The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.
The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.
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DOI：
10.1172/jci.insight.160437
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发表时间：
2023-01-24
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：
Granados, Jeffry C.;Ermakov, Vladimir;Maity, Koustav;Vera, David R.;Chang, Geoffrey;Nigam, Sanjay K.
有机阴离子转运蛋白1(OAT1/SLC22A6，NKT)是肾脏中的一种多特异性药物转运蛋白，具有多种底物，包括药物、内源性代谢产物、天然产物和尿毒症毒素。在这里，我们表明OAT1调节肠道微生物衍生代谢物的水平。我们耗尽了Oat1-KO和WT小鼠的肠道微生物组，并进行了代谢组学分析，以分析基因型(KO与WT)和微生物组耗竭的影响。OAT1是宿主和微生物之间的体内中介，162种依赖肠道微生物组的代谢物中有40种也受到Oat1缺失的影响。化学信息学分析表明，改变的代谢产物(如吲哚硫酸盐、对甲酚硫酸盐、脱氧胆酸盐)具有更多的环状结构和硫酸盐基团。这表明了一条从肠道微生物到肝脏II期代谢，再到肾脏OAT1介导的转运的途径。体外转运和磁珠结合实验证实了多种肠源性代谢物与OAT1直接相互作用的观点。我们发现依赖于OAT1的肠道微生物衍生的代谢物在慢性肾脏疾病(CKD)模型和人类药物-代谢物相互作用中受到影响。与遥感和信号理论一致，我们的结果支持药物转运蛋白(如OAT1、OAT3、OATP1B1、OATP1B3、MRP2、MRP4、ABCG2)在调节肠道微生物依赖的新陈代谢以及宿主和微生物群之间的组织间通信中发挥核心作用的观点。
Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome–derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1–mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome–derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe–dependent metabolism, as well as interorganismal communication between the host and microbiome.
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