Genetic prediction of blood metabolites mediating the relationship between gut microbiota and postpartum depression: A mendelian randomization study

Background: Observational studies have suggested an association between gut microbiota(GM) and postpartum depression (PPD). However, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive. Methods: This study firstly elucidated the causal relationship among 196 GM taxa, 224 blood metabolites, and PPD from a genetic perspective, employing two-sample Mendelian randomization (MR). Subsequently, a twostep mediation MR approach was employed to explore the role of blood metabolites as potential mediators. To validate the relevant findings, we further selected other data (GM and blood metabolites) from 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 multiple-testing correction (P FDR < 0.1), Bifidobacteriales (P FDR = 0.034), Bifidobacteriaceae (P FDR = 0.055) and Guanosine (P FDR = 0.081) showed significant causal relationships with PPD. In our validation results, the higher level of Alphaproteobacteria (OR: 1.057, 95% CI: 1.024-1.091; p = 0.0006) retained a 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 elucidated the underlying mechanisms between the GM, blood metabolites, and PPD. These findings contribute to the prevention and diagnosis of PPD, offering novel insights into microbiome-based therapies and metabolite-targeted interventions for the treatment of PPD.