Evaluation of the gut-kidney axis in kidney stone disease

项目摘要 肾结石疾病是非常普遍的，越来越常见，并与相当大的发病率。 然而，在过去的30年里，没有新的治疗方法来预防肾结石。理解 肠道微生物组的生态失调如何导致肾结石可能导致新的肾脏治疗方法 石头预防。然而，大多数关于该人群肠道微生物组的先前研究都集中在草酸钙上。 在不考虑整个肠道微生物组在肠-肾轴中的作用的情况下， 肠道和泌尿道在人类健康和疾病中的相互作用。发展的关键障碍 预防结石的新治疗方法是缺乏对肠道微生物组的扰动以及 肠道和尿道中代谢物的下游变化导致肾结石疾病。 在这项提案中，我们建立在我们最近发现的饮食，抗生素，肠道微生物组和 代谢组学在肾结石病中的应用我们利用一支跨学科的团队，以独特的姿态来定义 通过结合营养分析、调解和免疫调节方面的专业知识， 分析高维微生物组和代谢组学数据，以及大数据分析。拟议 研究验证了饮食和抗生素通过扰乱肠道而导致肾结石的核心假设， 肾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-肾轴中的通路，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岁的参与者的粪便和尿液，这些参与者最近没有抗生素暴露（150名使用钙 肾结石和150个匹配的对照组），对年轻参与者进行过度抽样。我们会对内脏进行测序 使用鸟枪宏基因组学和测量下游代谢物，使用非靶向 粪便和尿液代谢组学、粪便和24小时尿液靶向短链脂肪酸代谢组学 化学使用新的调解模型，我们将定义饮食对肠道的直接和间接影响 微生物组和肠道和尿液代谢产物及其对肾结石的贡献。在目标2中，我们将 首次确定口服抗生素暴露与肾结石尿液化学成分之间的关系 疾病我们将把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，包括超过4800万人。我们将进行巢式病例对照研究 确定抗生素暴露的剂量和持续时间与肾结石之间的关系， 确定风险最大的亚组。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代谢物，有助于肾结石后，扰动的 肠道微生物组，并为未来的一级和二级结石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.