Gut microbiota-associated N-Acetyl-L-leucine mediates fructose-induced hyperuricemia via the P300-URAT1 pathway.

Hyperuricemia (HUA), a metabolic disorder characterized by elevated uric acid (UA), is marked by a rising incidence and trend toward earlier onset, both strongly associated with fructose intake. However, the roles of gut microbiota and their metabolites remain unclear. This study employed a fructose-induced HUA mouse model and fecal microbiota transplantation (FMT) to assess the impact of fructose-altered gut microbiota on the microbial community structure and UA degradation capacity in recipient mice. Non-targeted metabolomics was then utilized to identify key metabolites, and the HUA-inducing effects and underlying mechanisms of the metabolite were further validated. The results confirmed that microbiota from fructose-induced HUA mice promoted HUA development in recipients, significantly increasing the abundance of Bacteroidota and reducing microbial UA degradation ability. Specifically, recipient mice exhibited disordered amino acid metabolism, primarily characterized by elevated N-Acetyl-L-leucine. This metabolite was subsequently shown to induce HUA by promoting UA synthesis through enhanced adenosine deaminase and xanthine oxidase activity, as well as inhibiting UA excretion via upregulation of the reabsorption transporter urate transporter 1 (URAT1) through E1A binding protein p300 (P300) regulation. These results highlight N-Acetyl-L-leucine as a pivotal gut microbiota-associated metabolite in fructose-induced HUA and offer new insights and potential targets for future interventions.