Restoration of Gut Microbiota and Metabolic Homeostasis by Lacticaseibacillus paracasei Zhang in Azithromycin‐Induced Dysbiosis

ABSTRACT Antibiotic‐induced gut dysbiosis poses significant risks to host health, including impaired microbial diversity, metabolic dysfunction, and antibiotic resistance gene dissemination. This study investigates the restorative potential of Lacticaseibacillus paracasei Zhang ( L. paracasei Zhang) in Sprague–Dawley rats following azithromycin‐induced dysbiosis. Using shotgun metagenomics and untargeted metabolomics, we demonstrate that L. paracasei Zhang partially reverses antibiotic‐driven phylum‐level disruptions, restoring Bacteroidetes and Verrucomicrobia abundance while suppressing the levels of specific bacteria, including Clostridium cocleatum and Murimonas intestini , which have been associated with dysbiosis in certain contexts. Probiotic intervention enriched beneficial taxa ( Limosilactobacillus reuteri , Oscillibacter sp. 1_3) and increased metabolites linked to inflammation (leukotriene A4, lauric acid), barrier function (vitamin A), and lipid metabolism (linoleic acid). Additionally, L. paracasei Zhang reduced antibiotic resistance gene abundance ( lnuA , vgaE , Mef(En2) ) substantially, likely through competitive niche exclusion. Pathway analysis revealed activation of steroidogenesis and fatty acid metabolism, critical for gut homeostasis. Despite promising results in microbiota and metabolic recovery, Akkermansia muciniphila depletion in probiotic groups highlights context‐dependent microbial interactions. These findings underscore the potential of L. paracasei Zhang as a therapeutic adjunct to mitigate antibiotic‐associated dysbiosis, though translational validation in humans remains essential.