Objectives

We hypothesize that in patients with Graves’ disease (GD) micro-organisms in the gut which induce local tolerance are under-represented or micro-organisms generating a pro-inflammatory cytokine milieu are over-represented. The balance may be even more skewed towards inflammation in those with Graves’ orbitopathy (GO); in both GD and GO the imbalance leads to autoimmunity.

To explore this hypothesis INDIGO applies four complementary approaches:
– Analysis of the gut microbiome of patients with GD and GO, and comparison with that of healthy individuals, using 16S RNA sequencing and next generation sequencing;

– Clinical trial of a probiotic formulation in GD patients to investigate whether the microbiome can be modified;

– Development of in vitro models comprising gut epithelium and immune cells plus micro-organisms from GD/GO patients followed by analysis of cytokines released;

– Modification of the gut microbiome of mice, using micro-organisms from GD/GO patients, to improve and extend an in vivo model of GO and be a prototype for similar         studies in other autoimmune disorders.

In addition, INDIGO is using several methodologies to identify novel biomarkers to identify GD patients most likely to develop GO and hence inform the early selection of the most appropriate treatment regimen: high throughput analysis of microRNA (miRNA) in serum/plasma, proteomics analyses of tears and serum and a comparison of antibody responses in GD/GO patients and controls to microbial or food derived antigens to determine whether these environmental triggers are involved in GD or associated with GO progression.