Hyperuricemia, a prevalent metabolic disorder, affects over 1 billion individuals worldwide. It not only serves as the direct precipitant of gouty arthritis but also correlates closely with severe comorbidities such as chronic kidney disease, cardiovascular diseases, and diabetes. Over the past five decades, the incidence of hyperuricemia has demonstrated a marked upward trend attributable to the widespread adoption of high-purine diets, thereby compromising the quality of life for an expanding population. Conventional pharmacotherapies, such as allopurinol, inhibit uric acid biosynthesis but are associated with substantial side effects including hepatorenal toxicity and cutaneous allergic reactions, presenting significant challenges for clinical management. Moreover, these pharmaceutical approaches fail to disrupt intestinal absorption of purine precursors, fundamentally remaining passive intervention strategies. Emerging synthetic biology-based therapies primarily rely on enzymatic degradation of uric acid to allantoin or live bacterial biocatalysis for excretion, yet such methods are constrained by enzymatic instability and suboptimal functional enhancement of microbial chassis.
Based on this, our team innovatively proposed a "prevention-first treatment" strategy: using synthetic biology to modify the probiotic Escherichia coli Nissle 1917 and develop the engineered strain YES301, which can efficiently intercept purine precursors in the intestine and block uric acid synthesis from the source. Through the F94Y/S88T mutation modeled by AlphaFold, the xanthine transporter XANQ was rationally designed. Then, through precise regulation of the promoter J23100 and the ribosome binding site B0034, YES301 ultimately achieved an 8.6-fold increase in xanthine transport capacity and a 4.0-fold increase in hypoxanthine transport capacity.
The innovation of this project lies in the first application of engineered bacteria for active intervention in purine absorption, breaking the passive mode of "produce first, then degrade" in existing treatments. The design inspiration comes from the reflection and learning of the limitations of previous studies - uricase is inactive in the anaerobic intestine and cannot block purine conversion.Moreover, the YES301 platform has high scalability and can be coupled with secreted uricase in the future to achieve "blockage + degradation" dual-mode treatment. This work not only provides a safe oral solution for hyperuricemia but also opens up a new paradigm for the treatment of metabolic diseases with live bacteria drugs.