Abstract
Lycium barbarum polysaccharides (LBPs) have recently attracted considerable attention for their immunomodulatory potential. However, their complex structures hinder efficient isolation and purification, making it challenging to identify the active components and establish clear structure-function relationships. We hypothesized that various LBP components exert distinct immunomodulatory effects by modulating gut microbiota composition and host metabolism. In this study, LBP fractions with distinct physicochemical properties were obtained via graded ethanol precipitation and evaluated using a cyclophosphamide (CTX)-induced immunosuppressed mouse model. Immunomodulatory effects and underlying mechanisms were investigated through gut microbiota profiling, short-chain fatty acid (SCFAs) quantification, and serum metabolomics analysis. The results showed that various LBP components alleviated CTX-induced weight loss, protected immune organs, enhanced the secretion of immune-related cytokines, and improved the activity of liver antioxidant enzymes to varying degrees. Various LBP components distinctly reshaped the gut microbiota composition and SCFAs production. Among them, the LBP3 component exhibited the strongest immunomodulatory activity, markedly enhanced acetic and propionic acids concentrations as well as the relative abundance of Bifidobacterium, Lactobacillus, Bacteroides, and Akkermansia. Furthermore, Serum metabolomics revealed that LBP3 intervention significantly upregulated metabolite levels, including inosine, pentadecanoic acid, propionylcarnitine, and fucoxanthin. These findings confirm our hypothesis that structurally distinct LBP components exert differential immunomodulatory effects by modulating gut microbiota and host metabolism, thereby providing a theoretical basis for the targeted development of LBP-based functional foods and natural immunomodulators.