摘要Background Perilla frutescens seeds(PFS)are gaining recognition as a natural alternative to antibiotics in livestock,supporting sustainable farming and animal health.However,the underlying molecular mechanisms through which PFS influence host immune function and antioxidant capacity,especially via the gut-liver-muscle axis,remain largely unknown.This study employed an integrative multi-omics approach to elucidate how PFS supplementation modu-lates the microbiota-gut-liver-muscle axis and enhances immune and antioxidant functions in lambs.Results PFS supplementation markedly improved immune and antioxidant profiles,demonstrated by elevated serum levels of IL-10,IgM,IgG,GSH-PX,and SOD,and reductions in IL-1β,TNF-α,and MDA.Microbial analysis revealed elevated abundances of ruminal and intestinal taxa commonly associated with gut homeostasis and metabolic health(Christensenellaceae_R-7_group)and reduced levels of species with pathogenic or pro-inflammatory potential(Bacillus cereus and Clostridioides)in the ileum.Transcriptomic and metabolomic profiling of liver tissue indicated modulation of key inflammatory and bile acid signaling pathways,including the downregulation of TLR4,NLRP3,ATF3,CYP2J2,and LXR-α.PFS also increased hepatic concentrations of anti-inflammatory metabolites such as chlorquinaldol and indole-3-carboxaldehyde,while reducing levels of LysoPC(20:4)and phosphatidic acid.Correlation and mediation analyses revealed strong interconnections among gut microbiota,hepatic gene expression,lipid metabolites in liver and muscle,and systemic immune-antioxidant markers.Conclusion These findings highlight the microbiota-gut-liver-muscle axis as a central mechanism through which PFS enhances immune function and antioxidant capacity in lambs.PFS supplementation represents a promising nutri-tional strategy to improve healthy lamb production,supporting the development of antibiotic-free and sustainable livestock systems.