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      Expansion of Urease- and Uricase-Containing, Indole- and p-Cresol-Forming and Contraction of Short-Chain Fatty Acid-Producing Intestinal Microbiota in ESRD

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          Abstract

          Background: Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure and function of the microbiome. Recently, we found marked differences in the abundance of numerous bacterial taxa between ESRD and healthy individuals. Influx of urea and uric acid and dietary restriction of fruits and vegetables to prevent hyperkalemia alter ESRD patients' intestinal milieu. We hypothesized that relative abundances of bacteria possessing urease, uricase, and p-cresol- and indole-producing enzymes is increased, while abundance of bacteria containing enzymes converting dietary fiber to short-chain fatty acids (SCFA) is reduced in ESRD. Methods: Reference sets of bacteria containing genes of interest were compiled to family, and sets of intestinal bacterial families showing differential abundances between 12 healthy and 24 ESRD individuals enrolled in our original study were compiled. Overlap between sets was assessed using hypergeometric distribution tests. Results: Among 19 microbial families that were dominant in ESRD patients, 12 possessed urease, 5 possessed uricase, and 4 possessed indole and p-cresol-forming enzymes. Among 4 microbial families that were diminished in ESRD patients, 2 possessed butyrate-forming enzymes. Probabilities of these overlapping distributions were <0.05. Conclusions: ESRD patients exhibited significant expansion of bacterial families possessing urease, uricase, and indole and p-cresol forming enzymes, and contraction of families possessing butyrate-forming enzymes. Given the deleterious effects of indoxyl sulfate, p-cresol sulfate, and urea-derived ammonia, and beneficial actions of SCFA, these changes in intestinal microbial metabolism contribute to uremic toxicity and inflammation.

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          Most cited references 23

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          Pyrosequencing-Based Assessment of Bacterial Community Structure Along Different Management Types in German Forest and Grassland Soils

          Background Soil bacteria are important drivers for nearly all biogeochemical cycles in terrestrial ecosystems and participate in most nutrient transformations in soil. In contrast to the importance of soil bacteria for ecosystem functioning, we understand little how different management types affect the soil bacterial community composition. Methodology/Principal Findings We used pyrosequencing-based analysis of the V2-V3 16S rRNA gene region to identify changes in bacterial diversity and community structure in nine forest and nine grassland soils from the Schwäbische Alb that covered six different management types. The dataset comprised 598,962 sequences that were affiliated to the domain Bacteria. The number of classified sequences per sample ranged from 23,515 to 39,259. Bacterial diversity was more phylum rich in grassland soils than in forest soils. The dominant taxonomic groups across all samples (>1% of all sequences) were Acidobacteria, Alphaproteobacteria, Actinobacteria, Betaproteobacteria, Deltaproteobacteria, Gammaproteobacteria, and Firmicutes. Significant variations in relative abundances of bacterial phyla and proteobacterial classes, including Actinobacteria, Firmicutes, Verrucomicrobia, Cyanobacteria, Gemmatimonadetes and Alphaproteobacteria, between the land use types forest and grassland were observed. At the genus level, significant differences were also recorded for the dominant genera Phenylobacter, Bacillus, Kribbella, Streptomyces, Agromyces, and Defluviicoccus. In addition, soil bacterial community structure showed significant differences between beech and spruce forest soils. The relative abundances of bacterial groups at different taxonomic levels correlated with soil pH, but little or no relationships to management type and other soil properties were found. Conclusions/Significance Soil bacterial community composition and diversity of the six analyzed management types showed significant differences between the land use types grassland and forest. Furthermore, bacterial community structure was largely driven by tree species and soil pH.
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            Enumeration of human colonic bacteria producing phenolic and indolic compounds: effects of pH, carbohydrate availability and retention time on dissimilatory aromatic amino acid metabolism.

