6
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease : C4B and paediatric inflammatory bowel disease

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          <p id="d3725270e363">Complement <i>C4</i> genes are linked to paediatric inflammatory bowel disease (PIBD), but the mechanisms have remained unclear. We examined the influence of <i>C4B</i> gene number on intestinal microbiota and <i>in‐vitro</i> serum complement activation by intestinal microbes in PIBD patients. Complement <i>C4A</i> and <i>C4B</i> gene numbers were determined by genomic reverse transcription–polymerase chain reaction (RT‐PCR) from 64 patients with PIBD (Crohn's disease or ulcerative colitis). The severity of the disease course was determined from faecal calprotectin levels. Intestinal microbiota was assessed using the HITChip microarray. Complement reactivity in patients was analysed by incubating their sera with <i>Yersinia pseudotuberculosis</i> and <i>Akkermansia muciniphila</i> and determining the levels of C3a and soluble terminal complement complex (SC5b‐9) using enzyme immunoassays. The microbiota diversity was wider in patients with no <i>C4B</i> genes than in those with one or two <i>C4B</i> genes, irrespective of intestinal inflammation. <i>C4B</i> and total <i>C4</i> gene numbers correlated positively with soluble terminal complement complex (TCC, SC5b‐9) levels when patient serum samples were stimulated with bacteria. Our results suggest that the <i>C4B</i> gene number associates positively with inflammation in patients with PIBD. Multiple copies of the <i>C4B</i> gene may thus aggravate the IBD‐associated dysbiosis through escalated complement reactivity towards the microbiota. </p>

          Related collections

          Most cited references 28

          • Record: found
          • Abstract: found
          • Article: not found

          The microbiome in inflammatory bowel disease: current status and the future ahead.

          Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults

            In this paper we present the in silico assessment of the diversity of variable regions of the small subunit ribosomal RNA (SSU rRNA) gene based on an ecosystem-specific curated database, describe a probe design procedure based on two hypervariable regions with minimal redundancy and test the potential of such probe design strategy for the design of a flexible microarray platform. This resulted in the development and application of a phylogenetic microarray for studying the human gastrointestinal microbiota – referred as the human intestinal tract chip (HITChip). Over 4800 dedicated tiling oligonucleotide probes were designed based on two hypervariable regions of the SSU rRNA gene of 1140 unique microbial phylotypes (< 98% identity) following analysis of over 16 000 human intestinal SSU rRNA sequences. These HITChip probes were hybridized to a diverse set of human intestinal samples and SSU rRNA clones to validate its fingerprinting and quantification potential. Excellent reproducibility (median Pearson's correlation of 0.99) was obtained following hybridization with T7 polymerase transcripts generated in vitro from SSU rRNA gene amplicons. A linear dose–response was observed with artificial mixtures of 40 different representative amplicons with relative abundances as low as 0.1% of total microbiota. Analysis of three consecutively collected faecal samples from ten individuals (five young and five elderly adults) revealed temporal dynamics and confirmed that the adult intestinal microbiota is an individual-specific and relatively stable ecosystem. Further analysis of the stable part allowed for the identification of a universal microbiota core at the approximate genus level (90% sequence similarity). This core consists of members of Actinobacteria, Bacteroidetes and Firmicutes. Used as a phylogenetic fingerprinting tool with the possibility for relative quantification, the HITChip has the potential to bridge the gaps in our knowledge in the quantitative and qualitative description of the human gastrointestinal microbiota composition.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans.

              Interindividual gene copy-number variation (CNV) of complement component C4 and its associated polymorphisms in gene size (long and short) and protein isotypes (C4A and C4B) probably lead to different susceptibilities to autoimmune disease. We investigated the C4 gene CNV in 1,241 European Americans, including patients with systemic lupus erythematosus (SLE), their first-degree relatives, and unrelated healthy subjects, by definitive genotyping and phenotyping techniques. The gene copy number (GCN) varied from 2 to 6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four copies of total C4, two copies of C4A, and two copies of C4B were the most common GCN counts, but each constituted only between one-half and three-quarters of the study populations. Long C4 genes were strongly correlated with C4A (R=0.695; P or =5 copies of C4 (patients 5.79%; controls 12%; OR=0.466; P=.016). Both zero copies (OR=5.267; P=.001) and one copy (OR=1.613; P=.022) of C4A were risk factors for SLE, whereas > or =3 copies of C4A appeared to be protective (OR=0.574; P=.012). Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA was more likely to be transmitted to patients with SLE. This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease.
                Bookmark

                Author and article information

                Journal
                Clinical & Experimental Immunology
                Clin Exp Immunol
                Wiley
                00099104
                December 2017
                December 2017
                September 25 2017
                : 190
                : 3
                : 394-405
                Affiliations
                [1 ]Immunobiology, Research Programs Unit; University of Helsinki; Helsinki Finland
                [2 ]Department of Bacteriology and Immunology; University of Helsinki; Helsinki Finland
                [3 ]Department of Medical and Clinical Genetics; University of Helsinki; Helsinki Finland
                [4 ]Transplantation Laboratory, Medicum; University of Helsinki; Helsinki Finland
                [5 ]Children's Hospital, University of Helsinki and Helsinki University Hospital; Helsinki Finland
                [6 ]Helsinki University Hospital Laboratory (HUSLAB); Helsinki Finland
                Article
                10.1111/cei.13040
                5680072
                28832994
                © 2017

                Comments

                Comment on this article