Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease
Abstract Background Graves’ disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves’ orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, propto...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-02-01
|
| Series: | Microbiome |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40168-020-00952-4 |
| _version_ | 1818411332267933696 |
|---|---|
| author | Sajad Moshkelgosha Hedda Luise Verhasselt Giulia Masetti Danila Covelli Filippo Biscarini Mareike Horstmann Anke Daser Astrid M. Westendorf Christoph Jesenek Svenja Philipp Salvador Diaz-Cano J. Paul Banga Daryn Michael Sue Plummer Julian R. Marchesi Anja Eckstein Marian Ludgate Utta Berchner-Pfannschmidt and the INDIGO consortium |
| author_facet | Sajad Moshkelgosha Hedda Luise Verhasselt Giulia Masetti Danila Covelli Filippo Biscarini Mareike Horstmann Anke Daser Astrid M. Westendorf Christoph Jesenek Svenja Philipp Salvador Diaz-Cano J. Paul Banga Daryn Michael Sue Plummer Julian R. Marchesi Anja Eckstein Marian Ludgate Utta Berchner-Pfannschmidt and the INDIGO consortium |
| author_sort | Sajad Moshkelgosha |
| collection | DOAJ |
| description | Abstract Background Graves’ disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves’ orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (βgal; age ~ 6 weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~ 22 weeks). Results In ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-βgal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors’ microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25+ Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO. Conclusions These results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments. Video abstract |
| first_indexed | 2024-12-14T10:29:44Z |
| format | Article |
| id | doaj.art-4d003daeb4e049e9aa64bd3dd0270407 |
| institution | Directory Open Access Journal |
| issn | 2049-2618 |
| language | English |
| last_indexed | 2024-12-14T10:29:44Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj.art-4d003daeb4e049e9aa64bd3dd02704072022-12-21T23:06:11ZengBMCMicrobiome2049-26182021-02-019112010.1186/s40168-020-00952-4Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced diseaseSajad Moshkelgosha0Hedda Luise Verhasselt1Giulia Masetti2Danila Covelli3Filippo Biscarini4Mareike Horstmann5Anke Daser6Astrid M. Westendorf7Christoph Jesenek8Svenja Philipp9Salvador Diaz-Cano10J. Paul Banga11Daryn Michael12Sue Plummer13Julian R. Marchesi14Anja Eckstein15Marian Ludgate16Utta Berchner-Pfannschmidt17and the INDIGO consortiumMolecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University of Duisburg-EssenInstitute of Medical Microbiology, University Hospital Essen, University of Duisburg-EssenDivision of Infection & Immunity, School of Medicine, Cardiff UniversityCultech Ltd.Department of Bioinformatics, PTP Science Park SrlMolecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University of Duisburg-EssenDepartment of Ophthalmology, University Hospital Essen, University of Duisburg-EssenInstitute of Medical Microbiology, University Hospital Essen, University of Duisburg-EssenMolecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University of Duisburg-EssenMolecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University of Duisburg-EssenDepartment of Histopathology, King’s College Hospital, King’s CollegeMolecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University of Duisburg-EssenCultech Ltd.Cultech Ltd.School of Biosciences, Cardiff UniversityDepartment of Ophthalmology, University Hospital Essen, University of Duisburg-EssenDivision of Infection & Immunity, School of Medicine, Cardiff UniversityMolecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University of Duisburg-EssenAbstract Background Graves’ disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves’ orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (βgal; age ~ 6 weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~ 22 weeks). Results In ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-βgal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors’ microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25+ Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO. Conclusions These results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments. Video abstracthttps://doi.org/10.1186/s40168-020-00952-4Graves’ diseaseGraves’ orbitopathyMurine modelGut microbiotaMicrobiome modulationVancomycin |
| spellingShingle | Sajad Moshkelgosha Hedda Luise Verhasselt Giulia Masetti Danila Covelli Filippo Biscarini Mareike Horstmann Anke Daser Astrid M. Westendorf Christoph Jesenek Svenja Philipp Salvador Diaz-Cano J. Paul Banga Daryn Michael Sue Plummer Julian R. Marchesi Anja Eckstein Marian Ludgate Utta Berchner-Pfannschmidt and the INDIGO consortium Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease Microbiome Graves’ disease Graves’ orbitopathy Murine model Gut microbiota Microbiome modulation Vancomycin |
| title | Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease |
| title_full | Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease |
| title_fullStr | Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease |
| title_full_unstemmed | Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease |
| title_short | Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease |
| title_sort | modulating gut microbiota in a mouse model of graves orbitopathy and its impact on induced disease |
| topic | Graves’ disease Graves’ orbitopathy Murine model Gut microbiota Microbiome modulation Vancomycin |
| url | https://doi.org/10.1186/s40168-020-00952-4 |
| work_keys_str_mv | AT sajadmoshkelgosha modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT heddaluiseverhasselt modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT giuliamasetti modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT danilacovelli modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT filippobiscarini modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT mareikehorstmann modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT ankedaser modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT astridmwestendorf modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT christophjesenek modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT svenjaphilipp modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT salvadordiazcano modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT jpaulbanga modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT darynmichael modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT sueplummer modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT julianrmarchesi modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT anjaeckstein modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT marianludgate modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT uttaberchnerpfannschmidt modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease AT andtheindigoconsortium modulatinggutmicrobiotainamousemodelofgravesorbitopathyanditsimpactoninduceddisease |