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

项目概要/摘要 出生后的肾脏运输有机阴离子的能力非常有限，而成年肾脏 （近曲小管）具有非常高容量的有机阴离子（PAH）转运系统。其中包括各种各样的 小的有机分子，包括代谢物（例如，肉毒碱）、膳食化合物（例如，类黄酮），信号传导 分子（例如，短链脂肪酸、气味剂）、抗氧化剂（例如，尿酸盐）、药物（例如，镇痛药）和毒素 （例如：汞剂）。肾有机阴离子转运系统包括以下转运蛋白： OAT 1（PI实验室首次发现为NKT）、OAT 3、MRP 2和MRP 4。OAT似乎是利率- 肾脏消除的限制步骤。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转运到非常高容量的有机阴离子转运 系统？我们对OAT 1和OAT 3的代谢组学研究表明，OAT是肾脏代谢的主要途径。 处理各种肠道微生物组衍生的代谢物（也是有机阴离子）。时间序列 分析（出生后至成人）表明，这些代谢物早期存在于出生后血浆/尿液中， 它们的消除对泛OAT抑制剂丙磺舒敏感。因为有机阴离子转运体 已知在出生后的“发育窗口”期间， 我提出，在正常条件下，正是这些肠道微生物组产物诱导了OAT的表达 (and可能是MRPs），因此在出生后发育窗口期间的功能能力。这确保了 高容量有机阴离子运输系统在成人近端小管，这是能够消除 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：SA 1。a）在每个阶段，肠道微生物组来源的内源性血浆代谢物是什么？ 产后发育？B）肠道植物群（出生后到成年）的变化与处理的关系是什么？ 肠道微生物群衍生产物在成熟的肾脏中的作用(time一系列16 S肠道植物群测序， 代谢组学时间序列数据的背景）？SA 2. a）新生儿在分娩期间肠道植物群的缺乏是否 “基质诱导窗口”减少（或以其他方式改变）成人对肾组织经典基质的处理 有机阴离子转运系统（PAH，硫酸雌酮）？如果我们能够定量地证明我们的假设-- 早期暴露于肠道微生物组衍生的产物对于肠道中适当的有机阴离子转运至关重要。 成年人，这将是该领域的一个重大进步，也为新的方法奠定了基础，以提高 管状功能（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).