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      Burn Injury Alters the Intestinal Microbiome and Increases Gut Permeability and Bacterial Translocation

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          Abstract

          Sepsis remains one of the leading causes of death in burn patients who survive the initial insult of injury. Disruption of the intestinal epithelial barrier has been shown after burn injury; this can lead to the translocation of bacteria or their products (e.g., endotoxin) from the intestinal lumen to the circulation, thereby increasing the risk for sepsis in immunocompromised individuals. Since the maintenance of the epithelial barrier is largely dependent on the intestinal microbiota, we examined the diversity of the intestinal microbiome of severely burned patients and a controlled mouse model of burn injury. We show that burn injury induces a dramatic dysbiosis of the intestinal microbiome of both humans and mice and allows for similar overgrowths of Gram-negative aerobic bacteria. Furthermore, we show that the bacteria increasing in abundance have the potential to translocate to extra-intestinal sites. This study provides an insight into how the diversity of the intestinal microbiome changes after burn injury and some of the consequences these gut bacteria can have in the host.

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          Most cited references26

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          Host-derived nitrate boosts growth of E. coli in the inflamed gut.

          Changes in the microbial community structure are observed in individuals with intestinal inflammatory disorders. These changes are often characterized by a depletion of obligate anaerobic bacteria, whereas the relative abundance of facultative anaerobic Enterobacteriaceae increases. The mechanisms by which the host response shapes the microbial community structure, however, remain unknown. We show that nitrate generated as a by-product of the inflammatory response conferred a growth advantage to the commensal bacterium Escherichia coli in the large intestine of mice. Mice deficient in inducible nitric oxide synthase did not support the growth of E. coli by nitrate respiration, suggesting that the nitrate generated during inflammation was host-derived. Thus, the inflammatory host response selectively enhances the growth of commensal Enterobacteriaceae by generating electron acceptors for anaerobic respiration.
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            Intestinal commensal microbes as immune modulators.

            Commensal bacteria are necessary for the development and maintenance of a healthy immune system. Harnessing the ability of microbiota to affect host immunity is considered an important therapeutic strategy for many mucosal and nonmucosal immune-related conditions, such as inflammatory bowel diseases (IBDs), celiac disease, metabolic syndrome, diabetes, and microbial infections. In addition to well-established immunostimulatory effects of the microbiota, the presence of individual mutualistic commensal bacteria with immunomodulatory effects has been described. These organisms are permanent members of the commensal microbiota and affect host immune homeostasis in specific ways. Identification of individual examples of such immunomodulatory commensals and understanding their mechanisms of interaction with the host will be invaluable in designing therapeutic strategies to reverse intestinal dysbiosis and recover immunological homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved.
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              NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression.

              Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                8 July 2015
                2015
                : 10
                : 7
                : e0129996
                Affiliations
                [1 ]Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL, 60153, United States of America
                [2 ]Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, IL, 60153, United States of America
                [3 ]Departments of Surgery, Loyola University Chicago Health Sciences Division, Maywood, IL, 60153, United States of America
                [4 ]Departments of Microbiology and Immunology, Loyola University Chicago Health Sciences Division, Maywood, IL, 60153, United States of America
                [5 ]DNA Services Facility, University of Illinois at Chicago, Chicago, IL, 60612, United States of America
                Georgia Regents University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exists.

                Conceived and designed the experiments: ZME SA JME RLG RHK MAC. Performed the experiments: ZME SA SJG AN OK ARC NLM XL. Analyzed the data: ZME SA SJG AN. Contributed reagents/materials/analysis tools: SJG AN. Wrote the paper: ZME SA SJG AN ARC AMH NLM RLG RHK MAC.

                [¤a]

                Current address: Department of Medicine, The University of Chicago, 900 East 57th Street, Chicago, Illinois, 60637, United States of America.

                [¤b]

                Current address: Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Avenue, Chicago, IL 6061, United States of America.

                Article
                PONE-D-14-53182
                10.1371/journal.pone.0129996
                4496078
                26154283
                c46f78b2-9fa5-41f4-8478-74b11e67897e
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 1 December 2014
                : 15 May 2015
                Page count
                Figures: 5, Tables: 1, Pages: 16
                Funding
                Support for this study comes from National Institutes of Health under award numbers R01AA015731 (MAC), R01AA015731 (MAC) and T32AA013527. Support was also provided by the Department of Defense W81XWH-09-1-0619 (RHK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                The amplicon sequence data from this study have been submitted to the NCBI Sequence Read Archive (SRA; http://www.ncbi.nlm.nih.gov/Traces/sra/sra.cgi) under the BioProject (PRJNA273295) accession number SRP052710. Sequences derived from mice were uploaded as two independent FASTQ files representing forward and reverse reads from each sample. In sequences derived from human feces, sequence reads were imported into the software package CLC genomics workbench and mapped against the Hg19 human genome reference. Reads mapping to the human genome (<0.05%) were removed from the dataset, and single FASTQ files, containing both forward and reverse reads were provided to the SRA.

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