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The Production of Uremic Solutes by Colon Microbes

结肠微生物产生尿毒症溶质

基本信息

批准号：
7896838
负责人：
TIMOTHY W MEYER
金额：
$ 19.83万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Conventional dialysis provides limited clearance of organic solutes that accumulate when the kidneys fail. Numerous studies are therefore examining the effects of increasing dialysis frequency and duration. An alternate approach would be to reduce solute production. This approach has been neglected because our knowledge of uremic solute production is so limited. The current proposal will focus on uremic solutes made by microbes in the colon. The colon microbes have until recently been difficult to study because most of them are not easily cultured. But new culture-independent, genomic techniques have made it possible to profile the entire colon microbial population, or "microbiome," and to identify microbes associated with the production of specific solutes. Metabolomic techniques have made it possible to expand our knowledge of the solutes that the microbes produce. This exploratory proposal will apply these new techniques to the study of microbially-derived uremic solutes. The first aim is to identify features of the colon microbial population associated with the production of well known uremic solutes. The investigators have found that production of the microbially-derived solutes indoxyl sulfate (indican) and p-cresol sulfate is much reduced in subjects consuming a vegetarian diet. The proposed studies will exploit this finding by using recently developed PhyloChip microarray technology to compare the microbiome in vegetarian subjects and subjects eating an unrestricted diet. Analysis of the array data will allow us to identify the microbial subfamilies associated with production of indican and p-cresol sulfate, which are at present unknown. The second aim is to identify alterations in the colon microbial population in dialysis patients. The investigators have identified large differences in indican and p-cresol sulfate production in patients on peritoneal dialysis and patients on hemodialysis. Application of PhyloChip technology will allow us to identify differences in the microbiome associated with these major differences in solute production. The third aim is to identify additional uremic solutes made by colon microbes. Use of FTICR-MS to compare samples from dialysis patients who have intact colons and dialysis patients with colectomies will provide a much more comprehensive picture of these solutes than is now available. The overall aim is to better understand the production of uremic solutes. Such understanding could eventually allow us to improve our treatment for end stage renal failure without burdensome intensifications of dialysis. Uremic solutes that are made in the colon provide a particularly attractive target for study. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than that of other solutes. The proposed studies represent an initial step toward the eventual goal of testing treatments which reduce the production of microbially-derived uremic solutes. PUBLIC HEALTH RELEVANCE: Much of the residual illness suffered by dialysis patients is due to retained waste chemicals that are not adequately removed by contemporary treatment. The current proposal will focus on uremic solutes made by microbes in the colon. DNA based techniques will be applied to identify microbes involved in the production of these solutes. Ultimately, we hope that manipulating the colon microbes could provide a means for improving the health of dialysis patients without increasing the time they spend on the dialysis machine.

描述（由申请人提供）：常规透析对肾衰竭时蓄积的有机溶质的清除有限。因此，许多研究正在检查增加透析频率和持续时间的影响。另一种方法是减少溶质的产生。这种方法一直被忽视，因为我们的知识尿毒症溶质生产是如此有限。目前的建议将集中在由结肠中的微生物产生的尿毒症溶质上。结肠微生物直到最近才很难研究，因为它们中的大多数不易培养。但新的不依赖培养的基因组技术使人们有可能分析整个结肠微生物种群或“微生物组”，并识别与特定溶质产生相关的微生物。代谢组学技术使我们有可能扩大对微生物产生的溶质的了解。这项探索性的提议将把这些新技术应用于微生物来源的尿毒症溶质的研究。第一个目的是确定与众所周知的尿毒症溶质的产生相关的结肠微生物种群的特征。研究人员发现，微生物来源的溶质硫酸吲哚酚（indoxyl sulfate，indican）和硫酸对甲酚的产生在食用素食的受试者中大大减少。拟议的研究将利用这一发现，使用最近开发的PhyloChip微阵列技术来比较素食受试者和饮食不受限制的受试者的微生物组。阵列数据的分析将使我们能够确定与生产靛聚糖和对甲酚硫酸盐，这是目前未知的微生物亚科。第二个目的是确定透析患者结肠微生物群的变化。研究者发现腹膜透析患者和血液透析患者的靛聚糖和对甲酚硫酸盐的产生存在很大差异。PhyloChip技术的应用将使我们能够识别与溶质产生的这些主要差异相关的微生物组差异。第三个目标是确定结肠微生物产生的其他尿毒症溶质。使用FTICR-MS比较来自结肠完整的透析患者和结肠切除术的透析患者的样品，将提供比现在更全面的这些溶质的图片。总体目标是更好地了解尿毒症溶质的产生。这样的理解可能最终使我们能够改善我们对终末期肾衰竭的治疗，而无需繁重的透析强化。在结肠中产生的尿毒症溶质为研究提供了特别有吸引力的目标。因为它们是由微生物在一个隔离的隔间中制造的，所以它们的生产可能比其他溶质更容易抑制。拟议的研究代表了朝着测试减少微生物源性尿毒症溶质产生的治疗的最终目标迈出的第一步。公共卫生关系：透析患者所遭受的大部分残留疾病是由于残留的废物化学品没有被当代治疗充分去除。目前的建议将集中在由结肠中的微生物产生的尿毒症溶质上。基于DNA的技术将被应用于鉴定参与这些溶质生产的微生物。最终，我们希望操纵结肠微生物可以提供一种改善透析患者健康的方法，而不会增加他们在透析机上花费的时间。