Oxalobacter formigenes colonization and oxalate excretion in calcium oxalate kidney stone disease

项目摘要 草酸钙肾结石疾病在大约9%的美国人口中发生，并在 大大降低了医疗保健成本。尿草酸排泄量的小幅减少被认为可以限制结石的风险。 最近的研究表明，缺乏形成草酸杆菌的定植是一个重要的危险因素。 用于草酸钙肾结石的形成。我们的初步数据显示，健康的人体受试者缺乏 产甲氧西林假单胞菌可以很容易地与活的产甲氧西林杆菌一起定植。这种殖民能力 个体提供了一种强大的手段来评估殖民前后对不同饮食的反应。它 目前还不清楚Oformgenes在什么条件下可以改变结石风险，还有很多东西需要了解 关于这种生物如何建立和维持肠道定植。在上一个供资周期中 我们在小鼠模型中确定了影响肠道中产甲氧西林杆菌生长的条件，其 草酸在肠道中的降解及其对尿液和肠道中草酸排泄量的影响， 以及它在没有草酸饮食的情况下的可持续性。在本应用程序中，我们将把这些发现扩展到 人类通过检查定植前和定植后的个人与产卵杆菌。饮食控制在他们的 草酸、钙和其他营养素的含量，包括超低草酸饮食，将被用来检查 饮食、产甲假单胞菌定植与尿草酸排泄的交互作用这项提案将使用 含有13-草酸碳的菠菜，以准确确定定居是否改变了反应 一顿富含草酸的大餐。持续静脉输注稳定的非放射性草酸同位素13C2- 草酸，定植前后将直接决定胃肠道草酸分泌是否发生和 殖民是否会影响这种分泌。最近的证据表明，个人被殖民了 不同的菌株，在某些情况下还不止一个菌株。然而，目前还不清楚生物是否 菌株之间的差异会影响定植持久性和尿草酸排泄，这将是 在此应用程序中进行了检查。如果具体目标顺利完成，它们将提供有价值的 有关产卵杆菌定植在影响草酸水平方面的重要性的信息，将创造洞察力 研究影响产卵杆菌定植的因素，并将有助于确定修改 肠道环境和草酸钙对肾结石的风险。

Project Summary Calcium oxalate kidney stone disease occurs in approximately 9 % of the U.S. population and contributes significantly to health care costs. Small reductions in urinary oxalate excretion are thought to limit stone risk. Recent studies have indicated that a lack of Oxalobacter formigenes colonization is a significant risk factor for calcium oxalate kidney stone formation. Our Preliminary data shows that healthy human subjects lacking O.formigenes can be readily colonized with live preparations of O.formigenes. This ability to colonize individuals offers a powerful means of assessing responses to varying diets before and after colonization. It is still not clear under what conditions O.formigenes modifies stone risk, and much still needs to be learned about how this organism establishes and maintains gut colonization. In the previous funding cycle we identified in a mouse model conditions that influence the growth of O.formigenes in the gut, its degradation of oxalate in the gut, its effects on the amount of oxalate excreted in urine and into the intestine, and its sustainability in the absence of dietary oxalate. In this application we will extend these findings to humans by examining individuals before and after colonization with O.formigenes. Diets controlled in their contents of oxalate, calcium and other nutrients, including a diet ultra-low in oxalate, will be used to examine the interaction between diet, O.formigenes colonization and urinary oxalate excretion. This proposal will use spinach that contains carbon 13-oxalate to accurately determine whether colonization modifies the response to an oxalate-rich meal. Continuous intravenous infusions of the stable, non-radioactive oxalate isotope, 13C2- oxalate, before and after colonization will directly determine if gastrointestinal oxalate secretion occurs and whether colonization influences such secretion. Recent evidence suggests individuals are colonized with different strains and in some cases more than one strain. However, it is not known whether the biological differences between strains influence colonization persistence and urinary oxalate excretion and this will be examined in this application. If the specific aims are successfully completed they will provide valuable information about the importance of O.formigenes colonization in influencing oxalate levels, will create insight into the factors that impact O.formigenes colonization, and will help identify new strategies for modifying the gut milieu and calcium oxalate kidney stone risk.