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

围产期肠道微生物组在成人肾脏有机阴离子转运发展中的作用

• 批准号: 9763594
• 负责人: SANJAY K NIGAM
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763594
• 关键词: Activities of Daily Living; Adult; Analgesics; Animals; Anions; Antibiotics; Antioxidants; Area; Behavioral Research; Biomedical Research; Birth; CCL21 gene; Carnitine; Clinical; Clinical Research; Controlled Environment; Cresol; Data; Development; Diet; Drug Kinetics; Ensure; Estrone-Sulfate; Exposure to; Family; Flavonoids; Germ-Free; Goals; Health; Indican; Indoles; Investigation; Kidney; Kidney Diseases; Kynurenine; Lead; Life; Mediating; Mus; Neonatal; Newborn Infant; Organic Anion Transporters; Pattern; Penicillins; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Physiological; Plasma; Play; Premature Infant; Probenecid; Propionates; Renal function; Research; Ribosomal RNA; Rodent; Role; Route; Series; Signaling Molecule; Slice; System; Time; Time Series Analysis; Toxin; Tubular formation; Unspecified or Sulfate Ion Sulfates; Urate; Urine; Volatile Fatty Acids; adverse outcome; base; driving force; gut microbiome; gut microbiota; in vivo; inhibitor/antagonist; member; metabolomics; metagenomic sequencing; neonate; novel; novel strategies; postnatal; postnatal development; postnatal period; prevent; solute; transcriptomics; uptake

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).

项目概要/摘要 出生后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）具有非常高容量的有机阴离子 (PAH) 运输系统。其中包括各种各样的 有机小分子，包括代谢物（例如肉碱）、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 （例如水银）。肾脏有机阴离子转运系统包括以下转运蛋白： OAT1（最初由 PI 实验室发现，称为 NKT）、OAT3、MRP2 和 MRP4。 OAT 的汇率似乎是- 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 新生儿中几乎没有有机阴离子转运至非常高容量的有机阴离子转运 系统？我们对 OAT1 和 OAT3 的代谢组学研究表明，OAT 是肾脏代谢的主要途径。 处理多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（产后至成人）表明这些代谢物早期存在于产后血浆/尿液中，并且 它们的消除对泛燕麦抑制剂丙磺舒敏感。由于有机阴离子转运体 已知系统在产后“发育窗口”期间可被其他 OAT 底物诱导，我们 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 （以及可能的 MRP）以及出生后发育窗口期间的功能能力。这确保了 成人近曲小管中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) 每个阶段肠道微生物组衍生的内源性血浆代谢物是什么 产后发育？ b) 肠道菌群的变化（出生后到成人）与处理有什么关系？ 成熟肾脏中肠道微生物组衍生产物的含量？ （16S肠道菌群测序的时间序列 代谢组学时间序列数据的背景）？ SA2。 a) 新生儿在出生期间是否缺乏肠道菌群？ “底物诱导窗口”减少（或以其他方式改变）成人对肾脏经典底物的处理 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—— 早期接触肠道微生物衍生的产品对于肠道内适当的有机阴离子转运至关重要 成年人，这将是该领域的重大进步，也为加强新方法奠定了基础 肾小管功能（例如，早产儿、肾脏疾病的早期阶段）。