ABSTRACT

Hyperuricemia is the second most prevalent metabolic disease to human health after diabetes. Only a few clinical drugs are available, and most of them have serious side effects. The human body does not have urate oxidase, and uric acid is secreted via the kidney or the intestine. Reduction through kidney secretion is often the cause of hyperuricemia. We hypothesized that the intestine secretion could be enhanced when a recombinant urate-degrading bacterium was introduced into the gut. We engineered an Escherichia coli Nissle 1917 strain with a plasmid containing a gene cassette that encoded two proteins PucL and PucM for urate metabolism from Bacillus subtilis, the urate importer YgfU and catalase KatG from E. coli, and the bacterial hemoglobin Vhb from Vitreoscilla sp. The recombinant E. coli strain effectively degraded uric acid under hypoxic conditions. A new method to induce hyperuricemia in mice was developed by intravenously injecting uric acid. The engineered Escherichia coli strain significantly lowered the serum uric acid when introduced into the gut or directly injected into the blood vessel. The results support the use of urate-degrading bacteria in the gut to treat hyperuricemia. Direct injecting bacteria into blood vessels to treat metabolic diseases is proof of concept, and it has been tried to treat solid tumors.

摘要

高尿酸血症是仅次于糖尿病的第二大危害人类健康的代谢疾病。可供临床使用的药物屈指可数，而且大多有严重的副作用。人体没有尿酸氧化酶，尿酸是通过肾脏或肠道分泌的。通过肾脏分泌减少通常是高尿酸血症的原因。我们假设将重组尿酸盐降解细菌引入肠道时可以增强肠道分泌。我们 设计 了 一种大肠杆菌Nissle 1917 菌株 , 其 质粒 包含 编码 两种 蛋白质 PucL 和 PucM 用于 来自枯草 杆菌的 尿酸盐 代谢 , 来自 大肠杆菌 的 尿酸盐 进口 体 YgfU 和 过氧化氢酶 KatG , 以及 来自大肠杆菌的 细菌 血红蛋白 Vhb .玻璃体颤菌 重组大肠杆菌菌株在缺氧条件下有效降解尿酸。通过静脉注射尿酸，开发了一种诱导小鼠高尿酸血症的新方法。工程大肠杆菌菌株在引入肠道或直接注入血管时显着降低了血清尿酸。该结果支持在肠道中使用降解尿酸盐的细菌来治疗高尿酸血症。将细菌直接注射到血管中治疗代谢性疾病是概念验证，并且已经尝试治疗实体瘤。