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Deciphering the role of the gut microbiome in autoimmune thyroid disease

Masetti, Giulia 2019. Deciphering the role of the gut microbiome in autoimmune thyroid disease. PhD Thesis, Cardiff University.
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Abstract

The aetiology of hyperthyroid Graves’ disease (GD) is incompletely understood. I hypothesized that the gut microbiome affects tolerance to the thyrotropin receptor (TSHR) leading to GD and associated Graves’ orbitopathy (GO). My work comprises two observational studies and two interventional trials, applied to a GD/GO mouse model and GD/GO patients. I applied metataxonomics (16S rRNA gene sequencing) to samples from TSHRimmunised mice from two independent laboratories and observed significant differences in alpha-diversity, beta-diversity and taxonomic profiles. I also compared TSHR-treated and control mice in one centre and identified disease-associated taxonomies (i.e. reduced Bacteroidetes and enriched Firmicutes), correlating with orbital-adipogenesis in diseased but not controls. Changes in gut microbiota taxonomy (e.g. reduced Bacteroides/increased Roseburia spp. and increased Firmicutes:Bacteroidetes ratio) were also observed in GD (n=59) and GO (n=46) patients compared with controls (n=41), and associated with hyperthyroidism or GO severity. Moreover, GD/GO patients-predicted metagenomic pathways included increased “Bacterial epithelial invasion” and “glycosaminoglycan synthesis”. The role of the gut-microbiota in TSHR-induced GD/GO was confirmed by manipulating it in early life using antibiotics which enriched Bacteroides spp. and reduced/ablated disease symptoms. The faecal material transplant from GO patients, despite showing similarities with the GO patients gut microbiota, did not exacerbate murine GO, which also remained unaffected by probiotics. In contrast, in a randomised trial, GD/GO patients receiving probiotics (in addition to anti-thyroid therapy) displayed a more stable gut microbiota composition and sustained improvement in thyroid hormone levels compared with placebo. My results illustrate significant perturbation in the gut microbiota in TSHR-induced murine GD/GO and patients with spontaneous disease. Furthermore, the similarities in differential abundance and disease-associated taxonomies noted in both species support their relevance to disease. Future studies are needed to dissect the mechanistic role of the gut microbiome in activating the immune system and determining the onset of GD/GO.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Funders: Marie-Sklodowska Curie Industry-Academia Pathways and Partnerships (IAPP)
Date of First Compliant Deposit: 3 May 2019
Last Modified: 03 May 2019 10:04
URI: http://orca.cf.ac.uk/id/eprint/122136

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