title: The thyroid, the eyes and the gut: a possible connection.
abstract: BACKGROUND
  Graves' disease (GD) is an autoimmune disorder responsible for 60-90% of thyrotoxicosis, with an incidence of 1 to 2 cases per 1000 population per year in England. Graves' orbitopathy (GO) is the most frequent extrathyroidal manifestation, not provoked directly by abnormal thyroid hormone levels, but by the consequence of the underlying autoimmune process. The aetiology of autoimmune disorders is due to an interplay between susceptibility genes and environmental factors, such as infections and stress. What triggers the autoimmune reaction to a specific site of the body is not yet clearly understood. The lack of knowledge in GD and GO pathogenesis implicates therapies that only limit damage but do not prevent disease onset.
  
  
  METHODS
  We performed on PubMed and the Cochrane Library a literature search for the articles published until July 2016 by using the search terms 'graves disease' and 'microbiome', 'orbitopathy' and 'autoimmune pathogenesis'. Reference lists of relevant studies were hand-searched for additional studies.
  
  
  CONCLUSIONS
  In this scenario, a Marie Sklodowska-Curie funded project INDIGO ( http://www.indigo-iapp.eu/ ) is investigating the role of the gut bacteria in GD and GO pathogenesis. The gut is the first and the widest area of bacteria access, with the highest concentration of T cells in the human body and trained to react to microorganisms. Interestingly, all the environmental factors involved in GD and GO pathogenesis can alter the balance within the microorganisms located in the gut, and influence the immune system, in particular the proportions of regulatory Treg and inflammatory TH17 cells. It is hoped that investigating GD and GO pathogenesis from this novel aspect will identify new targets for prevention and treatment.
authors.affiliation: Graves' Orbitopathy Centre, Endocrinology, Department of Clinical Sciences and Community Health, Fondazione Ca'Granda IRCCS, University of Milan, via Sforza 35, 20122, Milan, Italy. danila.covelli@alice.it.
authors.forename: D
authors.initials: D
authors.lastname: Covelli
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ludgate
mesh_terms: D005767:Gastrointestinal Diseases / Q000503:physiopathology*; D006111:Graves Disease / Q000503:physiopathology*; D049970:Graves Ophthalmopathy / Q000503:physiopathology*; D006801:Humans; D011989:Receptors, Thyrotropin / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology*
chemical_list: D011989:Receptors, Thyrotropin
keywords: Autoimmunity; Graves’ disease; Graves’ orbitopathy; Microbiota and dysbiosis