Antenatal depressive symptoms impair offspring neurodevelopment by inducing maternal gut microbiota dysbiosis during pregnancy

The effects of maternal antenatal depression (AND) across different stages of pregnancy on offspring neurodevelopment remain poorly understood, and the underlying microbiota-related mechanisms are largely unknown. In a multicenter prospective cohort of 2053 pregnant women, we found that elevated depressive symptoms at any trimester were significantly associated with delayed infant neurodevelopment. Using a nested case‒control design with 16S rRNA sequencing of 504 maternal fecal samples, we identified a consistent reduction of butyrate-producing bacteria and disruption of amino acid metabolism in women with AND symptoms - features that correlated with poorer infant cognitive outcomes. To establish causality, fecal microbiota transplantation (FMT) from women with AND symptoms was administered to germ-free dams, resulting in impaired intestinal barrier integrity, heightened neuroinflammatory signaling, and altered polyunsaturated fatty acid and amino acid metabolism in fetal brains at E18.5, leading to postnatal cognitive deficits in the offspring. Remarkably, maternal butyrate supplementation partially rescued these molecular and neurodevelopmental abnormalities. Together, these findings reveal a mechanistic link between maternal mood, gut microbial ecology, and fetal brain development, and identify the maternal gut microbiota and its metabolites as potential therapeutic targets to prevent the intergenerational effects of antenatal depression.