Origin of Excess Acid in Uric Acid Urolithiasis

尿酸尿石症中酸过多的根源

• 批准号: 10442425
• 负责人: JEFFREY D BROWNING
• 金额: $ 44.97万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442425
• 关键词: 16S ribosomal RNA sequencing; Acids; Address; Aging; Alkalinization; American; Ammonia; Animals; Antibiotics; Bacteria; Bacterial Model; Biochemical; Biochemistry; Bioinformatics; Biometry; Blood; Buffers; Chemistry; Clinical; Communities; Data; Defect; Diabetes Mellitus; Diet; Etiology; Excretory function; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feces; Female; Fibrinogen; Frequencies; Functional disorder; Generations; Germ-Free; Healthcare; Hepatic; Hepatocyte; High Fat Diet; Human; Impairment; Infiltration; Integration Host Factors; Intestines; Investigation; Kidney; Kidney Calculi; Lead; Leptin; Liver; Matched Group; Measurement; Measures; Metabolic; Metabolic syndrome; Modeling; Mus; NMR Spectroscopy; Nephrolithiasis; Non obese; Obesity; Oral; Pathogenicity; Pathology; Patients; Phenotype; Pioglitazone; Plasma; Precipitation; Prevalence; Production; Propionates; Rattus; Research Personnel; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk; Serum; Shotguns; Source; Testing; Thinness; Titrations; Transplantation; Urate; Uric Acid; Urine; Virulence Factors; analysis pipeline; care burden; cost; diabetic; disease phenotype; experimental study; fecal microbiome; gut bacteria; gut microbiota; host microbiota; human subject; in vivo; insight; liver metabolism; male; metabolomics; metagenomic sequencing; microbial; microbial genome; microbiome; microbiome analysis; microbiota; microbiota transplantation; microorganism; novel; novel therapeutics; obese patients; organic acid; urinary; urolithiasis

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.

项目总结/摘要 尿酸尿石症约占肾结石的10%，并且患病率正在增加 与此同时，肥胖、代谢综合征和糖尿病的患病率不断上升。 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 是酸尿过多。我们提出一个尿酸尿石症的多器官致病模型 可追溯到肠道微生物群（微生物区系的总体）产生的肠道有机酸 由于脂肪变性导致的肝脏细微缺陷， 然后增加肾脏的酸负荷。肾脏氨生成缺陷 要求排泄由替代缓冲液携带的过量酸， 尿酸盐，最终导致尿酸沉淀和结石。在这个模型中， 尿酸尿石症始于肠道和肝脏。该提案将使用动物和 人体研究，以检验肠道和肝脏作为尿酸肾致病源的假设 石头我们提出三个目标：1。微生物群-表型关联。微生物 （微生物基因组）从尿酸结石形成者，肥胖，和瘦非结石形成者将 与血浆和尿液参数相关。2.微生物群-表型因果关系。因果关系将 通过将来自Aim 1的三组人类的微生物群移植到 无菌小鼠，我们将检查是否赋予了适当的表型。3. 微生物-宿主相互作用我们将测试的假设，增加酸的生产，从 微生物群是必要的，但不足以赋予疾病表型。其他宿主因素 需要调用;特别是管腔衍生有机酸的肝脏代谢受损 肝细胞的脂肪浸润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。这些实验是第一个 探讨尿酸尿石症酸负荷的根本原因，并采取相应的研究和治疗措施， 尿酸尿石症的经验性管理尿碱化， 彻底阐明其病理生理学和随后的确定性治疗。研究还 开辟了新的研究路线的病理生物学的微生物-宿主相互作用， 代谢综合征