Reprogramming probiotic for uric acid modular degradation and hyperuricemia treatment by synthetic biology regulation

Hyperuricemia has emerged as the fourth most prevalent metabolic disorder, necessitating the development of safer and more effective therapeutic strategies. In this study, we constructed a recombinant probiotic strain expressing the PucL and PucM enzymes, which demonstrated a uric acid degradation rate of 65% in vitro. To enhance this activity, we performed modular optimization by employing three ribosome binding sites (RBSs) of different strengths-RBS 29, RBS 31, and RBS T7-to tune the expression levels of pucL and pucM, resulting in highly efficient uric acid degradation. Further improvement was achieved by overexpressing the uric acid transporter gene ygfU and the hydrogen peroxide-degrading catalase gene katG, leading to significant uric acid degradation. Furthermore, the engineered Escherichia coli Nissle 1917 strain was evaluated in a mouse model of hyperuricemia; treatment with the optimized probiotic reduced serum uric acid levels to 39.11 mg/L, representing a 15.98% decrease compared with the control group. Further analysis revealed that this engineered bacterium ameliorates hyperuricemia by modulating the Firmicutes-to-Bacteroidetes ratio, increasing microbial diversity, and promoting the growth of beneficial genera. Collectively, this study establishes an engineered probiotic cell factory for uric acid degradation and demonstrates a proof-of-concept for the microbial remediation of hyperuricemia.