Remote effects of kidney drug transporter OAT1 on gut microbiome composition and urate homeostasis.
Remote effects of kidney drug transporter OAT1 on gut microbiome composition and urate homeostasis.
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DOI：
10.1172/jci.insight.172341
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发表时间：
2023-11-08
期刊：
影响因子：
8
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Ermakov, Vladimir S.;Granados, Jeffry C.;Nigam, Sanjay K.
有机阴离子转运蛋白OAT 1（SLC 22 A6，最初被鉴定为NKT）是一种多特异性转运蛋白，负责通过肾脏消除来自肠道微生物组的小有机阴离子。许多是与慢性肾病（CKD）相关的尿毒症毒素。OAT 1是一组“药物”转运蛋白之一，在通过小分子调节器官间和生物体间通讯的大型稳态网络中充当枢纽。遥感和信号理论预测，网络中这样一个关键枢纽的基因缺失会导致补偿性的生物体间通信（例如，宿主肠道微生物动力学）。最近来自Oat 1-KO小鼠的代谢组学数据表明，一些受影响最严重的代谢物来自细菌酪氨酸、色氨酸、嘌呤和脂肪酸代谢。粪便16 S扩增子的功能宏基因组分析和全基因组测序显示，OAT 1的丢失与调节尿酸盐、肠源性对甲酚、色氨酸衍生物和脂肪酸产生的微生物途径显著相关。某些变化，如肠道微生物尿酸盐代谢的改变，似乎是补偿性的。因此，肾脏中的燕麦1似乎通过调节肠道微生物组组成和代谢能力来介导远程生物体间通讯。由于OAT 1在近端小管中的功能在CKD中受到很大影响，我们的结果可能揭示肠道微生物组动力学的相关改变。
The organic anion transporter OAT1 (SLC22A6, originally identified as NKT) is a multispecific transporter responsible for the elimination by the kidney of small organic anions that derive from the gut microbiome. Many are uremic toxins associated with chronic kidney disease (CKD). OAT1 is among a group of “drug” transporters that act as hubs in a large homeostatic network regulating interorgan and interorganismal communication via small molecules. The Remote Sensing and Signaling Theory predicts that genetic deletion of such a key hub in the network results in compensatory interorganismal communication (e.g., host-gut microbe dynamics). Recent metabolomics data from Oat1-KO mice indicate that some of the most highly affected metabolites derive from bacterial tyrosine, tryptophan, purine, and fatty acid metabolism. Functional metagenomic analysis of fecal 16S amplicon and whole-genome sequencing revealed that loss of OAT1 was impressively associated with microbial pathways regulating production of urate, gut-derived p-cresol, tryptophan derivatives, and fatty acids. Certain changes, such as alterations in gut microbiome urate metabolism, appear compensatory. Thus, Oat1 in the kidney appears to mediate remote interorganismal communication by regulating the gut microbiome composition and metabolic capability. Since OAT1 function in the proximal tubule is substantially affected in CKD, our results may shed light on the associated alterations in gut-microbiome dynamics.
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