Causal effects of gut microbiota and blood metabolites on subtypes of perinatal depression classified based on depressive symptom trajectories: a mendelian randomization study

Abstract Background Perinatal depression (PD) is classified into four subtypes: pregnancy, early postpartum, late postpartum, and chronic, based on depressive symptom trajectories, with each subtype potentially involving distinct biological mechanisms. However, the causal effects of gut microbiota and blood metabolites on these PD subtypes have not been systematically investigated. Methods Using genome-wide association study (GWAS) data from East Asian cohorts, we performed two-sample Mendelian randomization (MR) to assess causal effects of 341 gut microbial taxa and 67 blood metabolites on four PD subtypes. Reverse MR analyses were performed to exclude potential reverse causality. A two-step mediation MR analysis was conducted to examine whether blood metabolites mediate the effects of gut microbiota on specific subtypes. To ensure robustness, gut microbial taxa showing suggestive causal associations were validated using independent GWAS data from the MiBioGen consortium. Results We identified 21 gut microbial taxa and five blood metabolites that showed suggestive causal associations with specific PD subtypes (P < 0.05, uncorrected). No reverse causality was detected between the subtypes and identified microbes or metabolites. Shared feature analysis indicated that s_Bacteroides caccae was a potential protective gut microbiota shared between early postpartum PD and late postpartum PD, whereas g_Collinsella was a potential risk-associated gut microbiota shared between these two subtypes, with its risk effect on early postpartum PD confirmed using independent GWAS data from the MiBioGen consortium. No blood metabolites were shared across subtypes. After multiple testing correction, only the protective effect of Bacteroides caccae on early postpartum PD remained statistically significant. Mediation analyses showed that s_Prevotella veroralis increased the risk of pregnancy PD by elevating phenylalanine levels (mediation proportion: 19.6%), whereas s_Bacteroides caccae reduced the risk of early postpartum PD by lowering ornithine levels (mediation proportion: 5.1%). Conclusions This study establishes evidence for a gut microbiota–blood metabolite–PD subtype regulatory network in East Asian populations. These findings elucidate the heterogeneous mechanisms underlying PD subtypes and provide a foundation for the development of subtype-specific precision interventions.