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:
- 金额:$ 72.65万
- 依托单位:
- 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:
- 关键词:4 year oldAdolescentAdultAffectAgeAge-YearsAntibioticsBacteriaButyratesCalciumCardiovascular DiseasesCephalosporinsChemistryChildChronic Kidney FailureClinical DataCohort StudiesCommunitiesComplexDataData AnalyticsData LinkagesDatabasesDiabetes MellitusDietDiseaseDoseEnvironmental ExposureEvaluationEventExcretory functionExposure toFecesFluoroquinolonesFractureFutureGoalsGut MucosaHealthHourHumanHypertensionIncidenceIndividualIntakeIntestinal AbsorptionIntestinesKidneyKidney CalculiLeadLifeLinkMacronutrients NutritionMeasuresMediatingMediationMedicalMetabolicMetabolic PathwayMetabolismMetagenomicsMineralsModelingMorbidity - disease rateNephrolithiasisNested Case-Control StudyNitrofurantoinNutritionalOralOrganismOxalatesOxalobacterOxalobacter formigenesPainParticipantPatientsPenicillinsPharmacoepidemiologyPharmacologic SubstancePharmacy facilityPopulationPrevalencePreventionReportingResearchResearch DesignRiskRisk FactorsRoleShotgunsSubgroupTestingTimeUnited StatesUrinary tractUrineVolatile Fatty AcidsZinccostdysbiosisgut microbiomehigh dimensionalityinsightmetabolomemetabolomicsmicrobial communitymicrobiomemicrobiome alterationmultidimensional datanew therapeutic targetnovelpreventtherapeutic targeturinaryyoung 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团队,该团队已做好独特的准备来定义
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
并收集300名近期未接触抗生素的≥4岁参与者的粪便和尿液(150名服用钙)
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
首次确定肾结石患者口服抗生素暴露与尿液化学之间的关系
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michelle Denburg其他文献
Michelle Denburg的其他文献
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{{ truncateString('Michelle Denburg', 18)}}的其他基金
Mentoring of Early Career Researchers from Diverse Backgrounds
指导来自不同背景的早期职业研究人员
- 批准号:
10797793 - 财政年份:2023
- 资助金额:
$ 72.65万 - 项目类别:
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:
10133067 - 财政年份:2019
- 资助金额:
$ 72.65万 - 项目类别:
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:
10385846 - 财政年份:2019
- 资助金额:
$ 72.65万 - 项目类别:
The impact of glomerular disorders on bone quality and strength
肾小球疾病对骨质量和强度的影响
- 批准号:
10452536 - 财政年份:2018
- 资助金额:
$ 72.65万 - 项目类别:
The impact of glomerular disorders on bone quality and strength
肾小球疾病对骨质量和强度的影响
- 批准号:
10226160 - 财政年份:2018
- 资助金额:
$ 72.65万 - 项目类别:
The impact of glomerular disorders on bone quality and strength
肾小球疾病对骨质量和强度的影响
- 批准号:
9789870 - 财政年份:2018
- 资助金额:
$ 72.65万 - 项目类别:
CHOP Pediatric Center of Excellence in Nephrology
CHOP 儿科肾病卓越中心
- 批准号:
10705295 - 财政年份:2017
- 资助金额:
$ 72.65万 - 项目类别:
CHOP Pediatric Center of Excellence in Nephrology
CHOP 儿科肾病卓越中心
- 批准号:
10529731 - 财政年份:2017
- 资助金额:
$ 72.65万 - 项目类别:
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