Preconception maternal gut dysbiosis affects enteric nervous system development and disease susceptibility in offspring

Maternal health, specifically changes in the gut microbiota, profoundly affects the health of offspring. However, our understanding of how gut microbiota alterations during preconception period influence their offspring remains limited. In this study, we are dedicated to investigate the impact of preconception maternal gut microbiota disturbance on offspring enteric nervous system (ENS) development in mice and explore the underlying mechanisms. Through in vivo and in vitro experiments, we made a novel discovery that preconception maternal exposure to antibiotics before pregnant leads abnormal development of the offspring’s ENS, increasing their susceptibility to water avoidance stress. Supported by metagenomic, targeted metabolome, and transcriptome analysis, we identified that preconception antibiotic exposure disrupts the expression of genes crucial for embryonic ENS development by altering the composition of the maternal gut microbiota. Furthermore, our multi-omics analysis combined with Limosilactobacillus reuteri (L. reuteri) gestational supplementation illustrated that maternal gut microbiota and metabolites influence embryonic ENS development via the propionate-GPR41-GDNF/RET/SOX10 signaling pathway. Our findings highlight the critical importance of maintaining a healthy maternal gut microbiota during the preconception period for proper ENS development in offspring.