Ganoderma lucidum is a legendary traditional Chinese medicine with various bioactivities. This study was conducted (a) to explore the in vitro fermentation of the water extracts of G. lucidum fruiting body with Lactobacillus acidophilus and Bifidobacterium breve and (b) to investigate the effect of fermentation broth (GLFB) on dexamethasone (DEX)-induced immunosuppressed mice. Our results demonstrated that probiotic fermentation of G. lucidum fruiting body extracts underwent structural changing of major ganoderic acid components, such as ganoderic acid A (GA) into GC2, and this fermentation process involves changing of several metabolic pathways in the probiotic strains. GLFB could significantly improve the immunity, intestinal integrity, and gut microbiota dysbiosis in DEX-treated mice, and the immunostimulatory activity of GLFB was found closely related to its direct regulation on the expansion of CD4⁺ T cells in Peyer’s patches of mice. These data implied that probiotic fermentation of G. lucidum fruiting body extracts promoted its immunostimulatory activity via biotransformation of components such as GA. This research provides a theoretical support for the development and application of G. lucidum fermentation by probiotics.

Probiotic fermentation of G. lucidum fruiting body undergoes structural changing of major ganoderic acid components, such as ganoderic acid A (GA) into GC2. Probiotic G. lucidum fermentation broth (GLFB) could inhibite DEX-induced immunosuppression by significantly improving the immunity, intestinal integrity, and gut microbiota dysbiosis in DEX-treated mice.