Maternal Preconception Antibiotic Exposure Disrupts Microbial Succession: A Transgenerational Risk for Offspring Gut Mucosal Immaturity and Colitis Susceptibility

ABSTRACT The early‐life microbiome plays a pivotal role in host development and lifelong health. Maternal factors are increasingly recognized as crucial in shaping offspring microbiome. However, how maternal preconception perturbations affects offspring health remain unclear. Thus, we combined animal and clinical data to elucidate whether preconception microbial perturbations disrupt microbial succession and increase offspring susceptibility to colitis. In animals, preconception antibiotic exposure induced long‐lasting disruptions in offspring microbial ecology, through enhanced maternal‐offspring microbial transmission, altered microbial developmental trajectories, and increased selective pressures during microbial community assembly. Ultimately, these alterations resulted in persistent gut mucosal immaturity and heightened susceptibility to colitis in adulthood. Complementary clinical studies revealed concordant alterations in gut microbiome and metabolome of children with inflammatory bowel disease (IBD) and their seemingly healthy mothers, characterized by pro‐inflammatory taxa and metabolites. Notably, mothers of IBD children reported significantly higher antibiotic exposure than controls, which was also associated with enhanced maternal‐offspring microbial transmission and increased selective pressures during microbial community assembly. Our findings reveal a potential intergenerational mechanism in which preconception perturbations are associated with disrupted microbial succession, transgenerational propagation of gut mucosal immaturity, and susceptibility to colitis. These results underscore the importance of judicious antibiotic use during the often‐overlooked preconception period.