He Lina, Tang Wei, Huang Ling, Zhou Wei, Huang Shaojia, Zou Linxuan, Yuan Lisha, Men Dong, Chen Shiyun, Hu Yangbo
CAS Key Laboratory of Special Pathogens and Biosafety Wuhan Institute of Virology, Chinese Academy of Sciences Wuhan China.
University of Chinese Academy of Sciences Beijing China.
Bioeng Transl Med. 2022 Nov 21;8(2):e10449. doi: 10.1002/btm2.10449. eCollection 2023 Mar.
Hyperuricemia is a prevalent disease worldwide that is characterized by elevated urate levels in the blood owing to purine metabolic disorders, which can result in gout and comorbidities. To facilitate the treatment of hyperuricemia through the uricolysis, we engineered a probiotic Nissle 1917 (EcN) named EcN C6 by inserting an FtsP-uricase cassette into an "insulated site" located between the and genes. Expression of FtsP-uricase in this insulated region did not influence the probiotic properties or global gene transcription of EcN but strongly increased the enzymatic activity for urate degeneration, suggesting that the genome-based insulated system is an ideal strategy for EcN modification. Oral administration of EcN C6 successfully alleviated hyperuricemia, related symptoms and gut microbiota in a purine-rich food-induced hyperuricemia rat model and a -knockout mouse model. Together, our study provides an insulated site for heterologous gene expression in EcN strain and a recombinant EcN C6 strain as a safe and effective therapeutic candidate for hyperuricemia treatment.
高尿酸血症是一种在全球范围内普遍存在的疾病，其特征是由于嘌呤代谢紊乱导致血液中尿酸水平升高，这可能会引发痛风及合并症。为了通过尿酸分解促进高尿酸血症的治疗，我们通过将FtsP-尿酸酶盒插入位于特定基因之间的“绝缘位点”，构建了一种名为EcN C6的益生菌Nissle 1917（EcN）。FtsP-尿酸酶在该绝缘区域的表达不影响EcN的益生菌特性或全局基因转录，但显著提高了尿酸降解的酶活性，这表明基于基因组的绝缘系统是EcN修饰的理想策略。在富含嘌呤食物诱导的高尿酸血症大鼠模型和特定基因敲除小鼠模型中，口服EcN C6成功缓解了高尿酸血症、相关症状及肠道微生物群。总之，我们的研究为EcN菌株中的异源基因表达提供了一个绝缘位点，并提供了重组EcN C6菌株作为治疗高尿酸血症的安全有效候选药物。
