Integrated multi-omics analysis reveals gut microbiota-associated placental metabolic and transcriptomic alterations in placenta previa.

UNLABELLED: Placenta previa is a major obstetric complication, yet its potential association with maternal microbiota-associated biological alterations remains largely unexplored. This study aimed to investigate microbiota-associated metabolic and transcriptomic alterations in placenta previa using an integrated multi-omics approach. A total of 72 third-trimester pregnant women (28 with complete placenta previa and 44 controls) were enrolled. Maternal gut, oral, and vaginal microbiota were profiled using 16S rRNA gene sequencing, while placental tissues underwent targeted short-chain fatty acid (SCFA) metabolomic profiling and RNA sequencing. Multi-omics integration, ecological network analysis, and pathway enrichment analyses were performed to identify microbiota-associated biological alterations linked to placenta previa. Global microbial diversity remained largely preserved across maternal body sites in placenta previa. However, gut microbiota demonstrated prominent ecological network remodeling and was associated with coordinated placental SCFA and transcriptomic alterations. Several placental SCFAs, including acetic acid, propionic acid, isobutyric acid, and isovaleric acid, exhibited increased abundance trends in placenta previa. Integrated metabolomic and transcriptomic analyses convergently identified cholinergic synapse signaling as a shared altered pathway. In addition, cholinergic signaling-related genes, including CHRNB4 and GNB5, demonstrated coordinated associations with altered placental SCFAs and specific gut microbial taxa. These findings suggest the existence of a potential gut microbiota-placental metabolite-transcriptome axis associated with placenta previa. Multi-omics convergence on cholinergic synapse signaling highlights a potential biological pathway linking gut microbiota-associated metabolic alterations with placental transcriptomic remodeling in placenta previa.

IMPORTANCE: Placenta previa is a major obstetric complication with poorly understood biological mechanisms beyond established anatomical and clinical risk factors. This study provides the first integrated multi-omics investigation linking maternal microbiota, placental short-chain fatty acids (SCFAs), and placental transcriptomic alterations in placenta previa. Rather than identifying broad microbial ecosystem disruption, we observed coordinated ecological remodeling of gut microbiota together with altered placental SCFA profiles and transcriptomic pathways. Notably, metabolomic and transcriptomic analyses convergently implicated cholinergic synapse signaling as a shared altered pathway associated with placenta previa. These findings support the existence of a potential gut microbiota-placental metabolite-transcriptome axis and provide new biological insights into microbiota-associated signaling alterations in placenta previa.