Integrated Foodomics Reveals Gut Microbiota-Metabolite-Gene Interactions Associated with the Immunoprotective Effects of Ganoderma lucidum Polysaccharide Peptide.

Ganoderma lucidum polysaccharide peptide (GLPP) is a food-derived macromolecule with immunomodulatory potential, but its gut-centered mechanisms under chemotherapy-associated immunosuppressive stress remain unclear. This study aimed to evaluate the protective effects of GLPP against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury in mice and to explore the associated microbiota-metabolite-gene interaction network using integrated foodomics. BALB/c mice were treated with CTX and then administered GLPP at 50, 100, or 200 mg/kg/day for 42 days, with levamisole as a positive control. High-dose GLPP restored spleen index from 1.592 ± 0.266 to 1.902 ± 0.212 mg/g and thymus index from 0.322 ± 0.146 to 0.656 ± 0.081 mg/g compared with the CTX group. It also enhanced lymphocyte proliferation (OD450: 1.529 ± 0.073 vs. 1.065 ± 0.051), increased carbon clearance index (3.403 ± 0.223 vs. 2.650 ± 0.164), elevated IL-2 and IgA levels, and reduced excessive IFN-γ and TNF-α responses. GLPP alleviated intestinal mucosal injury and reshaped gut microbial profiles, particularly taxa related to Bacteroidota and Bacteroides. Metabolomics revealed putatively annotated differential metabolites associated with amino acid, nicotinate-nicotinamide, and glycerophospholipid metabolism, while transcriptomics indicated modulation of PRR/MAPK-related immune signaling. Integrated correlation analysis suggested a microbiota-metabolite-gene-immune association network involving putative gamma-Glutamylleucine(γ-Glu-Leu), leukotriene D4(LTD4)-like lipid features, and hippuric acid. These findings support GLPP as a promising immune-supporting functional food ingredient, although metabolite assignments and causal mechanisms require further validation.