Evaluation of the gut-kidney axis in kidney stone disease

肾结石疾病中肠-肾轴的评估

• 批准号: 9802990
• 负责人: Michelle Denburg
• 金额: $ 72.65万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9802990
• 关键词: 4 year old; Adolescent; Adult; Affect; Age; Age-Years; Antibiotics; Bacteria; Butyrates; Calcium; Cardiovascular Diseases; Cephalosporins; Chemistry; Child; Chronic Kidney Failure; Clinical Data; Cohort Studies; Communities; Complex; Data; Data Analytics; Data Linkages; Databases; Diabetes Mellitus; Diet; Disease; Dose; Environmental Exposure; Evaluation; Event; Excretory function; Exposure to; Feces; Fluoroquinolones; Fracture; Future; Goals; Gut Mucosa; Health; Hour; Human; Hypertension; Incidence; Individual; Intake; Intestinal Absorption; Intestines; Kidney; Kidney Calculi; Lead; Life; Link; Macronutrients Nutrition; Measures; Mediating; Mediation; Medical; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Minerals; Modeling; Morbidity - disease rate; Nephrolithiasis; Nested Case-Control Study; Nitrofurantoin; Nutritional; Oral; Organism; Oxalates; Oxalobacter; Oxalobacter formigenes; Pain; Participant; Patients; Penicillins; Pharmacoepidemiology; Pharmacologic Substance; Pharmacy facility; Population; Prevalence; Prevention; Reporting; Research; Research Design; Risk; Risk Factors; Role; Shotguns; Subgroup; Testing; Time; United States; Urinary tract; Urine; Volatile Fatty Acids; Zinc; cost; dysbiosis; gut microbiome; high dimensionality; insight; metabolome; metabolomics; microbial community; microbiome; microbiome alteration; multidimensional data; new therapeutic target; novel; prevent; therapeutic target; urinary; young woman

PROJECT SUMMARY Kidney stone disease is highly prevalent, increasingly common, and associated with considerable morbidity. However, no new treatments to prevent kidney stones have been introduced in the last 30 years. Understanding how dysbiosis of the gut microbiome contributes to nephrolithiasis could lead to novel new treatments for kidney stone prevention. However, most prior studies of the gut microbiome in this population focused on Oxalobacter formigenes without considering the role of the entire gut microbiome in the gut-kidney axis, which is the complex interplay between the intestinal and urinary tracts in human health and disease. A critical barrier to developing new treatments for stone prevention is a lack of understanding of how perturbations of the gut microbiome and downstream changes in metabolites in the intestinal and urinary tracts contribute to kidney stone disease. In this proposal, we build on our recent discoveries of the role of diet, antibiotics, the gut microbiome, and the metabolome in kidney stone disease. We leverage an interdisciplinary team that is uniquely poised to define the human gut-kidney axis in kidney stone disease by combining expertise in using nutritional profiling, mediation analyses of high-dimensional microbiome and metabolomic data, and large data analytics. The proposed research tests the central hypothesis that diet and antibiotics contribute to nephrolithiasis by perturbing the gut- kidney axis through alterations of the gut microbiome. In doing so, the proposed studies will identify metabolic pathways in the gut-kidney axis that could be targets for novel therapeutics to prevent kidney stones. In Aim 1, we will identify perturbations of the microbiome and metabolome in kidney stone disease. We will assess diet and collect stool and urine from 300 participants ≥4 years old without recent antibiotic exposure (150 with calcium kidney stones and 150 matched controls), oversampling younger participants. We will sequence the gut microbiome using shotgun metagenomics and measure downstream metabolites using untargeted metabolomics of stool and urine, targeted short-chain fatty acid metabolomics of stool, and 24-hour urine chemistries. Using novel mediation models, we will define the direct and indirect effect of diet on the gut microbiome and intestinal and urinary metabolites and its contribution to kidney stones. In Aim 2, we will, for the first time, determine the relationship between oral antibiotic exposure and urine chemistries in kidney stone disease. We will link 24-hour urine chemistry results with pharmaceutical claims and clinical data of individuals in the HealthCore database, which includes >48 million individuals. We will conduct a nested case-control study to determine the relationship between the dose and duration of antibiotic exposure and kidney stones and to identify sub-groups at greatest risk. We will then perform a cohort study to identify how oral antibiotics alter urine chemistries. These results will identify metabolites that contribute to kidney stones following perturbation of the gut microbiome and provide key insights for future studies of primary and secondary stone prevention.

项目摘要 肾结石疾病高度普遍，越来越普遍，并且与考虑发病率有关。 但是，在过去30年中，没有引入任何新的治疗方法来防止肾结石。理解 肠道微生物组的营养不良如何有助于肾石器症，可能导致新的肾脏治疗 预防石材。然而，大多数对肠道微生物组的先前研究都集中在草酸菌上 孔基因源不考虑整个肠道微生物组在肠道轴轴上的作用，这是复合物 人类健康和疾病中的肠道和尿道之间的相互作用。发展的关键障碍 预防石材的新疗法是缺乏了解肠道微生物组和 肠道和尿路中代谢产物的下游变化导致肾结石疾病。 在这一建议中，我们建立在饮食，抗生素，肠道微生物组和饮食作用的最新发现的基础上 肾脏疾病中的代谢组。我们利用一支跨学科的团队，该团队被中毒以定义 通过使用营养概况，调解的专业知识，人类肠道肠道轴肾脏疾病中的肠道轴轴 高维微生物组和代谢组数据以及大数据分析的分析。提议 研究检验的中心假设是，饮食和抗生素通过干扰肠道造成肾石器症有助于 肾脏轴通过肠道微生物组的改变。在这样做的过程中，拟议的研究将确定代谢 肠道轴的途径可能是预防肾结石的新疗法的靶标。在AIM 1中， 我们将确定肾脏疾病中微生物组和代谢组的扰动。我们将评估饮食 并从300名参与者中收集粪便和尿液，没有最近的抗生素暴露（150钙 肾结石和150个匹配的对照），对年轻参与者进行了过采样。我们将对肠道进行排序 使用shot弹枪宏基因组学并使用不靶向的微生物组测量下游代谢产物 粪便和尿液的代谢组学，靶向的短链脂肪酸代谢组学和24小时尿液 化学。使用新颖的中介模型，我们将定义饮食对肠道的直接和间接影响 微生物组，肠道和泌尿代谢物及其对肾结石的贡献。在AIM 2中，我们将 第一次，确定肾结石中口服抗生素暴露与尿液化学的关系 疾病。我们将将24小时的尿液化学结果与个体的药物主张和临床数据联系起来 在包括4800万个人的医疗数据库中。我们将进行嵌套的病例对照研究 确定抗生素暴露与肾结石的剂量和持续时间之间的关系以及 确定最大风险的子组。然后，我们将进行一项队列研究，以确定口服抗生素如何改变尿液 化学。这些结果将确定在扰动后导致肾结石的代谢产物 肠道微生物组，并为预防原发性和次要石材的未来研究提供关键见解。