Origin of Excess Acid in Uric Acid Urolithiasis

项目摘要/摘要 尿酸尿石症约占肾结石的10%，而且患病率正在上升。 与此同时，肥胖、代谢综合征和糖尿病的患病率也在不断上升。 尿酸尿石症是肥胖患者多系统紊乱的肾脏表现， 代谢综合征和糖尿病。尿酸尿石症的主要病理生理特征 是过度的酸尿症。我们提出了尿酸尿石症的多脏器致病模型。 肠道微生物区系可追踪到肠道有机酸的产生(微生物区系总数) 由于脂肪变性引起的肝脏微小缺陷而逃脱了完全的肝脏新陈代谢， 然后对肾脏施加更多的酸负荷。肾脏缺陷性氨生成 肾脏脂肪变性要求排泄由替代缓冲液携带的过量酸，包括 尿酸盐，最终导致尿酸沉淀和结石。在此模型中，第一步 尿酸尿石症始于肠道和肝脏。这项提案将结合使用动物和 人体研究验证肠道和肝脏是尿酸肾病源的假说 石头。我们提出了三个目标来解决：1.微生物区系-表型关联。微生物群 (微生物基因组)来自尿酸结石形成者、肥胖和瘦肉型非结石形成者 与血、尿参数相关。2.微生物区系表型成因。因果关系将 通过将来自AIM 1的三组人的微生物区系移植到 无菌小鼠，我们将检查是否授予了适当的表型。3. 微生物区系与宿主的相互作用。我们将检验这样一种假设，即增加的酸产量来自 微生物区系是确定疾病表型所必需的，但不是充分的。其他主机因素 需要调用；特别是管腔衍生的有机酸的肝脏代谢受损 由肝细胞的脂肪渗透所致。我们将使用动物和人类来绘制所有目标 来自人类研究人员、动物病理生理学家、 微生物群生物学家和生物信息学家来测试我们的模型。这些实验是第一次 探讨尿酸尿石症的酸负荷来源，并进行研究和治疗 尿酸尿石症从经验性尿碱化治疗到真正意义上的 彻底阐明其病理生理学，以及随后的最终治疗。这些研究还包括 开辟了微生物群-寄主相互作用的新的研究路线 代谢综合征。

Project Summary/Abstract Uric acid urolithiasis composes up to about 10% of kidney stones and is increasing in prevalence contemporaneously with the escalating prevalence of obesity, metabolic syndrome, and diabetes. Uric acid urolithiasis is the renal manifestation of the multi-systemic disturbances in obesity, metabolic syndrome and diabetes. The primary pathophysiologic feature of uric acid urolithiasis is excessive aciduria. We propose a multi-organ pathogenic model of uric acid urolithiasis traceable to intestinal organic acid generation by the gut microbiota (totality of the microbial fauna) that escapes complete hepatic metabolism due to subtle defects in the liver from steatosis, which then imposes an increased acid load on the kidneys. Defective ammoniagenesis in the kidney from renal steatosis mandates excretion of the excess acid carried by alternative buffers including urate which ultimately leads to uric acid precipitation and stones. In this model, the first step in uric acid urolithiasis starts in the gut and liver. This proposal will use a combination of animal and human studies to test the hypothesis of the gut and liver as pathogenic origin of uric acid kidney stones. We propose three Aims to address: 1. Microbiota-phenotype association. Microbiome (microbial genome) from uric acid stone formers, obese, and lean non-stone-formers will be correlated with plasma and urinary parameters. 2. Microbiota-phenotype causation. Causality will be tested by transplantation of the microbiota from the three groups of humans from Aim 1 into germ-free mice and we will examine whether the appropriate phenotype is conferred. 3. Microbiota-host interaction. We will test the hypothesis that increased acid production from the microbiota is necessary but not sufficient to confer the disease phenotype. Additional host factors need to be invoked; specifically impaired hepatic metabolism of the lumen-derived organic acids from fatty infiltration of hepatocytes. We will use both animals and humans for all Aims drawing expertise from a diverse synergistic team of human researchers, animal pathophysiologists, microbiota biologists, and bioinformaticians to test our model. These experiments are the first to explore the very origin of the acid load in uric acid urolithiasis, and take the study and treatment of uric acid urolithiasis from empirical management by urinary alkalinization to a genuine and thorough elucidation of its pathophysiology, and subsequent definitive therapy. The studies also open up novel lines of investigation of the pathobiology of microbiota-host interaction in the metabolic syndrome.