PMID- 29801507 OWN - NLM STAT- MEDLINE DCOM- 20190111 LR - 20190111 IS - 2049-2618 (Electronic) IS - 2049-2618 (Linking) VI - 6 IP - 1 DP - 2018 May 25 TI - Gut microbiota in experimental murine model of Graves' orbitopathy established in different environments may modulate clinical presentation of disease. PG - 97 LID - 10.1186/s40168-018-0478-4 [doi] LID - 97 AB - 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 betagal control-immunized mice and naive 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. FAU - Masetti, Giulia AU - Masetti G AD - Division of Infection & Immunity, School of Medicine, Cardiff University, UHW main building, Heath Park, Cardiff, CF14 4XW, UK. AD - Departments of Bioinformatics, PTP Science Park Srl, via Einstein loc. Cascina Codazza, 29600, Lodi, Italy. FAU - Moshkelgosha, Sajad AU - Moshkelgosha S AD - Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen/University of Duisburg-Essen, 45147, Essen, Germany. AD - Faculty of Life Sciences and Medicine, King's College London, London, SE5 9NU, UK. AD - Latner Thoracic Surgery Laboratories, Toronto General Research Institute, University Health Network and University of Toronto, Toronto, M5G 1L7, Canada. FAU - Kohling, Hedda-Luise AU - Kohling HL AD - Cultech Ltd., Baglan, Port Talbot, SA127BZ, UK. AD - University Hospital Essen, University of Duisburg-Essen, Institute of Medical Microbiology, 45147, Essen, Germany. FAU - Covelli, Danila AU - Covelli D AD - Cultech Ltd., Baglan, Port Talbot, SA127BZ, UK. AD - Graves' Orbitopathy Center, Endocrinology, Department of Clinical Sciences and Community Health, Fondazione Ca'Granda IRCCS, University of Milan, via Sforza 35, 20122, Milan, Italy. FAU - Banga, Jasvinder Paul AU - Banga JP AD - Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen/University of Duisburg-Essen, 45147, Essen, Germany. AD - Faculty of Life Sciences and Medicine, King's College London, London, SE5 9NU, UK. FAU - Berchner-Pfannschmidt, Utta AU - Berchner-Pfannschmidt U AD - Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen/University of Duisburg-Essen, 45147, Essen, Germany. FAU - Horstmann, Mareike AU - Horstmann M AD - Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen/University of Duisburg-Essen, 45147, Essen, Germany. FAU - Diaz-Cano, Salvador AU - Diaz-Cano S AD - King's College Hospital NHS Foundation Trust (SDC), London, SE5 9RS, UK. FAU - Goertz, Gina-Eva AU - Goertz GE AD - Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen/University of Duisburg-Essen, 45147, Essen, Germany. FAU - Plummer, Sue AU - Plummer S AD - Cultech Ltd., Baglan, Port Talbot, SA127BZ, UK. FAU - Eckstein, Anja AU - Eckstein A AD - Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen/University of Duisburg-Essen, 45147, Essen, Germany. FAU - Ludgate, Marian AU - Ludgate M AD - Division of Infection & Immunity, School of Medicine, Cardiff University, UHW main building, Heath Park, Cardiff, CF14 4XW, UK. FAU - Biscarini, Filippo AU - Biscarini F AD - Division of Infection & Immunity, School of Medicine, Cardiff University, UHW main building, Heath Park, Cardiff, CF14 4XW, UK. AD - Departments of Bioinformatics, PTP Science Park Srl, via Einstein loc. Cascina Codazza, 29600, Lodi, Italy. AD - Italian National Council for Research (CNR), via Bassini 15, 20133, Milan, Italy. FAU - Marchesi, Julian Roberto AU - Marchesi JR AD - School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK. MarchesiJR@cardiff.ac.uk. AD - Center for Digestive and Gut Health, Imperial College London, W2 1NY, London, UK. MarchesiJR@cardiff.ac.uk. CN - INDIGO consortium LA - eng GR - 612116/FP7 People: Marie-Curie Actions/International GR - BE3177/2-1/Deutsche Forschungsgemeinschaft/International GR - Not applicable/Internal KCL grant/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180525 PL - England TA - Microbiome JT - Microbiome JID - 101615147 RN - 0 (Autoantibodies) RN - 0 (RNA, Ribosomal, 16S) RN - 0 (Receptors, Thyrotropin) SB - IM MH - Animals MH - Autoantibodies/immunology MH - Autoimmunity/immunology MH - Bacterial Load MH - Disease Models, Animal MH - Firmicutes/*isolation & purification MH - Gastrointestinal Microbiome/*physiology MH - Graves Ophthalmopathy/*pathology MH - Intestines/*microbiology MH - Mice MH - Mice, Inbred BALB C MH - RNA, Ribosomal, 16S/genetics MH - Receptors, Thyrotropin/*immunology PMC - PMC5970527 OTO - NOTNLM OT - Firmicutes OT - Graves' disease OT - Graves' orbitopathy OT - Gut microbiota OT - Induced animal model OT - Metataxonomics OT - Orbital adipogenesis OT - TSHR COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study was approved by the North Rhine Westphalian State Agency for Nature, Environment and Consumer Protection, Germany and by the Ethics Committee of King's College London, United Kingdom (UK). COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/05/29 06:00 MHDA- 2019/01/12 06:00 PMCR- 2018/05/25 CRDT- 2018/05/27 06:00 PHST- 2017/10/18 00:00 [received] PHST- 2018/05/08 00:00 [accepted] PHST- 2018/05/27 06:00 [entrez] PHST- 2018/05/29 06:00 [pubmed] PHST- 2019/01/12 06:00 [medline] PHST- 2018/05/25 00:00 [pmc-release] AID - 10.1186/s40168-018-0478-4 [pii] AID - 478 [pii] AID - 10.1186/s40168-018-0478-4 [doi] PST - epublish SO - Microbiome. 2018 May 25;6(1):97. doi: 10.1186/s40168-018-0478-4.