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      Age and fecal microbial strain-specific differences in patients with spondyloarthritis

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          Abstract

          Background

          Prior studies have demonstrated abnormalities in the composition of the gastrointestinal microbiota in pediatric and adult patients with spondyloarthritis (SpA). In particular, diminished fecal abundance of Faecalibacterium prausnitzii and abnormalities in both directions in the abundance of the Bacteroides genus have been identified.

          Methods

          We obtained fecal specimens from 30 children with treatment-naïve enthesitis-related arthritis (ERA) and 19 healthy controls, as well as specimens from 11 adult patients with longstanding SpA and 10 adult healthy controls. All of the samples underwent sequencing of the 16S ribosomal DNA. A subset of the pediatric fecal samples was subjected to shotgun metagenomics sequencing.

          Results

          ERA patients had decreased abundance of the anti-inflammatory F. prausnitzii A2-165 strain (41 ± 28% versus 54 ± 20% of all sequences matching F. prausnitzii, p = 0.084) and an increased abundance of the control F. prausnitzii L2/6 strain (28 ± 28% versus 15 ± 15%, p = 0.038). Similar trends were observed in adults with longstanding SpA (n = 11) and controls ( n = 10). In contrast, the fecal abundance of Bacteroides fragilis was increased in ERA subjects (2.0 ± 4.0% versus 0.45 ± 0.7% of all sequences, p = 0.045), yet was diminished in adult subjects (0.2 ± % versus 1.0 ± % of all sequences, p = 0.106). Shotgun metagenomics sequencing of the fecal DNA in the pediatric subjects revealed diminished coverage of the butanoate pathway (abundance normalized to controls of 1 ± 0.48 versus 0.72 ± 0.33 in ERA, p = 0.037).

          Conclusions

          The anti-inflammatory F. prausnitzii A2-165 strain appears to be depleted in both pediatric and adult SpA. In contrast, B. fragilis may be depleted in adult disease yet abundant in pediatric SpA, suggesting developmental effects on the immune system.

          Electronic supplementary material

          The online version of this article (10.1186/s13075-018-1510-6) contains supplementary material, which is available to authorized users.

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          Most cited references 31

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          The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.

          Mucosal surfaces constantly encounter microbes. Toll-like receptors (TLRs) mediate recognition of microbial patterns to eliminate pathogens. By contrast, we demonstrate that the prominent gut commensal Bacteroides fragilis activates the TLR pathway to establish host-microbial symbiosis. TLR2 on CD4(+) T cells is required for B. fragilis colonization of a unique mucosal niche in mice during homeostasis. A symbiosis factor (PSA, polysaccharide A) of B. fragilis signals through TLR2 directly on Foxp3(+) regulatory T cells to promote immunologic tolerance. B. fragilis lacking PSA is unable to restrain T helper 17 cell responses and is defective in niche-specific mucosal colonization. Therefore, commensal bacteria exploit the TLR pathway to actively suppress immunity. We propose that the immune system can discriminate between pathogens and the microbiota through recognition of symbiotic bacterial molecules in a process that engenders commensal colonization.
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            Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.

             J.-P. Segain (2000)
            Proinflammatory cytokines are key factors in the pathogenesis of Crohn's disease (CD). Activation of nuclear factor kappa B (NFkappaB), which is involved in their gene transcription, is increased in the intestinal mucosa of CD patients. As butyrate enemas may be beneficial in treating colonic inflammation, we investigated if butyrate promotes this effect by acting on proinflammatory cytokine expression. Intestinal biopsy specimens, isolated lamina propria cells (LPMC), and peripheral blood mononuclear cells (PBMC) were cultured with or without butyrate for assessment of secretion of tumour necrosis factor (TNF) and mRNA levels. NFkappaB p65 activation was determined by immunofluorescence and gene reporter experiments. Levels of NFkappaB inhibitory protein (IkappaBalpha) were analysed by western blotting. The in vivo efficacy of butyrate was assessed in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis. Butyrate decreased TNF production and proinflammatory cytokine mRNA expression by intestinal biopsies and LPMC from CD patients. Butyrate abolished lipopolysaccharide (LPS) induced expression of cytokines by PBMC and transmigration of NFkappaB from the cytoplasm to the nucleus. LPS induced NFkappaB transcriptional activity was decreased by butyrate while IkappaBalpha levels were stable. Butyrate treatment also improved TNBS induced colitis. Butyrate decreases proinflammatory cytokine expression via inhibition of NFkappaB activation and IkappaBalpha degradation. These anti-inflammatory properties provide a rationale for assessing butyrate in the treatment of CD.
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              The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats

              A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.
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                Author and article information

                Contributors
                (205) 638-9438 , mstoll@peds.uab.edu
                weisspa@email.chop.edu
                Jennifer.Weiss@hackensackmeridian.org
                pnigrovic@partners.org
                bedelhe@ccmckids.org
                sbridges@uabmc.edu
                mdanila@uabmc.edu
                Charles.spencer@nationwidechildrens.org
                Marilynn.punaro@TSRH.org
                kenneth.schikler@louisville.edu
                areiff@chla.usc.edu
                rkumar@uab.edu
                rcron@peds.uab.edu
                caseym@uab.edu
                elliotl@uab.edu
                Journal
                Arthritis Res Ther
                Arthritis Res. Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                30 January 2018
                30 January 2018
                2018
                : 20
                Affiliations
                [1 ]ISNI 0000000106344187, GRID grid.265892.2, University of Alabama at Birmingham, ; Birmingham, AL USA
                [2 ]ISNI 0000 0001 0680 8770, GRID grid.239552.a, Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [3 ]ISNI 0000 0004 0407 6328, GRID grid.239835.6, Hackensack University Medical Center, ; Hackensack, NJ USA
                [4 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Boston Children’s Hospital and Brigham and Women’s Hospital, ; Boston, MA USA
                [5 ]ISNI 0000 0001 0440 7332, GRID grid.414666.7, Connecticut Children’s Medical Center, ; Hartford, CT USA
                [6 ]ISNI 0000 0004 0392 3476, GRID grid.240344.5, Nationwide Children’s Hospital, ; Columbus, OH USA
                [7 ]ISNI 0000 0000 8680 5133, GRID grid.416991.2, Texas Scottish Rite Hospital, ; Dallas, TX USA
                [8 ]ISNI 0000 0001 2113 1622, GRID grid.266623.5, University of Louisville, ; Louisville, KY USA
                [9 ]ISNI 0000 0001 2153 6013, GRID grid.239546.f, Children’s Hospital of Los Angeles, ; Los Angeles, CA USA
                Article
                1510
                10.1186/s13075-018-1510-6
                5791354
                29382366
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: Childhood arthritis and rheumatology research alliance
                Funded by: FundRef http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
                Award ID: P60 AR064172
                Award ID: K23 AR062100
                Award Recipient :
                Funded by: Fundación Bechara
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100011305, Comprehensive Cancer Center, University of Alabama at Birmingham;
                Award ID: P30 CA013148
                Funded by: Center for AIDS Research, UAB
                Award ID: 5P30AI027767
                Funded by: Center for Clinical and Translational Science, University of Illinois at Chicago (US)
                Award ID: UL1TR001417
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Orthopedics

                microbiota, spondyloarthritis, sequencing, bacteroides, faecalibacterium

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