Gut Microbiome in BALB/c and C57BL/6J Mice Undergoing Experimental Thyroid Autoimmunity Associate with Differences in Immunological Responses and Thyroid Function

Sajad Moshkelgosha; Giulia Masetti; Utta Berchner-Pfannschmidt; Hedda Luise Verhasselt; Mareike Horstmann; Salvador Diaz-Cano; Alistair Noble; Barbel Edelman; Danila Covelli; Sue Plummer; Julian R. Marchesi; Marian Ludgate; Filippo Biscarini; Anja Eckstein; J. Paul Banga

doi:10.1055/a-0653-3766

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2018; 50(12): 932-941
DOI: 10.1055/a-0653-3766

Endocrine Research

Gut Microbiome in BALB/c and C57BL/6J Mice Undergoing Experimental Thyroid Autoimmunity Associate with Differences in Immunological Responses and Thyroid Function

Sajad Moshkelgosha^*

¹Faculty of Life Sciences & Medicine, King’s College London, London, UK

²Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany

³Present address: Latner Thoracic Surgery Research Laboratories, University Health Network (UHN), Toronto, Canada

,

Giulia Masetti^*

⁴Departments of Bioinformatics, PTP Science Park, via Einstein loc. Cascina Codazza, Lodi, Italy

⁵Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, UK

,

Utta Berchner-Pfannschmidt

²Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany

,

Hedda Luise Verhasselt

⁶Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

,

Mareike Horstmann

²Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany

,

Salvador Diaz-Cano

⁷King’s College Hospital NHS Foundation Trust, Department of Histopathology, London, UK

,

Alistair Noble

⁸Present address: Antigen Presentation Research Group, Imperial College London, Harrow, UK

,

Barbel Edelman

²Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany

,

Danila Covelli

⁹Graves’ Orbitopathy Centre, Department of Clinical Sciences and Community Health, Fondazione Ca’Granda IRCCS, University of Milan, Milan, Italy

,

Sue Plummer

¹⁰Cultech Ltd., Baglan, Port Talbot, UK

,

Julian R. Marchesi

¹¹School of Biosciences, Cardiff University, Cardiff and Centre for Digestive and Gut Health, Imperial College London, London, UK

,

Marian Ludgate

¹²Division of Infection & Immunity, Cardiff University, Cardiff, UK

,

Filippo Biscarini

¹²Division of Infection & Immunity, Cardiff University, Cardiff, UK

¹³Italian National Council for Research (CNR), Milan, Italy and INDIGO Consortium http://www.indigo-iapp.eu

,

Anja Eckstein

²Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany

,

J. Paul Banga

¹Faculty of Life Sciences & Medicine, King’s College London, London, UK

²Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany

› Institutsangaben

Abstract

Experimental models of hyperthyroid Graves’ disease (GD) and Graves’ orbitopathy (GO) are efficiently developed by genetic immunisation by electroporation with human thyrotropin hormone receptor (hTSHR) A-subunit plasmid in female BALB/c (H-2d) mice. We investigated susceptibility in C57BL/6 J (H-2b) animals to allow studies on disease mechanisms in transgenic and immune response gene knock-out mice. Higher numbers of female C57BL/6 J were positive for pathogenic thyroid stimulating antibodies, but induced hyperthyroidism remained at a low frequency compared to BALB/c animals. Assessment of hTSHR specific T cells showed reduced proliferation in C57BL/6 J animals accompanied with anti-inflammatory IL-10, with less pro-inflammatory IFN-γ compared to BALB/c. Whilst the orbital tissue from immune BALB/c mice showed inflammation and adipogenesis, in contrast C57BL/6 J animals showed normal pathology. We characterised the gut microbiota using 16 S ribosomal RNA gene sequencing to explore its possible pathogenic role in the model. Despite being housed under identical conditions, we observed significantly different organisation of the microbiota (beta-diversity) in the two strains. Taxonomic differences were also noted, with C57BL/6 J showing an enrichment of Operational Taxonomic Units (OTUs) belonging to the Paludibacter and Allobaculum, followed by Limibacter, Anaerophaga and Ureaplasma genera. A higher number of genera significantly correlating with clinical features was observed in C57BL/6 J compared to BALB/c; for example, Limibacter OTUs correlated negatively with thyroid-stimulating antibodies in C57BL/6 J mice. Thus, our data suggest gut microbiota may play a pivotal immunomodulatory role that differentiates the thyroid function and orbital pathology outcome in these two inbred strains undergoing experimental GO.

Key words

Graves’ disease - autoimmunity - TSH-receptor antibodies

Volltext

Referenzen

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