Abstract

Maternal prenatal stress confers elevated neuropsychiatric risk to offspring, yet the mechanisms underlying fetal neurodevelopmental impairment remain elusive. The gut microbiota has emerged as a key regulator of brain development and behavior. However, the mechanisms mediating the interactions between the microbiota and the developing brain are still poorly understood. Here, utilizing a prenatal stress mouse model integrated with multi-omics approaches, comprehensive behavioral assays, and molecular validations, we demonstrate that prenatal stress not only induces maternal gut microbiota dysbiosis during pregnancy but also, more critically, leads to fetal blood‒brain barrier (BBB) developmental defects and subsequent abnormalities in emotional behavior and cognitive function in adult offspring. Maternal probiotic supplementation during gestation can reverse both gut microbial dysbiosis and fetal BBB dysfunction. Notably, transcriptomic analysis reveals that the maternal gut microbiota modulates interferon-β (IFN-β) signaling along the placenta‒fetal brain axis under stress. Furthermore, metabolomic profiling suggests that prenatal stress exposure profoundly influences the maternal fecal and serum metabolome. In conclusion, our findings establish a placenta‒brain axis wherein maternal microbial signals orchestrate fetal neurovascular development, identifying microbiota-targeted interventions as a neuroprotective strategy.