Preconception maternal gut dysbiosis affects enteric nervous system development and disease susceptibility in offspring via the GPR41–GDNF/RET/SOX10 signaling pathway

Maternal health, specifically changes in the gut microbiota, can profoundly impact offspring health; however, our understanding of how gut microbiota alterations during the preconception period influence the offspring remains limited. In this study, we investigated the impact and mechanisms of preconception maternal gut dysbiosis on the development of the enteric nervous system (ENS) in mice. We found that preconception maternal exposure to antibiotics led to the abnormal development of the ENS in offspring, increasing their susceptibility to water avoidance stress at the adult stage. Metagenomic, targeted metabolomic, and transcriptomic analyses revealed that preconception antibiotic exposure disrupted the expression of genes crucial for embryonic ENS development by altering maternal gut microbiota composition. Multi-omics analysis combined with Limosilactobacillus reuteri and propionate gestational supplementation demonstrated that the maternal gut microbiota and metabolites may influence embryonic ENS development via the GPR41–GDNF/RET/SOX10 signaling pathway. Our findings highlight the critical importance of maintaining a healthy maternal gut microbiota before conception to support normal ENS development in offspring. Graphical Preconception administration of antibiotics to female mice reduces the abundance of Limosilactobacillus reuteri in the maternal gut microbiota during pregnancy, subsequently affecting propionate levels. Decreased propionate levels downregulated the expression of Gdnf / Ret / Sox10 mediated by GPR41, leading to abnormal development of the enteric nervous system during the embryonic period. This dysplasia results in colonic dysmotility, impaired colonic epithelium, and increased susceptibility to water-avoidance stress in offspring. Highlights Preconception maternal antibiotic exposure results in the abnormal development of the enteric nervous system (ENS) and intestinal mucosa in mouse offspring, thereby increasing their susceptibility to water avoidance stress in adulthood. Preconception maternal antibiotic exposure alters the composition of the maternal gut microbiota, leading to abnormal embryonic ENS development via the modulation of gene expression. Multi-omics analysis and supplementation with Limosilactobacillus reuteri and propionate during pregnancy indicate that the maternal gut microbiota and metabolites affect embryonic ENS development through the GPR41–GDNF/RET/SOX10 signaling pathway.