Gut-kidney axis in enteric hyperoxaluria

在美国，估计有超过200，000名患者患有肠型高尿酸血症（EH）。高血压影响吸收不良的胃肠道疾病患者，并众所周知会导致复发性肾结石。EH的治疗是有限的，仅部分减轻高血压尿。几种肠道细菌可以降解草酸盐，并可能在预防高尿酸血症中发挥重要作用。这些代谢物降解细菌，统称为代谢物生物组，在EH的病理生理学中的作用尚未阐明。我们开发了一种新的计算方法来进行第一次全面的研究，人类的脂肪酸降解微生物。我们定义了他们各自对健康和炎症性肠病（IBD）人群（EH风险人群）体内整体草酸盐降解的贡献。我们的数据显示，IBD患者的粪便草酸盐水平较高，相关的代谢生物组功能降低，这表明该人群可能受益于代谢生物组的恢复。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，并且随着对微生物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，UOx是由代谢生物组功能决定的。作为推论，我们假设微生物组可以在治疗上靶向减少高尿酸和肾结石的风险。为了验证这一假设，我们提出了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执行人源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UOx水平与生物素组改变的相关性。我们将在每日补充草酸盐诱导其代谢生物组之前和之后将健康和EH受试者置于受控饮食中，以使用宏基因组测序分析代谢生物组结构，并使用元转录组测序分析功能。我们将鉴定健康和EH受试者中具有最高草酸盐代谢活性的代谢生物组成员，以及那些缺乏与高尿酸发展相关的代谢生物组成员。对微生物组动态和网络的全球分析将使我们能够识别与EH和健康成人中较低UOx相关的细菌分类群。我们的第二个目标是确定人-鼠转移整个和富集的生物群落是否会导致尿草酸盐减少。为此，我们将开发EH IBD小鼠模型，并进行完整和富集的生物群落的人-小鼠转移，以评估其对UOx的影响。使用最新开发的技术，结合我们的目标计算方法，破译EH中的微生物组功能，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学方法来控制EH中的高尿酸。

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.