Gut Microbiota Mediates Maternal PM2.5 Exposure-induced Neurodevelopmental Disorder in offspring via Disturbing the Glutamate Metabolism: Evidence from Multiomics Analysis

While accumulating evidence links maternal PM2.5 exposure to offspring neurodevelopmental impairments, yet the underlying biological pathways require further elucidation. To address this, female ICR mice are exposed to filtered air (FA) or concentrated ambient particulate matter (CAP) for three months before conception and 16 days during gestation. Behavioral tests indicate that declined memory function, anxiety-like behavior and social deficits accompanied by synaptic impairments are induced in offspring by maternal PM2.5 exposure in a gender-dependent manner. Fecal microbiota transplantation (FMT) from PM2.5-exposed dams to pseudo-germ-free recipients successfully remodels the neurodevelopmental deficits in offspring, confirming the key mediating role of maternal gut microbiota. Multi-omics analysis shows that maternal PM2.5 exposure causes dysbiosis of gut microbiota in both mother and offspring, disturbs glutamate metabolism and glutamatergic synapase-related pathways. Further in vivo and in vitro experiments indicate that these effects may be induced via ERK/CREB signaling pathway. Additionally, dietary glutamine supplementation effectively ameliorates behavioral deficits and synaptic dysfunction in offspring. In conclusion, this study reveals that maternal PM2.5 exposure can disrupt offspring neurodevelopment via the gut microbiota-glutamate-brain axis and glutamine supplementation may serve as a potential effective intervention strategy.