Dissecting Causal Relationships Between Gut Microbiota, Blood Metabolites, and Postpartum Depression : A Mendelian Randomization Study

Background: There is substantial evidence indicating a significant link between the gut microbiota (GM), blood metabolites and postpartum depression (PPD) . However, the causal relationships underlying these associations have yet to be established. Methods: This study elucidated the causal relationship among 196 GM taxa, 224 blood metabolites, and PPD from a genetic perspective, employing two-sample Mendelian randomization (MR) and mediation analyses. To validate the relevant findings, we further selected data (GM and blood metabolites) from the the IEU Open GWAS and GWAS Catalog for analysis. Our primary analysis utilized the inverse variance weighted method. To enhance the robustness of our results, we also applied MR-Egger method, weighted median method, Cochran’s Q test, MR-Egger regression, and MR-PRESSO. Results: MR analysis results revealed a nominal association (p < 0.05) between 13 GM taxa, 6 blood metabolites, and PPD. After Bonferroni correction, only Bifidobacteriales (OR: 0.844, 95% CI: 0.760-0.938; p = 0.0017) showed a significant causal relationship with a lower risk of PPD. In our validation results, the higher level of Alphaproteobacteria (OR: 1.057, 95% CI: 1.024-1.091; Bonferroni-corrected p = 0.0006) retained a strong causal relationship with a higher risk of PPD. Finally, mediation analysis revealed that the impact of Odoribacter on PPD was mediated indirectly through Hyodeoxycholate, with a mediation proportion of 16.8%. Conclusion: Our findings underscore the importance of elucidating the underlying mechanisms between the GM, blood metabolites, and PPD. These results provide novel insights into microbiome-based therapies and metabolite-targeted interventions for PPD.