Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease
Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease
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DOI：
10.1038/s41467-019-09735-4
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发表时间：
2019-04-23
影响因子：
16.6
通讯作者：
Abe, Takaaki
中科院分区：
文献类型：
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作者：
Kikuchi, Koichi;Saigusa, Daisuke;Abe, Takaaki
糖尿病肾病是肾衰竭的主要原因，迫切需要在疾病管理方面取得突破。在这里，我们使用非靶向代谢组学显示，在肾脏中过度表达人尿毒症毒素转运蛋白SLCO4C1的大鼠中，硫酸苯酯（一种肠道微生物群衍生的代谢物）的水平随着糖尿病的进展而增加，而在蛋白尿有限的大鼠中则减少。在糖尿病的实验模型中，硫酸苯酯给药诱导蛋白尿和足细胞损伤。在糖尿病患者队列中，硫酸苯酯水平与微量白蛋白尿患者的基础和预测2年白蛋白尿进展显著相关。酪氨酸苯酚裂解酶是一种细菌酶，负责在肝脏中代谢为硫酸苯酯之前从饮食酪氨酸合成苯酚，抑制酪氨酸苯酚裂解酶可减少糖尿病小鼠的白蛋白尿。总之，我们的研究结果表明，硫酸苯酯有助于蛋白尿，并可用作糖尿病肾病的疾病标志物和未来的治疗靶点。
Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.