Antibiotic Remodeling of the Gut Microbiota Impairs Host Resistance to Secondary Infection

Antibiotics disrupt commensal microbiota, but how this predisposes to secondary infections remains unclear. Metagenomic and whole‐transcriptome sequencing were employed to analyze alterations in microbial compositions and host defense. Fecal microbiota transplantation (FMT) and pathogen infection experiments were performed to identify the effects of antibiotics on host. Gut microbial dynamics induced by four antibiotic classes, revealed distinct taxonomic and functional shifts. Vancomycin and ampicillin enriched antibiotic resistance genes and impaired pathogen clearance via FMT. Vancomycin triggered overgrowth of opportunistic pathogens and increased genes of virulence factors, exacerbating colonic inflammation. Metronidazole selectively enriched Enterococcus avium , which correlated with MHC class I upregulation and impaired gut barrier function, promoting systemic Salmonella dissemination. LncRNA NR_166682.1 mediated E. avium ‐induced barrier damage and immune dysregulation, as validated in colon organoids. Antibiotics compromise host resistance through microbiota‐dependent mechanisms, with vancomycin and metronidazole exhibiting distinct, detrimental profiles via enrichment of resistant pathobionts or barrier‐disrupting species, respectively.