Gut-kidney axis in enteric hyperoxaluria

在美国，估计有超过20万名患者患有肠源性高草酸尿(EH)。EH影响患有吸收不良的胃肠道疾病的患者，众所周知，EH会导致肾结石复发。EH的治疗是有限的，而且只能部分缓解高草酸尿。几种肠道细菌可以降解草酸，可能在预防高草酸尿方面发挥重要作用。这些草酸降解菌，统称为草酸体，在EH的病理生理学中所起的作用尚未阐明。我们开发了一种新的计算方法来对人类草酸降解微生物进行第一次全面的研究。我们定义了他们在健康和炎症性肠病(IBD)人群中对体内整体草酸降解的个体贡献，IBD人群是EH的危险人群。我们的数据显示，IBD患者的草小体功能下降与粪便草酸水平升高有关，这表明这一群体可能受益于草小体的恢复。因此，这项提议的科学前提是，微生物群是尿草酸(UOx)水平的重要决定因素，随着对草酸体生物学的更多了解，我们可以操纵它来预防高血压和肾结石。我们的总体假设是草本体功能决定了UOx。作为推论，我们假设微生物组可以作为治疗靶点，以减少高草酸尿和肾结石的风险。为了验证这一假设，我们提出了一些研究，这些研究除了我们在人性化方面的经验外，还利用了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。我们的第一个目标是分析高血压患者草小体改变与UOx水平的关系。我们将在每天补充草酸盐诱导健康和EH患者的草体之前和之后，让他们接受控制饮食，以使用元基因组测序来分析草体结构，并使用元转录测序来分析功能。我们将确定在健康和EH受试者中草酸代谢活性最高的草酸体成员，以及那些缺失与高草酸尿症发展相关的草酸体成员。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和健康成年人的UOx较低相关的细菌分类群。我们的第二个目标是确定人到鼠之间转移整个和丰富的草小体群落是否会导致尿草酸减少。为此，我们将建立EH IBD小鼠模型，并进行完整和丰富的草本生物体群落的人到鼠移植，以评估其对UOx的影响。使用最近开发的技术，结合我们的靶向计算方法，破译EH中的草体功能，然后在小鼠模型中测试我们的假设，将使我们能够开发出有前景的微生物学方法来控制EH中的高草酸尿。

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.