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Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease
BACKGROUND: Variation in induced models of autoimmunity has been attributed to the housing environment and its effect on the gut microbiota. In Graves’ disease (GD), autoantibodies to the thyrotropin receptor (TSHR) cause autoimmune hyperthyroidism. Many GD patients develop Graves’ orbitopathy or op...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970527/ https://www.ncbi.nlm.nih.gov/pubmed/29801507 http://dx.doi.org/10.1186/s40168-018-0478-4 |
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author | Masetti, Giulia Moshkelgosha, Sajad Köhling, Hedda-Luise Covelli, Danila Banga, Jasvinder Paul Berchner-Pfannschmidt, Utta Horstmann, Mareike Diaz-Cano, Salvador Goertz, Gina-Eva Plummer, Sue Eckstein, Anja Ludgate, Marian Biscarini, Filippo Marchesi, Julian Roberto |
author_facet | Masetti, Giulia Moshkelgosha, Sajad Köhling, Hedda-Luise Covelli, Danila Banga, Jasvinder Paul Berchner-Pfannschmidt, Utta Horstmann, Mareike Diaz-Cano, Salvador Goertz, Gina-Eva Plummer, Sue Eckstein, Anja Ludgate, Marian Biscarini, Filippo Marchesi, Julian Roberto |
author_sort | Masetti, Giulia |
collection | PubMed |
description | BACKGROUND: Variation in induced models of autoimmunity has been attributed to the housing environment and its effect on the gut microbiota. In Graves’ disease (GD), autoantibodies to the thyrotropin receptor (TSHR) cause autoimmune hyperthyroidism. Many GD patients develop Graves’ orbitopathy or ophthalmopathy (GO) characterized by orbital tissue remodeling including adipogenesis. Murine models of GD/GO would help delineate pathogenetic mechanisms, and although several have been reported, most lack reproducibility. A model comprising immunization of female BALBc mice with a TSHR expression plasmid using in vivo electroporation was reproduced in two independent laboratories. Similar orbital disease was induced in both centers, but differences were apparent (e.g., hyperthyroidism in Center 1 but not Center 2). We hypothesized a role for the gut microbiota influencing the outcome and reproducibility of induced GO. RESULTS: We combined metataxonomics (16S rRNA gene sequencing) and traditional microbial culture of the intestinal contents from the GO murine model, to analyze the gut microbiota in the two centers. We observed significant differences in alpha and beta diversity and in the taxonomic profiles, e.g., operational taxonomic units (OTUs) from the genus Lactobacillus were more abundant in Center 2, and Bacteroides and Bifidobacterium counts were more abundant in Center 1 where we also observed a negative correlation between the OTUs of the genus Intestinimonas and TSHR autoantibodies. Traditional microbiology largely confirmed the metataxonomics data and indicated significantly higher yeast counts in Center 1 TSHR-immunized mice. We also compared the gut microbiota between immunization groups within Center 2, comprising the TSHR- or βgal control-immunized mice and naïve untreated mice. We observed a shift of the TSHR-immunized mice bacterial communities described by the beta diversity weighted Unifrac. Furthermore, we observed a significant positive correlation between the presence of Firmicutes and orbital-adipogenesis specifically in TSHR-immunized mice. CONCLUSIONS: The significant differences observed in microbiota composition from BALBc mice undergoing the same immunization protocol in comparable specific-pathogen-free (SPF) units in different centers support a role for the gut microbiota in modulating the induced response. The gut microbiota might also contribute to the heterogeneity of induced response since we report potential disease-associated microbial taxonomies and correlation with ocular disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40168-018-0478-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5970527 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-59705272018-05-30 Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease Masetti, Giulia Moshkelgosha, Sajad Köhling, Hedda-Luise Covelli, Danila Banga, Jasvinder Paul Berchner-Pfannschmidt, Utta Horstmann, Mareike Diaz-Cano, Salvador Goertz, Gina-Eva Plummer, Sue Eckstein, Anja Ludgate, Marian Biscarini, Filippo Marchesi, Julian Roberto Microbiome Research BACKGROUND: Variation in induced models of autoimmunity has been attributed to the housing environment and its effect on the gut microbiota. In Graves’ disease (GD), autoantibodies to the thyrotropin receptor (TSHR) cause autoimmune hyperthyroidism. Many GD patients develop Graves’ orbitopathy or ophthalmopathy (GO) characterized by orbital tissue remodeling including adipogenesis. Murine models of GD/GO would help delineate pathogenetic mechanisms, and although several have been reported, most lack reproducibility. A model comprising immunization of female BALBc mice with a TSHR expression plasmid using in vivo electroporation was reproduced in two independent laboratories. Similar orbital disease was induced in both centers, but differences were apparent (e.g., hyperthyroidism in Center 1 but not Center 2). We hypothesized a role for the gut microbiota influencing the outcome and reproducibility of induced GO. RESULTS: We combined metataxonomics (16S rRNA gene sequencing) and traditional microbial culture of the intestinal contents from the GO murine model, to analyze the gut microbiota in the two centers. We observed significant differences in alpha and beta diversity and in the taxonomic profiles, e.g., operational taxonomic units (OTUs) from the genus Lactobacillus were more abundant in Center 2, and Bacteroides and Bifidobacterium counts were more abundant in Center 1 where we also observed a negative correlation between the OTUs of the genus Intestinimonas and TSHR autoantibodies. Traditional microbiology largely confirmed the metataxonomics data and indicated significantly higher yeast counts in Center 1 TSHR-immunized mice. We also compared the gut microbiota between immunization groups within Center 2, comprising the TSHR- or βgal control-immunized mice and naïve untreated mice. We observed a shift of the TSHR-immunized mice bacterial communities described by the beta diversity weighted Unifrac. Furthermore, we observed a significant positive correlation between the presence of Firmicutes and orbital-adipogenesis specifically in TSHR-immunized mice. CONCLUSIONS: The significant differences observed in microbiota composition from BALBc mice undergoing the same immunization protocol in comparable specific-pathogen-free (SPF) units in different centers support a role for the gut microbiota in modulating the induced response. The gut microbiota might also contribute to the heterogeneity of induced response since we report potential disease-associated microbial taxonomies and correlation with ocular disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40168-018-0478-4) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-25 /pmc/articles/PMC5970527/ /pubmed/29801507 http://dx.doi.org/10.1186/s40168-018-0478-4 Text en © 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. |
spellingShingle | Research Masetti, Giulia Moshkelgosha, Sajad Köhling, Hedda-Luise Covelli, Danila Banga, Jasvinder Paul Berchner-Pfannschmidt, Utta Horstmann, Mareike Diaz-Cano, Salvador Goertz, Gina-Eva Plummer, Sue Eckstein, Anja Ludgate, Marian Biscarini, Filippo Marchesi, Julian Roberto Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
title | Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
title_full | Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
title_fullStr | Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
title_full_unstemmed | Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
title_short | Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
title_sort | gut microbiota in experimental murine model of graves’ orbitopathy established in different environments may modulate clinical presentation of disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970527/ https://www.ncbi.nlm.nih.gov/pubmed/29801507 http://dx.doi.org/10.1186/s40168-018-0478-4 |
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