Role of the Perinatal Gut Microbiome in the Development of Adult Kidney Organic Anion Transport

项目摘要/摘要 出生后的肾脏运输有机阴离子的能力极其有限，而成人肾脏 (近端小管)有一个非常高容量的有机阴离子(PAH)运输系统。其中包括种类繁多的 指包括代谢物在内的有机小分子(例如，肉碱)、饮食化合物(如黄酮类)，发出信号 分子(例如短链脂肪酸、香料)、抗氧化剂(例如尿酸)、药物(如止痛药)和毒素 (例如，水银)。肾脏有机阴离子转运系统包括以下转运体等： OAT1(由PI的实验室首次发现的NKT)、OAT3、MRP2和MRP4。燕麦看起来就是- 限制肾脏消除的步骤。我们要问的问题是：这种转变是如何发生的 在新生儿中几乎没有有机阴离子的运输，而是有很高的有机阴离子转运能力。 系统？我们对OAT1和OAT3的代谢组学研究表明，燕麦是肾脏的主要途径 处理各种肠道微生物衍生的代谢物(也是有机阴离子)。时间序列 分析(从出生到成人)表明，这些代谢物存在于出生后早期的血浆/尿液和 它们的消除对PAN-OAT抑制剂丙磺舒敏感。因为有机阴离子转运体 我们知道，在出生后的“发育窗口期”，系统可以被其他燕麦底物诱导。 提出，在正常情况下，正是这些肠道微生物产物诱导燕麦的表达 (可能还有MRP)，因此在出生后发育窗口期的功能能力。这确保了 成人近端小管的高容量有机阴离子转运系统能够消除 上述有机小分子以及尿毒症溶质。我们建议回答以下问题 问题：SA1。A)肠道微生物群衍生的内源性血浆代谢物是什么 出生后发育吗？B)肠道菌群的变化(出生后到成人)与处理有什么关系 肠道微生物群衍生产品在成熟的肾脏中的作用？(16S肠道菌群序列的时间序列 代谢组学时间序列数据的背景)？SA2.A)新生儿的肠道菌群在出生后 “底物诱导窗口”减少(或改变)成人对肾脏经典底物的处理 有机阴离子传输系统(多环芳烃、硫酸雌酮)？如果我们能够从数量上证明我们的假设-- 早期接触肠道微生物衍生产品对于有机阴离子在体内的适当传输是必不可少的 成年人来说，这将是该领域的一大进步，也为加强 肾小管功能(例如，早产儿、早期肾病)。

PROJECT SUMMARY/ABSTRACT The postnatal kidney has an extremely limited ability to transport organic anions, whereas the adult kidney (proximal tubule) has a very high capacity organic anion (PAH) transport system. These include a wide variety of small organic molecules including metabolites (eg. carnitine), dietary compounds (eg. flavonoids), signaling molecules (eg. short chain fatty acids, odorants), antioxidants (eg. urate), drugs (eg. analgesics) and toxins (eg. mercurials). The renal organic anion transport system includes the following transporters, among others: OAT1 (first discovered by the PI's lab as NKT), OAT3, MRP2 and MRP4. The OATs appear to be the rate- limiting step in renal elimination. The question we are asking is: How does this transformation occur such that there is almost no organic anion transport in the neonate to a very high capacity organic anion transport system? Our metabolomics studies of the OAT1 and OAT3 indicate that the OATs are the main routes of renal handling of a wide range of gut microbiome-derived metabolites (which are also organic anions). Time series analysis (postnatal to adult) indicates that these metabolites are present early in postnatal plasma/urine and that their elimination is sensitive to the pan-OAT inhibitor probenecid. Since the organic anion transporter system is known to be inducible by other OAT substrates during a post-natal "developmental window," we propose that, under normal conditions, it is these gut microbiome products that induce the expression of OATs (and possibly MRPs) and thus functional capacity during the postnatal developmental window. This ensures a high capacity organic anion transport system in the adult proximal tubule which is able to eliminate the aforementioned small organic molecules as well as uremic solutes. We propose to answer the following questions: SA1. a) What are the gut microbiome-derived endogenous plasma metabolites at each stage of postnatal development? b) What is the relationship of the changing gut flora (postnatal to adult) to the handling of gut microbiome-derived products in the maturing kidney? (time series of 16S gut flora sequencing in the context of metabolomics time series data)? SA2. a) Does absence of the gut flora in the newborn during the "substrate-inducibility window" diminish (or otherwise alter) adult handling of classic substrates of the renal organic anion transport system (PAH, estrone sulfate)? If we are able to quantitatively prove our hypothesis-- that early exposure to gut microbiome-derived products is essential to proper organic anion transport in the adults, this would be a major advance for the field and also set the stage for new approaches to enhancing tubular function (e.g., premature infant, early stages of kidney disease).