Multi-omics analysis reveals gut microbiota-host transcriptomic remodeling associated with the protective effects of Lacticaseibacillus rhamnosus GG against rotavirus enteritis.

OBJECTIVE: Rotavirus enteritis is closely associated with intestinal epithelial injury, gut microbial dysbiosis, and mucosal immune perturbation; however, the microbiota-host mechanisms underlying the protective effects of Lacticaseibacillus rhamnosus GG (LGG) remain incompletely defined. This study aimed to characterize LGG-induced microbiota-host transcriptomic remodeling in neonatal mice with rotavirus enteritis using an integrated multi-omics framework. METHODS: BALB/c suckling mice were assigned to Control, Model, and LGG groups. Rotavirus enteritis was induced by oral gavage with SA11 rotavirus, and mice in the LGG group received oral LGG intervention for 7 consecutive days. Diarrhea symptoms and jejunal histopathological changes were evaluated. Gut microbial composition was analyzed using 16S rRNA sequencing, while jejunoileal transcriptional responses were profiled by RNA sequencing. Differentially abundant bacterial taxa, differentially expressed genes, KEGG-enriched pathways, mucosal B-cell/IgA-related transcriptional modules, and integrated Genus-Gene-Pathway networks were further analyzed. RESULTS: LGG alleviated rotavirus-induced diarrhea, dehydration, body weight loss, and jejunal mucosal injury. Rotavirus infection disrupted the gut microbial ecosystem, with reduced α-diversity, altered community structure, increased Rodentibacter and Proteus, and decreased Muribacter, Alistipes, Paraclostridium, and Tuzzerella; these dysbiotic changes were partially reversed by LGG. Transcriptomic analysis identified 323, 91, and 552 differentially expressed transcripts in the Control vs Model, Model vs LGG, and LGG vs Control comparisons, respectively. Rotavirus infection mainly activated infection-related, inflammatory, endoplasmic reticulum stress, NF-κB, and MAPK signaling pathways, whereas LGG intervention was associated with epithelial repair, cytoskeletal remodeling, cell-death clearance, nucleocytoplasmic transport, and Notch signaling. Rotavirus infection also enhanced mucosal B-cell/IgA-related transcriptional programs, while LGG reduced Ighv3-8 and Ighv4-2 expression and tended to attenuate B-cell class-switching, plasma-cell differentiation, and IgA-production module scores. Integrated Genus-Gene-Pathway analysis identified 645 significant genus-gene correlations, revealing that LGG-associated microbial alterations were associated with host pathways related to epithelial barrier repair, immune regulation, PI3K-Akt/Rap1 signaling, iron metabolism, and ferroptosis. CONCLUSION: LGG may promote the restoration of intestinal mucosal homeostasis after rotavirus infection by modulating coordinated changes between specific gut bacterial genera and host transcriptional programs related to mucosal repair and immune homeostasis. These findings provide integrated multi-omics evidence for microbiota-host interaction mechanisms underlying LGG-mediated protection against rotavirus enteritis.