Limosilactobacillus fermentum-derived 4-guanidinobutyric acid promotes intestinal urate excretion via the HNF4α-ABCG2 axis to alleviate hyperuricemia

Hyperuricemia is a prevalent metabolic illness and an established risk factor for gout and chronic renal disease. Present urate-lowering medications are often limited by side effects, highlighting the necessity for innovative strategies. The gut microbiota has a role in urate homeostasis; however, the precise bacterial components and molecular processes involved are largely unidentified. In this study, we demonstrated that a human-derived Limosilactobacillus fermentum strain M5e mitigates hyperuricemia in mice. Both live bacteria and their cell-free conditioned media specifically increased the expression of the colonic urate exporter ABCG2, hence augmenting intestinal urate excretion. Utilizing integrated metabolomics, we discovered 4-guanidinobutyric acid (4-GBA) as the principal active metabolite in the M5e conditioned media. Subsequent analysis demonstrated that 4-GBA directly interacts with and activates the transcription factor HNF4α, promoting its nuclear translocation and selective transactivation of ABCG2. This work clarifies a detailed gut microbiota-to-host route, linking a functioning bacterium and its effector chemical to the control of a host urate transporter, therefore offering a molecular foundation for innovative treatment strategies in hyperuricemia.