Selenylation of naturally acetylated Dendrobium officinale polysaccharides enhances immune protection via gut microbiota and metabolic modulation

Selenium is essential for maintaining immune homeostasis, yet its inorganic form is characterized by low bioavailability and potential toxicity. A naturally acetylated Dendrobium officinale polysaccharide (DOP) with prominent immunomodulatory activities, but its was isolated in our previous study, whereas its immunological efficacy can be further improved throughvia structural modification. Selenium-modified D. officinale polysaccharides (SeDOP) were synthesized via the HNO 3 -Na 2 SeO 3 method in this study, with a selenium content of 0.076 ± 0.015%, and the preparation yield of SeDOP reached 62.5 ± 3.48% based on the initial DOP mass. The immunoregulatory function of SeDOP was further evaluated using a cyclophosphamide (CTX)-induced mouse model. Results demonstrated that the compositions of gut microbiota were positively regulated by SeDOP, as evidenced by the significant enrichment of beneficial bacterial genera including Lactobacillus , Limosilactobacillus , and Truepera . Metabolomic analysis revealed that SeDOP specifically activated indole alkaloid biosynthesis pathways, which were correlated with restored CD19 + B cell proportions in mice. Collectively, SeDOP attenuates CTX-induced immune injury by remodeling gut microbiota compositions and modulating indole alkaloid metabolism, and promotes the regeneration of lymphocytes, highlighting its potential as a dual-functional selenium-modified polysaccharide for immunoprotection and gut health.