Evaluation of the gut-kidney axis in kidney stone disease

肾结石疾病中肠-肾轴的评估

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肾结石疾病非常普遍，越来越常见，并且与相当大的发病率相关。然而，在过去 30 年里，并没有推出预防肾结石的新疗法。肠道微生物群失调如何导致肾结石可能导致新的肾脏治疗方法然而，大多数先前对该人群肠道微生物组的研究都集中在草酸杆菌上。没有考虑整个肠道微生物组在肠-肾轴中的作用，这是复杂的肠道和泌尿道之间的相互作用是人类健康和疾病发展的关键障碍。预防结石的新疗法缺乏对肠道微生物群的扰动和肠道和泌尿道代谢物的下游变化会导致肾结石疾病。在这项提案中，我们以最近关于饮食、抗生素、肠道微生物组和肠道菌群作用的发现为基础。我们利用跨学科团队来定义肾结石疾病的代谢组。通过结合营养分析、调节方面的专业知识，研究肾结石疾病中的人类肠肾轴高维微生物组和代谢组数据分析以及大数据分析。研究测试了一个中心假设，即饮食和抗生素通过扰乱肠道而导致肾结石通过改变肠道微生物群来改变肾轴，拟议的研究将确定代谢。在目标 1 中，肠肾轴中的通路可能成为预防肾结石的新疗法的目标。我们将确定肾结石疾病中微生物组和代谢组的扰动我们将评估饮食。收集 300 名年龄≥4 岁且近期未接触过抗生素的参与者的粪便和尿液（其中 150 名参与者服用钙剂）肾结石和 150 名匹配的对照），对年轻参与者进行过采样，我们将对肠道进行测序。使用鸟枪宏基因组学分析微生物组并使用非靶向测量下游代谢物粪便和尿液代谢组学、粪便靶向短链脂肪酸代谢组学和24小时尿液使用新的介导模型，我们将定义饮食对肠道的直接和间接影响。微生物组、肠道和尿液代谢物及其对肾结石的影响在目标 2 中，我们将针对首次确定口服抗生素暴露与肾结石尿液化学之间的关系我们会将 24 小时尿液化学结果与药物声明和个人临床数据联系起来。 HealthCore 数据库包含超过 4800 万人，我们将进行一项巢式病例对照研究。确定抗生素暴露的剂量和持续时间与肾结石之间的关系然后，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。这些结果将确定在扰动后导致肾结石的代谢物。肠道微生物组，为未来的初级和二级结石预防研究提供重要见解。