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      The gut microbiota and inflammatory bowel disease

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          Abstract

          Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut. Although the precise cause of IBD remains unknown, the most accepted hypothesis of IBD pathogenesis to date is that an aberrant immune response against the gut microbiota is triggered by environmental factors in a genetically susceptible host. The advancement of next-generation sequencing technology has enabled identification of various alterations of the gut microbiota composition in IBD. While some results related to dysbiosis in IBD are different between studies owing to variations of sample type, method of investigation, patient profiles, and medication, the most consistent observation in IBD is reduced bacterial diversity, a decrease of Firmicutes, and an increase of Proteobacteria. It has not yet been established how dysbiosis contributes to intestinal inflammation. Many of the known IBD susceptibility genes are associated with recognition and processing of bacteria, which is consistent with a role of the gut microbiota in the pathogenesis of IBD. A number of trials have shown that therapies correcting dysbiosis, including fecal microbiota transplantation and probiotics, are promising in IBD.

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          High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease

          Background The gut microbiota is thought to play a key role in the development of the inflammatory bowel diseases Crohn's disease (CD) and ulcerative colitis (UC). Shifts in the composition of resident bacteria have been postulated to drive the chronic inflammation seen in both diseases (the "dysbiosis" hypothesis). We therefore specifically sought to compare the mucosa-associated microbiota from both inflamed and non-inflamed sites of the colon in CD and UC patients to that from non-IBD controls and to detect disease-specific profiles. Results Paired mucosal biopsies of inflamed and non-inflamed intestinal tissue from 6 CD (n = 12) and 6 UC (n = 12) patients were compared to biopsies from 5 healthy controls (n = 5) by in-depth sequencing of over 10,000 near full-length bacterial 16S rRNA genes. The results indicate that mucosal microbial diversity is reduced in IBD, particularly in CD, and that the species composition is disturbed. Firmicutes were reduced in IBD samples and there were concurrent increases in Bacteroidetes, and in CD only, Enterobacteriaceae. There were also significant differences in microbial community structure between inflamed and non-inflamed mucosal sites. However, these differences varied greatly between individuals, meaning there was no obvious bacterial signature that was positively associated with the inflamed gut. Conclusions These results may support the hypothesis that the overall dysbiosis observed in inflammatory bowel disease patients relative to non-IBD controls might to some extent be a result of the disturbed gut environment rather than the direct cause of disease. Nonetheless, the observed shifts in microbiota composition may be important factors in disease maintenance and severity.
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            Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.

            Abnormal host-microbe interactions are implicated in the pathogenesis of inflammatory bowel diseases. Previous 16S rRNA sequence analysis of intestinal tissues demonstrated that a subset of Crohn's disease (CD) and ulcerative colitis (UC) samples exhibited altered intestinal-associated microbial compositions characterized by depletion of Bacteroidetes and Firmicutes (particularly Clostridium taxa). We hypothesize that NOD2 and ATG16L1 risk alleles may be associated with these alterations. To test this hypothesis, we genotyped 178 specimens collected from 35 CD, 35 UC, and 54 control patients for the three major NOD2 risk alleles (Leu 1007fs, R702W, and G908R) and the ATG16L1T300A risk allele, that had undergone previous 16S rRNA sequence analysis. Our statistical models incorporated the following independent variables: 1) disease phenotype (CD, UC, non-IBD control); 2) NOD2 composite genotype (NOD2(R) = at least one risk allele, NOD2(NR) = no risk alleles); 3) ATG16L1T300A genotype (ATG16L1(R/R), ATG16L1(R/NR), ATG16L1(NR/NR)); 4) patient age at time of surgery and all first-order interactions. The dependent variable(s) were the relative frequencies of bacterial taxa classified by applying the RDP 2.1 classifier to previously reported 16S rRNA sequence data. Disease phenotype, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions by nonparametric multivariate analysis of covariance (MANCOVA). Shifts in the relative frequencies of Faecalibacterium and Escherichia taxa were significantly associated with disease phenotype by nonparametric ANCOVA. These results support the concept that disease phenotype and genotype are associated with compositional changes in intestinal-associated microbiota. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.
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              Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis.

              A leading hypothesis for the role of bacteria in inflammatory bowel diseases is that an imbalance in normal gut flora is a prerequisite for inflammation. Testing this hypothesis requires comparisons between the microbiota compositions of ulcerative colitis and Crohn's disease patients and those of healthy individuals. In this study, we obtained biopsy samples from patients with Crohn's disease and ulcerative colitis and from healthy controls. Bacterial DNA was extracted from the tissue samples, amplified using universal bacterial 16S rRNA gene primers, and cloned into a plasmid vector. Insert-containing colonies were picked for high-throughput sequencing, and sequence data were analyzed, yielding species-level phylogenetic data. The clone libraries yielded 3,305 sequenced clones, representing 151 operational taxonomical units. There was no significant difference between floras from inflamed and healthy tissues from within the same individual. Proteobacteria were significantly (P = 0.0007) increased in Crohn's disease patients, as were Bacteroidetes (P < 0.0001), while Clostridia were decreased in that group (P < 0.0001) in comparison with the healthy and ulcerative colitis groups, which displayed no significant differences. Thus, the bacterial flora composition of Crohn's patients appears to be significantly altered from that of healthy controls, unlike that of ulcerative colitis patients. Imbalance in flora in Crohn's disease is probably not sufficient to cause inflammation, since microbiotas from inflamed and noninflamed tissues were of similar compositions within the same individual.
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                Author and article information

                Contributors
                +81-3-3353-1211 , takagast@z2.keio.jp
                Journal
                Semin Immunopathol
                Semin Immunopathol
                Seminars in Immunopathology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1863-2297
                1863-2300
                25 November 2014
                25 November 2014
                2015
                : 37
                : 47-55
                Affiliations
                Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku, Tokyo 160-8582 Japan
                Article
                454
                10.1007/s00281-014-0454-4
                4281375
                25420450
                e2acb5bc-ff0c-49f0-acc0-2f2e0a6f6827
                © The Author(s) 2014

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 4 August 2014
                : 2 October 2014
                Categories
                Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2015

                Pathology
                inflammatory bowel disease,ulcerative colitis,crohn’s disease,dysbiosis
                Pathology
                inflammatory bowel disease, ulcerative colitis, crohn’s disease, dysbiosis

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