Synergy effects of Ganoderic acid A and Ganoderma lucidum polysaccharides on enhancing protection against DSS-induced colitis via gut microbiota rebalancing and inflammation suppression

Inflammatory bowel disease (IBD) is characterized by persistent intestinal inflammation and gut microbiota dysbiosis. The study investigated the protective effects of Ganoderma lucidum polysaccharide (GLP) and ganoderic acid A (GAA) administered individually and in combination on dextran sulfate sodium (DSS)-induced colitis in mice. Disease activity index (DAI), colon length, histopathology, serum inflammatory cytokines (TNF-α, IL-1β, IL-6), TLR4/NF-κB pathway proteins, gut microbiota composition, and short-chain fatty acids (SCFAs) were evaluated. Combination therapy of GLP and GAA (GL-PA) significantly ameliorated body weight loss, reduced DAI scores, and restored colon length compared to individual treatments (P < 0.05). Histopathological analysis revealed preserved crypt architecture and reduced inflammatory infiltration. GL-PA markedly suppressed serum cytokine levels and inhibited TLR4/NF-κB activation more effectively than GLP or GAA alone (P < 0.05). Microbiota analysis showed GL-PA restored gut diversity, increased Firmicutes/Bacteroidetes ratio, promoted beneficial bacteria (Lactobacillus, Turicibacter) while suppressing pathogenic bacteria (Bacteroides, Escherichia-Shigella, and Desulfovibrionaceae). GL-PA significantly enhanced SCFAs production, particularly propionate and butyrate (P < 0.01). Correlation analysis revealed associations between harmful bacteria and inflammatory markers, while beneficial bacteria correlated with SCFAs levels. The combination exhibits synergistic protective effects through dual mechanisms: inflammatory pathway suppression and gut microbiota homeostasis restoration. GL-PA represents a promising natural therapeutic strategy for IBD treatment.