Antibiotics administration during weaning ameliorates intestinal mucosal inflammation in adult mice and their offspring.

Abstract

BACKGROUND AND AIMS: Antibiotic use in early life is increasingly being scrutinized for its potential effects on health, particularly its association with inflammatory bowel disease (IBD). The weaning period is a critical developmental window for maturation of the intestinal barrier, immune system and gut microbiota. However, it remains unknown how administering antibiotics to male mice starting at weaning affects the susceptibility of their future offspring to IBD. METHODS: Three-week-old weaned male mice were used to investigate the effects of short-term (1 week) and long-term (6 weeks) administration with ampicillin and cefixime on colitis susceptibility in adulthood and in the subsequent F1 generation. Paternal and F1 offspring were administered dextran sodium sulfate (DSS) to induce colitis. Quantitative real-time polymerase chain reaction, immunoblotting, immunofluorescence staining, and histological examination were used to assess mRNA and protein expression and morphological changes. Full 16S rRNA and miRNA sequencing was used to assess changes in the gut microbiota compositions and the mechanisms of intergenerational transmission of intestinal phenotypes. A dual-luciferase reporter assay was used to decipher the direct regulation of miR-10b-5p and miR-200b-3p on Occludin 3' UTR. RESULTS: Both short- and long-term antibiotic administration during the weaning period significantly alleviated DSS-induced colitis in male paternal mice, with long-term administration conferring a more pronounced protective effect. Interestingly, the protective effect against DSS-induced colitis was observed in LONG_F1 offspring, which was more pronounced in F1 males than in F1 females. Mechanistically, the protective effect was associated with increased expression of Occludin in epithelial cells, which was negatively modulated by miR-10b-5p and miR-200b-3p. This effect was inherited via the sperm. Furthermore, long-term antibiotic administration significantly altered the gut microbiota of paternal males, increasing the abundance of certain beneficial bacteria, such asand, while promoting the enrichment of antibiotic-resistant strains. CONCLUSIONS: Long-term antibiotic administration initiated at the weaning stage in male mice improves colitis in adulthood and in their offspring that associates with decreasing miR-10b-5p and miR-200b-3p expression, thus providing a theoretical basis for optimizing the use of antibiotics and prevention of IBD.