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

项目摘要 草酸钙肾结石病发生在大约9%的美国人口中， 大大提高了医疗保健成本。尿草酸盐排泄的少量减少被认为可以限制结石的风险。 最近的研究表明，缺乏草酸杆菌定植是一个重要的风险因素 草酸钙肾结石的形成。我们的初步数据显示，缺乏 产甲酸奥氏杆菌可以很容易地用产甲酸奥氏杆菌的活制剂定殖。这种殖民的能力 个体提供了一个强大的手段来评估殖民化前后对不同饮食的反应。它 目前尚不清楚在何种条件下产甲酸杆菌会改变结石风险，仍有许多需要了解的内容 这种微生物是如何建立和维持肠道定植的在上一个供资周期， 我们在小鼠模型中确定了影响肠道中产甲酸杆菌生长的条件， 草酸盐在肠道中的降解，其对尿中和肠道中草酸盐排泄量的影响， 以及在缺乏膳食草酸盐的情况下的可持续性。在本申请中，我们将这些发现扩展到 人类通过检查个人之前和之后的殖民与O. formigenes。控制饮食 草酸盐、钙和其他营养素的含量，包括超低草酸盐的饮食，将被用来检查 饮食、产甲酸杆菌定植和尿草酸排泄之间的相互作用。该提案将使用 菠菜，含有碳13-草酸，以准确地确定是否殖民修改的反应 一顿丰盛的晚餐持续静脉输注稳定的非放射性草酸盐同位素13 C2- 在定植之前和之后，草酸盐将直接决定胃肠道草酸盐分泌是否发生， 定植是否影响这种分泌。最近的证据表明， 不同的菌株，在某些情况下不止一种菌株。然而，目前尚不清楚是否生物 菌株之间的差异影响定植持久性和尿草酸排泄，这将是 在这个应用程序中检查。如果这些具体目标能够顺利实现， 关于产甲酸杆菌定殖在影响草酸盐水平方面的重要性的信息， 影响产甲酸杆菌定殖的因素，并将有助于确定新的策略， 肠道环境和草酸钙肾结石风险。

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.