Salidroside and mesenchymal stem cells alleviate hypobaric hypoxia-induced lung injury and are associated with alterations in the gut-lung axis

High-altitude pulmonary injury (HAPI) results from hypobaric hypoxia and is characterized by excessive inflammation, oxidative imbalance, and disrupted barrier integrity. Salidroside and mesenchymal stem cells (MSCs) have shown protective effects against HAPI. However, it remains unclear whether these effects are associated with alterations in the gut-lung axis and whether combined therapy provides synergistic advantages. A rat model of hypobaric hypoxia was established. Lung injury was assessed by histopathology analysis and determination of IL-6, TNF-α, glutathione (GSH), and catalase (CAT) levels in lung tissues. Gut microbial composition was characterized using 16S rRNA sequencing of cecal samples, and serum metabolomics was analyzed using untargeted LC-MS/MS. Correlation and network analyses were performed to evaluate associations among lung injury indicators, differential metabolites, and microbial taxa. Treatment with either salidroside or MSCs significantly decreased lung injury scores, reduced IL-6, TNF-α, and CAT levels, and increased GSH concentrations (all p < 0.05). The combined treatment reduced TNF-α levels and increased GSH concentrations ( p < 0.05), but no additional protective effect on lung injury was observed. Both salidroside and MSCs independently altered serum metabolite profiles and gut microbial composition. Correlation analysis revealed significant associations among lung injury indicators, differential serum metabolites, and differential gut microbiota taxa, suggesting a potential involvement of the gut-lung axis in the observed protective effects. These findings provide insight into the associations among lung injury, gut microbiota, and serum metabolites under hypobaric hypoxia and support further investigation of salidroside and MSCs as potential interventions for HAPI.