Spleen metabolomics coupled with gut microbiome analysis to elucidate the immunomodulatory mechanisms of longan polysaccharides against cyclophosphamide-induced immunosuppression in mice.

Longan polysaccharide (LP) has exhibited excellent immunomodulatory activities by modifying gut microbiota but the specific regulatory mechanism remains unclear. Therefore, spleen metabolomics and metagenomic sequencing of gut microbiota were combined to investigate the immunomodulatory mechanism of LP in cyclophosphamide (CPA)-induced immunosuppressed mice with an intact and antibiotic-depleted microbiota. The results indicated that LP significantly restored thymic and splenic indices, increased lymphocyte proliferation, and mitigated damage to immune organs. LP up-regulated the ratio of CD4+/CD8+ in the mouse spleen to modulated cytokine secretion, thereby increasing serum concentrations of IFN-γ, TNF-α, IL-12, and IL-6. The metabolomic analysis indicated that LP alleviated CPA-induced splenic disturbance by coordinately improving amino acid metabolism, unsaturated fatty acid metabolism, and pyrimidine metabolism. Furthermore, LP significantly reshaped the CPA-induced gut microbiota imbalance, particularly by increasing the relative abundance of unclassified_f__Muribaculaceae and Bacteroides. However, antibiotic intervention almost offset the LP-mediated alleviation of immunosuppression. Our findings provide novel insights into the mechanisms underlying the immunosuppression-alleviating effects of natural polysaccharides.