Antibiotic treatment in weaned male mice improves colitis in adulthood and their offspring through modulating miRNAs

Antibiotics use in early life is increasingly scrutinized for its potential long-term effects on health, particularly its association with inflammatory bowel disease (IBD). The weaning period is a critical developmental window for the maturation of the gut microbiota, immune system, and intestinal barrier, and antibiotic-induced disruptions during this time can have lasting consequences. However, the impact of early-life paternal antibiotic treatment on offspring IBD susceptibility, and the molecular mechanisms that might mediate such a transgenerational effect, have not been described.In this study, we used a mouse model to investigate the effects of short-term (1 week) and long-term (6 weeks) treatment with ampicillin and cefixime, starting from the weaning period, on susceptibility to DSS-induced colitis in adulthood and in the subsequent F1 generation.The results revealed that both short- and long-term antibiotic treatments during weaning significantly alleviated DSS-induced colitis in paternal male mice, with long-term treatment conferring a more pronounced protective effect. Notably, this protective phenotype was transmitted to male offspring of long-term treated sires, but not to female offspring or offspring of short-term treated sires. Mechanistically, the protection was associated with increased expression of the tight junction protein Ocln, mediated by reduced levels of miR-10b-5p and miR-200b-3p, which was shown to be via sperm.These findings provide new insights into the intergenerational effects of early antibiotic treatment and highlight the importance of the weaning period for long-term gut health and disease risk.