Multi-omics profiling of oral microbial functional signatures and systemic immune-metabolic features in perinatal depression.

Background: Perinatal depression (PND) occurs during a period marked by profound endocrine, metabolic, and immune adaptation. Although alterations in immune-metabolic regulation have been reported in PND, how such changes manifest across distinct biological compartments remains unclear. The oral mucosal ecosystem represents an immunologically active interface with direct connections to systemic circulation, yet its functional characteristics in PND have been insufficiently explored. In this study, we examined whether PND is characterized by differences in oral microbial functional profiles alongside systemic immune-metabolic features. Methods: We performed an integrated multi-omics analysis combining salivary shotgun metagenomics and untargeted serum metabolomics in 31 women with PND and 32 healthy controls. Oral microbial taxonomic composition and inferred functional profiles were analyzed together with circulating metabolites related to endocrine and immune processes. Cross-omics analyses were used to evaluate overall concordance as well as pathway- and feature-level associations between microbial functional signals and host metabolic features. Findings: The oral microbiome of women with PND showed largely preserved community structure and diversity, while differences were observed at the level of inferred functional pathways, including enrichment of lipopolysaccharide biosynthesis and virulence-associated functional categories. Concurrently, the serum metabolome exhibited differences in steroid-related metabolites, bile acid profiles, and lipid mediator-associated features involved in immune modulation, including putatively annotated resolvin D5. Global concordance between oral microbial functional profiles and systemic metabolomic patterns was limited; however, reproducible associations were observed at the pathway and feature levels, such as an inverse association between the relative abundance of the genus Interpretation: Together, these findings describe concurrent differences in oral microbial functional signatures and systemic immune-metabolic features in women with PND, occurring in the context of minimal changes in microbial community composition. The limited global concordance and selective pathway-level correspondence across omic layers are consistent with asynchronous patterns of biological variation during the perinatal period. These observations support the potential relevance of the oral-systemic axis as a non-invasive perspective for characterizing biological heterogeneity associated with perinatal depression.