EMERGING evidence closely links the intrauterine microbiome to fetal brain development and lifelong mental health trajectories.
Maternal Microbiota and Fetal Neurodevelopment
Challenging the long-held concept of a sterile womb, this narrative review synthesizes more than 90 preclinical and clinical studies on maternal microbiota and fetal neurodevelopment. Sequencing studies detecting low-biomass microbial DNA in placenta, amniotic fluid, and fetal tissues suggest that microbial signals reach the developing brain during pregnancy and may shape future neuropsychiatric risk.
Immune And Metabolic Pathways in the Intrauterine Microbiome
Maternal immune activation is highlighted as a key pathway. In mouse models, elevated cytokines such as IL-6 and IL-17A disrupt cortical layering and synaptic organization. Complementary human cohort data involving over 250,000 pregnancies link raised inflammatory markers in pregnancy with increased autism spectrum disorder risk, supporting an immune mediated microbiome-brain connection that begins before birth.
The review also underscores the role of microbial metabolites in the intrauterine microbiome-neurodevelopment axis. Short-chain fatty acids including butyrate, acetate, and propionate, as well as bile acids and tryptophan derivatives, help regulate microglial maturation, blood-brain barrier integrity, and hippocampal neurogenesis. Epigenetic mechanisms such as DNA methylation, histone acetylation, and chromatin remodeling have been observed in placenta and cord blood from pregnancies complicated by obesity or dysbiosis, suggesting durable molecular imprints on neurodevelopment.
Large-scale epidemiological studies further associate prenatal infection and antibiotic exposure with higher rates of autism spectrum disorder and attention-deficit/hyperactivity disorder. Together these converging immune, metabolic, epigenetic, and hormonal pathways support a model in which the maternal microbiome acts as a modifiable prenatal factor in mental health trajectories, although most human data remain observational and cannot yet establish causality.
Translational Opportunities and Clinical Caution
Looking ahead, the authors note that maternal microbiota profiling, targeted dietary optimization, and probiotic supplementation are emerging as potential translational strategies. For now, these approaches remain investigational and require rigorous clinical validation, but they point toward future prenatal care models that may one day incorporate the intrauterine microbiome into risk stratification and early prevention of neurodevelopmental disorders.
Reference: Andonotopo W et al. The intrauterine microbiome-neurodevelopment axis: decoding the prenatal microbial imprint on lifelong mental health. J Perinat Med. 2025;doi:10.1515/jpm-2025-0242.
