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      Altered gut microbiota in Rett syndrome

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          Abstract

          Background

          The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT’s gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status.

          Results

          Our findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida.

          We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles.

          Conclusions

          We demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40168-016-0185-y) contains supplementary material, which is available to authorized users.

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          Most cited references35

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis.

            The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
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              The story of Rett syndrome: from clinic to neurobiology.

              The postnatal neurodevelopmental disorder Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor involved in chromatin remodeling and the modulation of RNA splicing. MECP2 aberrations result in a constellation of neuropsychiatric abnormalities, whereby both loss of function and gain in MECP2 dosage lead to similar neurological phenotypes. Recent studies demonstrate disease reversibility in RTT mouse models, suggesting that the neurological defects in MECP2 disorders are not permanent. To investigate the potential for restoring neuronal function in RTT patients, it is essential to identify MeCP2 targets or modifiers of the phenotype that can be therapeutically modulated. Moreover, deciphering the molecular underpinnings of RTT is likely to contribute to the understanding of the pathogenesis of a broader class of neuropsychiatric disorders.
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                Author and article information

                Contributors
                c.de.filippo@ibimet.cnr.it
                Journal
                Microbiome
                Microbiome
                Microbiome
                BioMed Central (London )
                2049-2618
                30 July 2016
                30 July 2016
                2016
                : 4
                : 41
                Affiliations
                [1 ]Department of Computational Biology, Research and Innovation Centre, Fondazione Edmund Mach, Via E. Mach 1, 38010 San Michele all’ Adige, Italy
                [2 ]Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123 Trento, Italy
                [3 ]Department of Biology, University of Florence, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Florence Italy
                [4 ]Neonatal Intensive Care Unit, University Hospital AOUS, Viale Bracci 16, 53100 Siena, Italy
                [5 ]Child Neuropsychiatry Unit, University Hospital AOUS, Viale Bracci 16, 53100 Siena, Italy
                [6 ]Department of Genomics and Biology of Fruit Crop, Research and Innovation Centre, Fondazione Edmund Mach, Via E. Mach 1, 38010 San Michele all’ Adige, Italy
                [7 ]Department of Experimental and Clinical Biomedical Sciences, Gastroenterology Unit, University of Florence, Viale Morgagni 40, 50139 Florence, Italy
                [8 ]Institute of Biometeorology (IBIMET), National Research Council (CNR), Via Giovanni Caproni 8, I-50145 Florence, Italy
                Article
                185
                10.1186/s40168-016-0185-y
                4967335
                27473171
                8ae93d47-4891-42c1-b418-0df2f8f1e865
                © The Author(s). 2016

                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.

                History
                : 18 April 2016
                : 21 July 2016
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                gut microbiota,mycobiota,rett syndrome,scfas,metataxonomics,intestinal dysbiosis,constipation

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