Integrated bioinformatics and multi-omics reveal Astragalus extract's gut-kidney axis mechanism in hyperuricemic nephropathy via purine metabolism.

BACKGROUND

Astragalus has demonstrated clinical efficacy in treating renal diseases. However, its therapeutic potential in hyperuricemic nephropathy (HN) remains underexplored.

PURPOSE: This study explores the therapeutic mechanisms of Astragalus aqueous extract (AAE) in HN via gut-kidney axis-mediated regulation of purine metabolism using bioinformatics and multi-omics approaches.

STUDY

DESIGN

Integrated bioinformatics and multi-omics reveal the molecular mechanism by which AAE treats hyperuricemic nephropathy through gut-kidney axis-mediated regulation of purine metabolism.

METHODS

An HN rat model was established to assess AAE's therapeutic effects via biochemical analysis, histological staining, and network pharmacology to identify key bioactive components and targets. Renal and fecal metabolomics, 16S rRNA sequencing, and metabolite analyses provided mechanistic insights, while molecular docking, molecular dynamics (MD) simulations, immunohistochemistry (IHC), and real-time PCR (RT-PCR) validated findings.

RESULTS

AAE alleviated HN-induced renal tubular injury and reduced biochemical markers and proinflammatory cytokines. Network pharmacology identified calycosin-7-O-β-d-glucoside (CAL), kumatakenin, isorhamnetin, and astragalin as potential bioactive components. Metabolomics revealed that AAE modulated 119 renal and 306 intestinal differential metabolites, with purine metabolism as the core perturbed pathway. Moreover, 16S rRNA sequencing showed AAE increased Firmicutes/Bacteroidetes (F/B) ratios, enhanced Lactobacillus abundance, and promoted short-chain fatty acid (SCFA) biosynthesis. Docking and MD simulations confirmed that the binding free energies of active ingredients such as CAL to xanthine dehydrogenase (XDH) were all significantly lower than that of xanthine, and XDH, myeloperoxidase (MPO) and hypoxanthine phosphoribosyltransferase 1 Gene (HPRT1) mRNA expressions in renal were significantly decreased after the intervention.

CONCLUSION

AAE reshaped renal and intestinal metabolic networks and modulated gut microbiota and SCFA profiles. It regulated uric acid metabolism primarily by balancing intestinal microbiota-mediated purine metabolism and inhibiting XDH, MPO, HPRT1 activity. This study provides a molecular basis for traditional Chinese medicine (TCM) analysis in HN through multi-target integration of "gut-kidney axis".