            Concentrations of phenolic compounds in human gut contents were more than fourfold higher in the distal colon (6.2 mmol kg-1) compared to the proximal bowel (1.4 mmol kg-1). Tryptophan metabolites were never found in more than trace amounts in large intestinal contents and phenol substituted fatty acids were the major products of aromatic amino acid fermentation that accumulated in the proximal colon, whereas phenol and p-cresol were more important in the distal gut, accounting for 70% of all products of dissimilatory aromatic amino acid metabolism. In vitro incubations of colonic material showed that phenol was produced most rapidly (1.0 mumol g-1 h-1), whereas indole was formed comparatively slowly (0.06 mumol g-1 h-1). Most probable number (MPN) estimations demonstrated that large populations of phenol and indole producing bacteria occur in the large intestine (range log10 9.8-11.5 (g dry wt faeces)-1, mean 10.6, N = 7). With respect to phenolic compounds, phenylacetate and phenylpropionate producers predominated, while indoleacetate-forming bacteria were the major tryptophan-utilizing organisms. Quantitation of products of dissimilatory aromatic amino acid metabolism in MPN tubes showed that phenol and phenylpropionate mainly accumulated at low sample dilutions, whereas phenylacetate, p-cresol, indoleacetate and indolepropionate were formed in greatest amounts at high sample dilutions. The significance of pH and carbohydrate availability with respect to aromatic amino acid metabolism was shown in batch culture fermentation studies, where net production of phenolic compounds by mixed populations of intestinal bacteria was reduced by approximately 33% during growth at pH 5.5 compared to pH 6.8, and by 60% in the presence of a fermentable carbohydrate. Experiments with 16 species of intestinal bacteria belonging to six different genera showed that environmental factors such as low pH and high carbohydrate availability markedly reduced dissimilatory aromatic amino acid metabolism in some organisms, but stimulated this process in others. A three-stage continuous culture model of the colon was used to investigate the effect of system retention time (27.1 or 66.7 h) on aromatic amino acid fermentation. Qualitative and quantitative increases in phenol production occurred from vessel 1 to vessel 3 in this model. Concentrations of phenolic compounds in vessel 3 were three times greater at R = 66.7 h compared to R = 27.1 h. Phenol and p-cresol were not detected in vessel 1, though formation of these metabolites increased from vessel 2 to vessel 3, in a pattern similar to that observed in the distal colon.
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              Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation.

              Inflammation is a constant feature and a major mediator of the progression of chronic kidney disease (CKD) and its numerous complications. There is increasing evidence pointing to the impairment of intestinal barrier function and its contribution to the prevailing inflammation in advanced CKD. Under normal condition, the intestinal epithelium and its apical tight junction prevent entry of the luminal microorganisms, harmful microbial by-products and other noxious contents in the host's internal milieu. This study was designed to test the hypothesis that impaired intestinal barrier function in uremia must be due to disruption of the intestinal tight junction complex. Sprague-Dawley (SD) rats were randomized to undergo 5/6 nephrectomy (CKD) or sham-operation (control) and observed for 8 weeks. In a separate experiment, SD rats were rendered uremic by addition of 0.7% adenine to their food for 2 weeks and observed for an additional 2 weeks. Rats consuming a regular diet served as controls. The animals were then euthanized and their colons were removed and processed for expression of the key constituents of the tight junction complex using real-time polymerase chain reaction, western blot analysis and immunohistological examinations. The CKD groups showed elevated plasma urea and creatinine, reduced creatinine clearance, thickened colonic wall and heavy infiltration of mononuclear leukocytes in the lamina propria. This was associated with marked reductions in protein expressions of claudin-1 (70-90%), occludin (50-70%) and ZO-1 (80-90%) in the colonic mucosa in both CKD models compared with the corresponding controls. The reduction in the abundance of the given proteins was confirmed by immunohistological examinations. In contrast, messenger RNA abundance of occludin, claudin-1 and ZO-1 was either unchanged or elevated pointing to the post-transcriptional/post-translational modification as a cause of the observed depletion of the tight junction proteins. The study revealed, for the first time, that uremia results in depletion of the key protein constituents of the colonic tight junction, a phenomenon which can account for the impaired intestinal barrier function and contribute to the systemic inflammation in CKD.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2014
                April 2014
                08 March 2014
                : 39
                : 3
                : 230-237
                Affiliations
                aCenter for Environmental Biotechnology, Lawrence Berkeley National Laboratory, Berkeley, Calif., bSecond Genome, San Bruno, Calif., and cDivision of Nephrology and Hypertension, University of California Irvine, Irvine, Calif., USA
                Author notes
                *Prof. Nosratola D. Vaziri, MD, Division of Nephrology and Hypertension, Schools of Medicine, University of California Irvine, 92868 Irvine CA (USA), E-Mail ndvaziri@uci.edu
                Article
                360010 PMC4049264 Am J Nephrol 2014;39:230-237
                10.1159/000360010
                PMC4049264
                24643131
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 4, Pages: 8
                Categories
                Original Report: Patient-Oriented, Translational Research

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