Therapeutic Potential of Irpex lacteus Polysaccharides in Lupus Nephritis: Insights From Gut Microbiota and Metabolomics Analysis in MRL/Lpr Mice

ABSTRACT Polysaccharides from Irpex lacteus (PCP) were evaluated for their therapeutic effects on lupus nephritis (LN) in MRL/lpr mice. After 8‐week interventions with low‐ and high‐dose PCP, we systematically evaluated the therapeutic efficacy by measuring the levels of autoantibodies, the expression of inflammatory cytokines, and renal function‐related parameters. Finally, 16S rDNA gut microbiome sequencing with metabolomics analysis was used to explore the pharmacological mechanism of PCP intervention in LN. PCP could reverse the phenotype of MRL/lpr mice, reduce autoantibody levels, alleviate inflammatory responses, and improve renal function. Gut microbiome analysis found that PCP can improve gut microbiota composition and abundance of two phyla ( Firmicutes , Bacteroidota ) and five genera ( Lachnospiraceae NK4A136 group, Alistipes , Butyricicoccus , Bacteroides , Lactobacillus ), which play an important role in the process of PCP intervention on metabolism in MRL/lpr mice. UHPLC–MS untargeted metabolomics showed that PCP significantly affects multiple key differential metabolites, including Linoleic acid, L‐Phenylalanine, L‐Tyrosine, and 56 other metabolites. These metabolites are primarily involved in metabolic pathways such as tryptophan metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, tyrosine metabolism, linoleic acid metabolism, and arachidonic acid metabolism. Correlation analysis between gut microbiota and differential metabolites reveals a close relationship, suggesting that gut microbiota promoting host metabolism may be one of the mechanisms by which PCP treats LN. PCP alleviates LN by modulating the “microbiota‐metabolism axis,” reducing autoantibodies, inflammation, and renal damage, while reshaping gut microbiota and regulating key metabolic pathways.