Evaluation of the gut-kidney axis in kidney stone disease

项目总结 肾结石疾病非常普遍，越来越常见，并与相当大的发病率相关。 然而，在过去的30年里，没有新的治疗方法被引入来预防肾结石。理解 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 防止结石。然而，先前对该人群肠道微生物群的大多数研究都集中在草酸杆菌上。 在没有考虑整个肠道微生物群在肠道-肾脏轴上的作用的情况下，这是复合体 肠道和尿路在人类健康和疾病中的相互作用。发展的关键障碍 预防结石的新疗法是缺乏对肠道微生物群和 肠道和尿路代谢产物的下游变化导致肾结石疾病。 在这项建议中，我们建立在我们最近发现的饮食、抗生素、肠道微生物群和 肾结石疾病中的代谢组学研究。我们利用一个跨学科的团队，这个团队独一无二地准备好定义 人类肠-肾轴在肾结石疾病中的结合使用营养简档、调解 分析高维微生物组和代谢组数据，以及大数据分析。建议数 研究验证了饮食和抗生素通过扰乱肠道而导致肾结石的中心假设。 通过肠道微生物群的改变而导致的肾轴。通过这样做，拟议的研究将确定新陈代谢 肠道-肾轴的通路可能成为预防肾结石的新疗法的靶点。在目标1中， 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4岁≥儿童的大便和尿液，最近没有接触过抗生素(含钙的有150名 肾结石和150名匹配的对照组)，过度抽样年轻参与者。我们会对内脏进行排序 用鸟枪式微基因组学和非靶向技术测量下游代谢物 大便和尿液代谢组学、大便和24小时尿靶向短链脂肪酸代谢组学 化学药学。使用新的中介模型，我们将定义饮食对肠道的直接和间接影响 微生物组、肠道和尿液代谢物及其对肾结石的贡献。在目标2中，我们将为 首次明确肾结石患者口服抗生素暴露与尿液化学指标的关系 疾病。我们会将24小时尿液化学结果与个人的药物声明和临床数据联系起来 在HealthCore数据库中，该数据库包括4800万人。我们将进行嵌套式病例对照研究 确定接触抗生素的剂量和持续时间与肾结石的关系，并 确定风险最大的子组。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。 化学药学。这些结果将确定导致肾结石的代谢物。 肠道微生物群，并为未来结石一级和二级预防研究提供关键见解。

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.