The maternal-infant microbiome axis as an epigenetic and immunometabolic orchestrator: redefining early-life programming and precision interventions for lifelong women's and children's health.

The maternal-infant microbiome axis represents a dynamic interface that shapes neonatal immune and metabolic development from the earliest stages of life. Microbial communities from the maternal gut, vaginal tract, and breast milk seed the infant microbiome, influencing chromatin remodeling, transcriptional activity, and immunometabolic programming. Rather than functioning solely as a conduit of microbial inheritance, this axis operates as a regulatory network where microbial metabolites such as short-chain fatty acids and indole derivatives modulate histone acetylation, DNA methylation, and noncoding RNA pathways that calibrate immune tolerance and pathogen defense. Perturbations, including cesarean delivery, perinatal antibiotic exposure, or maternal metabolic disorders, disrupt these processes and are associated with altered immune set points, heightened infection susceptibility, and increased risk of inflammatory and metabolic disease. Multi-omics studies now provide mechanistic insights linking microbial signals to epigenetic regulation of neonatal immune responses, while also exposing important controversies, such as the debated presence of a placental microbiome and the variable efficacy of probiotic interventions. Emerging strategies, including maternal dietary modulation of the microbiome, perinatal microbiota restoration, and development of live biotherapeutics, show promise, but their translational potential remains constrained by limited sample sizes, heterogeneous outcomes, and safety concerns. Framing the maternal-infant microbiome axis as an epigenetic and immunometabolic orchestrator highlights both its therapeutic promise and the need for rigorous mechanistic and clinical evaluation to advance preventive strategies for women's and children's health.