A pectic polysaccharide from Codonopsis pilosula alleviates cyclophosphamide-induced immunosuppression and intestinal immune dysregulation

Background Codonopsis pilosula is a classic immunomodulatory traditional Chinese medicine. Its polysaccharides exert dual regulatory effects on systemic and intestinal immune responses. Our previous work prepared a pectic polysaccharide from C. pilosula (CPP1b) exhibited significant bioactivity. However, whether CPP1b alleviates cyclophosphamide (CTX)-induced immunosuppression and intestinal immune dysregulation remains unclear. Objective This study investigated the immunomodulatory and intestinal protective effects of CPP1b in immunosuppressed mice. Methods The regulatory effects of CPP1b on systemic and intestinal immunity were evaluated by multiple indicators including body weight, immune organ indexes, hematological parameters, inflammatory cytokines, pathological changes in the spleen and intestine. 16S rDNA sequencing was employed to analyze the gut microbial composition. Meanwhile, we quantified the dynamic changes of short-chain fatty acids (SCFAs) in feces during the administration period by gas chromatography. The protein expression levels of GPR41, GPR43 and GPR109A were assessed by Western blotting. Finally, correlation heatmap was generated by cluster analysis to explore the associations between the key differential microbiota and physicochemical/immunological parameters. Results CPP1b significantly ameliorated CTX-induced body weight loss ( P < 0.01), increased thymus and spleen indexes ( P < 0.01), restored peripheral immune cell counts and CD4 + /CD8 + T cell ratios ( P < 0.05), increased pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and IFN-γ ( P < 0.05). Meanwhile, CPP1b alleviated intestinal mucosal damage and increased intestinal IgA expression, increased the number of colonic goblet cells. CPP1b reshaped the gut microbial community and diversity, with the microbiota composition shifting toward the normal state. Dynamic SCFAs profiling further demonstrated that CPP1b progressively elevated total SCFAs level, with acetate and butyrate showing significant differences ( P < 0.05). Western blotting results demonstrated that CPP1b significantly upregulated the protein expression of G-protein-coupled receptors (GPCRs)-GPR41, GPR43 and GPR109A ( P < 0.05). Correlation analysis suggested potential associations between gut microbiota and physiological, metabolic, and immunological changes during CPP1b treatment. Conclusion CPP1b can effectively alleviate CTX-induced immunosuppression and intestinal immune dysregulation by protecting immune organs and modulating humoral, cellular, and intestinal immunity. This study highlights the potential of CPP1b, a pectic polysaccharide from Codonopsis pilosula , as a source of bioactive polysaccharides with immunomodulatory effects.