The Production of Uremic Solutes by Colon Microbes

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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.