Gut microbiota and metabolomics reveal the combined effects of Alpinia oxyphylla fructus polysaccharide and nootkatone on chronic kidney disease via the "gut-kidney" axis.

BACKGROUND: Chronic kidney disease (CKD) imposes a substantial burden on healthcare systems worldwide. Traditional Chinese medicine has gained attention as a complementary and alternative selection given the limitations of current CKD management. Although the renoprotective potential of Alpinia oxyphylla fructus has been reported, existing studies mainly focus on crude extracts or individual metabolites, leaving interactions among metabolites unexplored. This study investigated the individual and combined effects of A. oxyphylla fructus polysaccharide (AOP) and nootkatone (NKT) in CKD. METHODS: The protective effects of AOP and NKT on CKD were evaluated using an adenine-induced mouse model. Renal and colonic injuries were assessed by plasma biochemistry, histopathological analysis, and inflammation-related gene expression. Plasma metabolic profiles were characterized by untargeted metabolomics. Intestinal microbiota structure was analyzed by microbial diversity sequencing. Fecal short-chain fatty acids (SCFAs) were quantified by gas chromatography, and intestinal barrier-related gene and protein expression levels were examined by RT-qPCR and immunohistochemistry, respectively. RESULTS: Combined intervention exerted stronger protective effects than either intervention administered alone. It markedly reduced plasma urea nitrogen and creatinine levels, alleviated renal inflammation and fibrosis, and improved metabolic dysregulation with reduced uremic toxin accumulation. Key regulated pathways included pyrimidine, purine, and ascorbate and aldarate metabolism. The combined intervention also ameliorated gut microbiota dysbiosis, preserved SCFA levels, and maintained intestinal barrier integrity. CONCLUSION: The combination of AOP and NKT exhibited combined effects through modulation of the plasma metabolic profile and the gut microenvironment, suggesting its potential protective role against CKD via the gut-kidney axis. These findings provide new insights into the combined effects of multiple bioactive metabolites from traditional Chinese medicine.