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      Bacterial protein signals are associated with Crohn’s disease


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          No Crohn’s disease (CD) molecular maker has advanced to clinical use, and independent lines of evidence support a central role of the gut microbial community in CD. Here we explore the feasibility of extracting bacterial protein signals relevant to CD, by interrogating myriads of intestinal bacterial proteomes from a small number of patients and healthy controls.


          We first developed and validated a workflow—including extraction of microbial communities, two-dimensional difference gel electrophoresis (2D-DIGE), and LC-MS/MS—to discover protein signals from CD-associated gut microbial communities. Then we used selected reaction monitoring (SRM) to confirm a set of candidates. In parallel, we used 16S rRNA gene sequencing for an integrated analysis of gut ecosystem structure and functions.


          Our 2D-DIGE-based discovery approach revealed an imbalance of intestinal bacterial functions in CD. Many proteins, largely derived from Bacteroides species, were over-represented, while under-represented proteins were mostly from Firmicutes and some Prevotella members. Most overabundant proteins could be confirmed using SRM. They correspond to functions allowing opportunistic pathogens to colonise the mucus layers, breach the host barriers and invade the mucosae, which could still be aggravated by decreased host-derived pancreatic zymogen granule membrane protein GP2 in CD patients. Moreover, although the abundance of most protein groups reflected that of related bacterial populations, we found a specific independent regulation of bacteria-derived cell envelope proteins.


          This study provides the first evidence that quantifiable bacterial protein signals are associated with CD, which can have a profound impact on future molecular diagnosis.

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          Most cited references40

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          Inflammatory bowel disease: clinical aspects and established and evolving therapies.

          Crohn's disease and ulcerative colitis are two idiopathic inflammatory bowel disorders. In this paper we discuss the current diagnostic approach, their pathology, natural course, and common complications, the assessment of disease activity, extraintestinal manifestations, and medical and surgical management, and provide diagnostic and therapeutic algorithms. We critically review the evidence for established (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging novel therapies--including biological therapies--directed at cytokines (eg, infliximab, adalimumab, certolizumab pegol) and receptors (eg, visilizumab, abatacept) involved in T-cell activation, selective adhesion molecule blockers (eg, natalizumab, MLN-02, alicaforsen), anti-inflammatory cytokines (eg, interleukin 10), modulation of the intestinal flora (eg, antibiotics, prebiotics, probiotics), leucocyte apheresis and many more monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. Finally, we summarise the practical aspects of standard therapies including dosing, precautions, and side-effects.
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            Towards the human intestinal microbiota phylogenetic core.

            The paradox of a host specificity of the human faecal microbiota otherwise acknowledged as characterized by global functionalities conserved between humans led us to explore the existence of a phylogenetic core. We investigated the presence of a set of bacterial molecular species that would be altogether dominant and prevalent within the faecal microbiota of healthy humans. A total of 10 456 non-chimeric bacterial 16S rRNA sequences were obtained after cloning of PCR-amplified rDNA from 17 human faecal DNA samples. Using alignment or tetranucleotide frequency-based methods, 3180 operational taxonomic units (OTUs) were detected. The 16S rRNA sequences mainly belonged to the phyla Firmicutes (79.4%), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%) and Verrumicrobia (0.1%). Interestingly, while most of OTUs appeared individual-specific, 2.1% were present in more than 50% of the samples and accounted for 35.8% of the total sequences. These 66 dominant and prevalent OTUs included members of the genera Faecalibacterium, Ruminococcus, Eubacterium, Dorea, Bacteroides, Alistipes and Bifidobacterium. Furthermore, 24 OTUs had cultured type strains representatives which should be subjected to genome sequence with a high degree of priority. Strikingly, 52 of these 66 OTUs were detected in at least three out of four recently published human faecal microbiota data sets, obtained with very different experimental procedures. A statistical model confirmed these OTUs prevalence. Despite the species richness and a high individual specificity, a limited number of OTUs is shared among individuals and might represent the phylogenetic core of the human intestinal microbiota. Its role in human health deserves further study.
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              Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease.

              The composition and spatial organization of the mucosal flora in biopsy specimens from patients with inflammatory bowel disease (IBD; either Crohn's disease or ulcerative colitis), self-limiting colitis, irritable-bowel syndrome (IBS), and healthy controls were investigated by using a broad range of fluorescent bacterial group-specific rRNA-targeted oligonucleotide probes. Each group included 20 subjects. Ten patients who had IBD and who were being treated with antibiotics were also studied. Use of nonaqueous Carnoy fixative to preserve the mucus layer was crucial for detection of bacteria adherent to the mucosal surface (mucosal bacteria). No biofilm was detectable in formalin-fixed biopsy specimens. Mucosal bacteria were found at concentrations greater than 10(9)/ml in 90 to 95% of IBD patients, 95% of patients with self-limiting colitis, 65% of IBS patients, and 35% of healthy controls. The mean density of the mucosal biofilm was 2 powers higher in IBD patients than in patients with IBS or controls, and bacteria were mostly adherent. Bacteroides fragilis was responsible for >60% of the biofilm mass in patients with IBD but for only 30% of the biofilm mass in patients with self-limiting colitis and 40% of the biofilm in IBS patients but for <15% of the biofilm in IBD patients. In patients treated with (5-ASA) or antibiotics, the biofilm could be detected with 4,6-diamidino-2-phenylindole but did not hybridize with fluorescence in situ hybridization probes. A Bacteroides fragilis biofilm is the main feature of IBD. This was not previously recognized due to a lack of appropriate tissue fixation. Both 5-ASA and antibiotics suppress but do not eliminate the adherent biofilm.

                Author and article information

                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                October 2014
                16 January 2014
                : 63
                : 10
                : 1566-1577
                [1 ]UMR1319 Micalis, INRA , Jouy-en-Josas, France
                [2 ]Chair of Bioinformatics, Boku University Vienna , Vienna, Austria
                [3 ]Department of Life Sciences, University of Warwick , Warwickshire, UK
                [4 ]UMR1313 GABI, Iso Cell Express (ICE), INRA , Jouy-en-Josas, France
                [5 ]Plate-forme d'Analyse Protéomique de Paris Sud-Ouest (PAPPSO), INRA , Gif-sur-Yvette, France
                [6 ]Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg , Strasbourg, France
                [7 ]Gastroenterology and Nutrition Unit, Hôpital Saint-Antoine, AP-HP , Paris, France
                [8 ]UR1077, Mathématique Informatique et Génome (MIG), INRA , Jouy-en-Josas, France
                [9 ]UR341, Mathématiques et Informatique Appliquées (MIA), INRA , Jouy-en-Josas, France
                Author notes
                [Correspondence to ] Dr Catherine Juste, Bâtiment 405, INRA Domaine de Vilvert, Jouy-en-Josas 78350, France; catherine.juste@ 123456jouy.inra.fr
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

                : 19 September 2012
                : 16 December 2013
                : 17 December 2013
                Inflammatory Bowel Disease
                Original article
                Custom metadata

                Gastroenterology & Hepatology
                crohn's disease,enteric bacterial microflora,inflammatory bowel disease


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