeutic target and prognostic biomarker for evaluating treatment efficacy. These findings offer novel insights into the diagnosis and management of male depression.

PMID:40835215 | DOI:10.1016/j.physbeh.2025.115070