Endocrine Abstracts

In Graves’ disease (GD) thyrotropin receptor (TSHR) stimulating autoantibodies cause hyperthyroidism. Many GD patients develop Graves’ orbitopathy (GO) characterized by orbital tissue remodelling including adipogenesis. Whilst progress has been made in understanding the processes causing expansion of orbital tissues, little is known about loss of tolerance to the TSHR target autoantigen. Mechanisms for triggering autoimmunity by microorganisms include molecular mimicry, but more recently the role of the gut microbiota in maintaining the balance between inflammatory Th17 and non-inflammatory Treg in the gut-associated lymphoid tissue has been recognised. Mothers transmit their genes and gut microbiota to their children. The microbial populations in the gut may affect metabolism; advances enable sequencing of microbial 16S rRNA genes, facilitating composition assessment of bacterial communities. We tested the hypothesis that in GD bacteria inducing tolerance (Treg) are under-represented or those generating pro-inflammatory cytokines are over-represented. I will present data from patients, untreated/within 6 weeks treatment commencing; GD (n=65) with no/minimal eye signs; GO (n=56), mild/moderate-severe and healthy controls (n=42) which demonstrate significant differences in phylum/genera composition between the three groups. Robust murine models would help delineate pathogenesis. Female BALBc mice, immunized with TSHR-A subunit expression plasmid/electroporation, generated a GD/GO model reproducible in London and Essen. Orbital disease was induced in both centres, but differences were apparent. We hypothesized that the gut microbiota influences the outcome and reproducibility of induced GD/GO. I will present data illustrating the significant differences in alpha, beta-diversity and taxonomic profiles observed in the two centres. Furthermore we identified disease-associated microbial taxonomies and correlation with ocular disease. Finally I will report preliminary findings of the effects of modifying the human and murine gut microbiota on spontaneous and induced disease outcomes achieved using probiotic (human and mouse), antibiotic or human GO faecal material transfer (in mice).