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）：常规的透析提供有限的有机溶质清除，这些溶质在肾脏失败时积累。因此，许多研究正在研究透析频率和持续时间增加的影响。另一种方法是减少溶质产量。这种方法被忽略了，因为我们对尿毒症溶质生产的了解是如此有限。当前的提案将集中于结肠中微生物的尿毒症溶质。直到最近，结肠微生物才难以研究，因为其中大多数都不容易培养。但是，新的与文化无关的基因组技术使得能够介绍整个结肠微生物种群或“微生物组”，并确定与特定溶质产生相关的微生物。代谢组技术使我们可以扩展我们对微生物产生的溶质的了解。该探索性建议将这些新技术应用于微生物衍生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产生相关的结肠微生物种群的特征。研究人员发现，在食用素食饮食的受试者中，生产微生物衍生的溶质硫酸盐（INDICAN）和硫酸盐含量大大降低了。拟议的研究将通过使用最近开发的Phylochip微阵列技术来利用这一发现，以比较素食受试者的微生物组和受试者吃不受限制的饮食。对阵列数据的分析将使我们能够识别与目前未知的Indigan和P-Cresol硫酸盐和硫酸盐的产生相关的微生物亚家族。第二个目的是确定透析患者结肠微生物种群的改变。研究人员已经确定了腹膜透析患者和血液透析患者的硫酸盐和硫酸盐生产的巨大差异。 Phylochip技术的应用将使我们能够确定与溶质生产中这些主要差异相关的微生物组的差异。第三个目的是确定结肠微生物产生的其他尿毒症溶质。使用FTICR-MS比较具有完整结肠和透析患者的透析患者的样本，将为这些溶质提供比现在可用的更全面的图片。总体目的是更好地了解尿毒症溶质的产生。这种理解最终可以使我们能够改善终端肾衰竭的治疗方法，而不会对透析进行负担重大。结肠中制作的尿毒症溶质为研究提供了特别有吸引力的靶标。因为它们是由微生物孤立的隔间制成的，所以它们的产生可能比其他溶质更容易抑制。提出的研究代表了朝着测试治疗的最终目标迈出的第一步，从而减少了微生物衍生的尿毒症溶质的产生。公共卫生相关性：透析患者遭受的许多残留疾病是由于保留的废物化学物质所导致的，而这些废物被当代治疗没有充分去除。当前的提案将集中于结肠中微生物的尿毒症溶质。基于DNA的技术将应用于确定与这些溶质生产有关的微生物。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状况的方法，而不会增加他们在透析机上的时间。