Gut-kidney axis in enteric hyperoxaluria

肠性高草酸尿症的肠肾轴

• 批准号: 10280276
• 负责人: Lama Nazzal
• 金额: $ 33.86万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280276
• 关键词: Address; Adult; Affect; Animal Model; Bacteria; Biology; Calcium Oxalate; Clinical; Clinical Research; Communities; Computer Analysis; Computing Methodologies; Culture Media; Data; Development; Diagnosis; Diet; Enrollment; Enteral; Evaluation; Excretory function; Functional disorder; Funding; Gastric Bypass; Gastrointestinal Diseases; Genes; Germ-Free; Goals; Growth; Health Care Costs; Human; Hyperoxaluria; Individual; Inflammatory Bowel Diseases; Intestines; Kidney; Kidney Calculi; Knowledge; Mammals; Measures; Metabolic; Metabolism; Metagenomics; Microbe; Microbiology; Modeling; Mus; Nephrocalcinosis; Nephrolithiasis; Organism; Oxalates; Oxalobacter formigenes; Patients; Permeability; Play; Population; Populations at Risk; Rattus; Recurrence; Research Design; Risk; Rodent Model; Role; Sampling; Series; Severities; Structure; Suggestion; Supplementation; Technology; Testing; United States; absorption; base; bench to bedside; clinically significant; cohort; design; experience; gut bacteria; gut microbiome; human subject; in vivo; member; metagenomic sequencing; metatranscriptomics; microbial community; microbiome; microbiome analysis; mouse model; novel; prevent; restoration; therapeutic target; urinary

In the United States, more than 200,000 patients are estimated to suffer from enteric hyperoxaluria (EH). EH affects patients with malabsorptive gastrointestinal diseases and is well-known to cause recurrent nephrolithiasis. Therapies for EH are limited and only partially mitigate hyperoxaluria. Several gut bacteria can degrade oxalate and likely play an essential role in protecting against hyperoxaluria. The role that these oxalate-degrading bacteria, collectively referred to as the oxalobiome, play in the pathophysiology of EH has not been elucidated. We developed a novel computational method to perform the first comprehensive study of human oxalate-degrading microbes. We defined their individual contributions to overall oxalate degradation in vivo in healthy and inflammatory bowel disease (IBD) population, a population at risk for EH. Our data showed that IBD patients have a reduction in the function of the oxalobiome associated with higher levels of fecal oxalate, suggesting that this population might benefit from the restoration of the oxalobiome. Hence, this proposal’s scientific premise is that the microbiome is an important determinant of urinary oxalate (UOx) levels and that with greater knowledge of the oxalobiome’s biology, we can manipulate it to prevent EH and kidney stones. Our overall hypothesis is that the oxalobiome function determines UOx. As a corollary, we hypothesize that the microbiome can be therapeutically targeted to reduce hyperoxaluria and the risk of kidney stones. To test this hypothesis, we propose studies that leverage our expertise in conducting microbiome trials and microbiome functional analyses in addition to our experience in performing humanizations. Our first aim is to analyze associations of oxalobiome alterations with UOx levels in patients with EH. We will place healthy and EH subjects on controlled diets before and after inducing their oxalobiome with daily oxalate supplementation to analyze the oxalobiome structure, using metagenomic sequencing, and function, using metatranscriptomic sequencing. We will identify the oxalobiome members with the highest oxalate metabolic activity in healthy and EH subjects, and those whose absence is associated with the development of hyperoxaluria. Global analysis of the microbiome dynamics and networks will allow us to identify bacterial taxa that are associated with lower UOx in EH and healthy adults. Our second aim is to determine whether human-to-mouse transfer of whole and enriched oxalobiome communities results in reduced urinary oxalate. For this aim, we will develop an EH IBD mouse model and perform human-to-mouse transfer of whole and enriched oxalobiome communities to evaluate its effects on UOx. Deciphering the oxalobiome function in EH, using recently developed technologies, in conjunction with our targeted computational methods, and then testing our hypotheses in mouse models, will permit us to develop promising microbiological approaches to control hyperoxaluria in EH.

在美国，估计有超过20万患者患有肠性高草酸尿症（EH）。EH影响消化不良的胃肠道疾病患者，众所周知会引起复发性肾结石。EH的治疗是有限的，只能部分缓解高草酸尿。几种肠道细菌可以降解草酸，并可能在防止高草酸尿中发挥重要作用。这些草酸降解细菌，统称为草酸菌组，在EH的病理生理中所起的作用尚未阐明。我们开发了一种新的计算方法来执行人类草酸降解微生物的首次全面研究。我们定义了它们在健康和炎症性肠病（IBD）人群（EH风险人群）体内总体草酸降解中的个体贡献。我们的数据显示，IBD患者的草酸组功能降低与较高水平的粪便草酸盐相关，这表明该人群可能受益于草酸组的恢复。因此，该提案的科学前提是微生物组是尿草酸盐（UOx）水平的重要决定因素，随着对草酸组生物学的更多了解，我们可以操纵它来预防EH和肾结石。我们的总体假设是oxalobiome功能决定了UOx。因此，我们假设微生物组可以作为治疗目标来降低高草酸尿和肾结石的风险。为了验证这一假设，我们建议利用我们在进行微生物组试验和微生物组功能分析方面的专业知识以及我们在进行人性化方面的经验进行研究。我们的第一个目的是分析EH患者中草酸组改变与UOx水平的关系。我们将对健康和EH受试者进行控制饮食，在每天补充草酸盐诱导其草酸组之前和之后，使用宏基因组测序和元转录组测序分析草酸组的结构和功能。我们将确定健康和EH受试者中草酸代谢活性最高的草酸组成员，以及与高草酸尿相关的草酸代谢活性缺失的草酸组成员。微生物组动态和网络的全球分析将使我们能够识别与EH和健康成人低UOx相关的细菌分类群。我们的第二个目标是确定人类向小鼠转移整个和富集的草酸组群落是否会导致尿草酸降低。为此，我们将建立EH IBD小鼠模型，并将整个和富集的草藻生物群落进行人-鼠转移，以评估其对UOx的影响。利用最近开发的技术，结合我们的目标计算方法，破译EH中的草酸组功能，然后在小鼠模型中测试我们的假设，将使我们能够开发有前途的微生物方法来控制EH中的高草酸尿。