The Production of Uremic Solutes by Colon Microbes

结肠微生物产生尿毒症溶质

• 批准号: 7712553
• 负责人: TIMOTHY W MEYER
• 金额: $ 20.74万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712553
• 关键词: Characteristics; Chemicals; Colectomy; Colon; Cresol; Cresols; DNA; Data; Dialysis patients; Dialysis procedure; Diet; Eating; End stage renal failure; Excision; Fourier transform ion cyclotron resonance; Frequencies; Genomics; Genus Cola; Goals; Health; Hemodialysis; Indican; Inorganic Sulfates; Kidney; Knowledge; Mass Spectrum Analysis; Metabolism; Microarray Analysis; Microbe; Patients; Peritoneal Dialysis; Population; Production; Research Personnel; Residual state; Sampling; Techniques; Technology; Testing; Time; Unspecified or Sulfate Ion Sulfates; Uremia; Vegetarian diet; base; improved; metabolomics; microbial; microbial community; microbiome; neglect; public health relevance; solute; wasting

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）：传统透析对肾脏衰竭时积聚的有机溶质的清除有限。因此，许多研究正在研究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。这种方法被忽视了，因为我们对尿毒症溶质产生的了解非常有限。目前的提案将重点关注结肠微生物产生的尿毒症溶质。直到最近，结肠微生物的研究还很困难，因为它们大多数不易培养。但新的独立于培养物的基因组技术使得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成为可能。代谢组学技术使我们能够扩展我们对微生物产生的溶质的了解。该探索性提案将应用这些新技术来研究微生物来源的尿毒症溶质。第一个目标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群的特征。研究人员发现，在吃素食的受试者中，微生物来源的溶质硫酸吲哚酚（indican）和硫酸对甲酚的产生大大减少。拟议的研究将利用这一发现，通过使用最近开发的 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。对阵列数据的分析将使我们能够识别与目前未知的印度和对甲酚硫酸盐生产相关的微生物亚科。第二个目标是确定透析患者结肠微生物种群的变化。研究人员发现腹膜透析患者和血液透析患者产生的印度聚糖和硫酸对甲酚存在很大差异。 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。第三个目标是识别结肠微生物产生的其他尿毒症溶质。使用 FTICR-MS 比较具有完整结肠的透析患者和患有结肠切除术的透析患者的样本，将提供比现在更全面的这些溶质的图像。总体目标是更好地了解尿毒症溶质的产生。这种理解最终可以让我们改善终末期肾衰竭的治疗，而无需繁琐的强化透析。结肠中产生的尿毒症溶质提供了一个特别有吸引力的研究目标。由于它们是由微生物在隔离室中产生的，因此它们的产生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衍生尿毒症溶质产生的治疗方法的最终目标迈出的第一步。公共卫生相关性：透析患者所遭受的大部分残余疾病是由于当代治疗未能充分清除残留的废弃化学物质造成的。目前的提案将重点关注结肠微生物产生的尿毒症溶质。基于 DNA 的技术将用于识别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能够提供一种改善透析患者健康的方法，而不增加他们在透析机上花费的时间。