Anti-Hyperuricemia Mechanism of Anserine Based on the Gut-Kidney Axis: Integrated Analyses of Metagenomic and Metabolomic

Abstract Background Due to the increasing prevalence of hyperuricemia and the lack of effective prevention and treatment methods, the development of safe and effective intervention substances has become a public health issue. Herein, the therapeutic ability of anserine, a bioactive peptide, was validated through a comprehensive multi-omics analysis of a rat model of hyperuricemia. Methods A total of 60 male Sprague–Dawley rats (180–220 g) were randomly divided into six groups (n = 10): normal control group (NC group), hyperuricemia group (HUA group), allopurinol group (Allo group, 10 mg/kg·bw allopurinol), three anserine groups (Ans1, Ans10 and Ans100 groups were treated with 1 mg/kg·bw, 10 mg/kg·bw and 100 mg/kg·bw anserine, respectively). Uric acid, liver and kidney function-related indexes and renal histology were detected. Five kidneys, intestinal feces and urine samples were selected from each group and the differences of uric-acid-related transporters, gut microbes and urine metabolites were detected and analyzed by western blot, metagenomic and UPLC-MS methods, respectively. Non-omics data was calculated using One-way analysis of variance (ANOVA) by SPSS 25.0 software. The omics data were analyzed using R software (version 4.1.1). The correlation between gut microbiota and metabolites was analyzed using the Pearson correlation coefficient method, with a significance threshold of P < 0.05. Results Anserine was observed to improve liver and kidney function and modulate urate-related transporter expressions in the kidneys. Urine metabolomics showed that 15 and 9 metabolites were significantly increased and decreased, respectively, in hyperuricemia rats after the anserine intervention. Key metabolites such as fructose, xylose, methionine, erythronic acid, glucaric acid, pipecolic acid and trans-ferulic acid were associated with ameliorating kidney injury. Additionally, anserine regularly changed the gut microbiota, thereby ameliorating purine metabolism abnormalities and alleviating inflammatory responses. The integrated multi-omics analysis indicated that Saccharomyces, Parasutterella excrementihominis and Emergencia timonensis were strongly associated with key differential metabolites. Conclusions We proposed that anserine improved hyperuricemia via the gut–kidney axis, highlighting its potential in preventing and treating hyperuricemia.