Abstract

Background

Perilla frutescensseeds (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 modulates 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 cereusandClostridioides) in the ileum. Transcriptomic and metabolomic profiling of liver tissue indicated modulation of key inflammatory and bile acid signaling pathways, including the downregulation ofTLR4,NLRP3,ATF3,CYP2J2, andLXR-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 nutritional strategy to improve healthy lamb production, supporting the development of antibiotic-free and sustainable livestock systems.

Data Availability

The rumen and ileum 16S rRNA raw data from this study were uploaded to the NCBI Sequence Read Archive (SRA) under the accession number PRJNA1156902 and PRJNA1156904, respectively. The raw reads of the transcriptome sequencing of the liver are available at NCBI SRA (accession number PRJNA1158691).

Abbreviations

  • ALA:: α-Linolenic acid
  • Alanine-CA:: Alanine-conjugated cholic acid
  • ANCOM-BC:: Analysis of compositions of microbiomes with bias correction
  • ASVs:: Amplicon sequence variants
  • DEGs:: Differentially expressed genes
  • DM:: Dry matter
  • FC:: Fold change
  • FcγR:: Fc gamma receptor
  • FDR:: False discovery rate
  • GCDCA:: Glycochenodeoxycholic acid
  • GDCA:: Glycodeoxycholic acid
  • GHDCA:: Glycohyodeoxycholic acid
  • GLU:: Glucose
  • GSEA:: Gene set enrichment analysis
  • GSH-Px:: Glutathione peroxidase
  • GUDCA:: Glycoursodeoxycholic acid
  • IDA:: Information-dependent acquisition
  • IgA:: Immunoglobulin A
  • IgG:: Immunoglobulin G
  • IgM:: Immunoglobulin M
  • IL-10:: Interleukin-10
  • IL-1β:: Interleukin-1β
  • KEGG:: Kyoto Encyclopedia of Genes and Genomes
  • LC:: Low-concentrate control diet
  • LEfSe:: Linear discriminant analysis effect size
  • LPCs:: Lysophosphatidylcholines
  • LPE:: Lysophosphatidylethanolamine
  • MDA:: Malondialdehyde
  • n-3 PUFA:: Omega-3 polyunsaturated fatty acid
  • NH3-N:: Ammonia-nitrogen
  • OPLS-DA:: Orthogonal projections to latent structures-discriminant analysis
  • PCoA:: Principal Coordinates Analysis
  • PCs:: Phosphatidylcholines
  • PFS:: Perilla frutescens seeds
  • QC:: Quality control
  • RGCCA:: Regularized generalized canonical correlation analysis
  • SOD:: Superoxide dismutase
  • SYK:: Spleen tyrosine kinase
  • TG:: Triglyceride
  • TGF-β:: Transforming growth factor-β
  • TLR:: Toll-like receptor
  • TNF-α:: Tumor necrosis factor-alpha
  • VFAs:: Volatile fatty acids
  • VIP:: Variable importance in projection
  • WGCNA:: Weighted gene co-expression network analysis

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Acknowledgements

We would like to thank Shanghai Biotree Biotech Co., Ltd. for providing help in metabolomics analysis.

Funding

This work was supported by the Central Government-Guided Local Science and Technology Development Fund Project (2025ZY0108), Bayannaoer Research Institute Young Scientist Project (2024BYNECAU002), Hainan Provincial Natural Science Foundation of China (324QN289), and the China Agriculture Research System (CARS-38).

Ethics Declaration

Ethics approval and consent to participate

All experimental procedures involving animals adhered to ethical guidelines and were approved by the Animal Care Committee of China Agricultural University (Beijing, China; approval No. AW30901202-1-1).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing financial interest.

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