Gastrodia elata polysaccharides ameliorate gastric mucosal injury by driving metabolic homeostasis and activating the PI3K/Rac1 signaling axis

Gastric mucosal injury represents a critical risk factor for gastric cancer development, with pathogenesis involving Helicobacter pylori infection, alcohol consumption, and nonsteroidal anti-inflammatory drugs. Conventional synthetic drug therapies offer incomplete relief with side effects, underscoring the need for alternatives like food-medicine homologous substances. Gastrodia elata polysaccharides (GEP), the primary active components of the food-medicine homologous plant, exhibit antioxidant and anti-inflammatory potential. However, their therapeutic mechanisms against gastric injury remain incompletely elucidated. This study aimed to investigate the protective effects and mechanisms of GEP on ethanol-induced acute gastric mucosal injury in rats. Results demonstrated that medium-dose crude GEP (GEP-M) and purified GEP (GBP) most effectively ameliorated gastric mucosal injury. GEP-M and GBP treatment modulated gastrointestinal microbiota, increasing the abundance of probiotics (e.g., Lactobacillus and Bifidobacterium) while reducing pathogenic bacteria (e.g., Helicobacter, Escherichia-Shigella, and Streptococcus). Untargeted gastric metabolomics identified 61 significantly altered metabolites, primarily enriched in the TCA cycle, glycolysis, tryptophan metabolism, and steroid hormone biosynthesis. Changes in probiotic and pathogenic bacterial abundances were strongly correlated with shifts in metabolites involved in tryptophan metabolism and steroid hormone biosynthesis. To further investigate the functional link between differentially metabolites and signaling pathways, we constructed a metabolite–gene interaction network, which revealed 94 key genes directly associated with these differential metabolites. Intersection analysis between these metabolite-targeted genes and genes strongly associated with gastric mucosal injury yielded 31 candidate genes. Subsequent expression level validation of these candidates confirmed the activation of the PI3K/Rac1 signaling pathway after GEP treatment. Collectively, these findings suggest that GEP may ameliorate gastric mucosal injury by driving metabolic homeostasis and activating the PI3K/Rac1 signaling axis, highlighting the potential of natural polysaccharides as promising therapeutic agents for gastric diseases.