Liu Yuanyuan, Zhou Zhiwei, Jarman J Bryce, Chen Haoqing, Miranda-Velez Michelle, Terkeltaub Robert, Dodd Dylan
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego, CA, USA.
Nat Microbiol. 2025 Aug 6. doi: 10.1038/s41564-025-02079-4.
Approximately one-third of urate, which at elevated levels contributes to hyperuricaemia and gout, is excreted into the intestinal tract of healthy individuals where bacteria aid its elimination. However, the molecular details of purine metabolism in the gut microbiome are unclear. Here we uncovered the 2,8-dioxopurine pathway, an anaerobic route for purine degradation in the gut bacteria, Clostridium sporogenes and Escherichia coli. Reconstitution with purified enzymes and mutational analysis combined with isotope tracking and mass spectrometry identified a selenium-dependent enzyme, 2,8-dioxopurine dehydrogenase (DOPDH), and seven additional enzymes that connect purine metabolism to short-chain fatty acid synthesis and ATP generation (measured via luciferase assay). Competition experiments in gnotobiotic mice showed that bacteria harbouring this pathway exhibit a fitness advantage, with wild-type bacteria rapidly outcompeting a DOPDH-deficient strain. Widespread presence of these genes across host-associated microbiomes suggests a host-microbe symbiosis, where host-secreted urate fosters a metabolic niche for bacteria that break it down. These findings could have therapeutic implications for the modification and enhancement of intestinal elimination of urate.
大约三分之一的尿酸（尿酸水平升高会导致高尿酸血症和痛风）会排泄到健康个体的肠道中，在那里细菌有助于其清除。然而，肠道微生物群中嘌呤代谢的分子细节尚不清楚。在这里，我们发现了2,8 - 二氧嘌呤途径，这是一种在肠道细菌（生孢梭菌和大肠杆菌）中进行嘌呤降解的厌氧途径。通过纯化酶的重组、突变分析，结合同位素追踪和质谱技术，鉴定出一种硒依赖性酶——2,8 - 二氧嘌呤脱氢酶（DOPDH），以及另外七种将嘌呤代谢与短链脂肪酸合成和ATP生成联系起来的酶（通过荧光素酶测定法测量）。在无菌小鼠中进行的竞争实验表明，携带该途径的细菌具有适应性优势，野生型细菌能迅速胜过DOPDH缺陷菌株。这些基因在与宿主相关的微生物群中广泛存在，表明存在宿主 - 微生物共生关系，即宿主分泌的尿酸为分解尿酸的细菌营造了一个代谢生态位。这些发现可能对改变和增强肠道尿酸清除具有治疗意义。
