Gut microbiome associated with Graves disease and Graves orbitopathy: the INDIGO Multicenter European Study

Biscarini, Filippo ORCID: https://orcid.org/0000-0002-3901-2354, Masetti, Giulia, Muller, Ilaria, Verhasselt, Hedda Luise, Covelli, Danila, Colucci, Giuseppe, Zhang, Lei ORCID: https://orcid.org/0000-0003-3536-8692, Draman, Mohd Shazli, Okosieme, Onyebuchi, Taylor, Pete ORCID: https://orcid.org/0000-0002-3436-422X, Daumerie, Chantal, Burlacu, Maria-Cristina, Marinò, Michele, Ezra, Daniel George, Perros, Petros, Plummer, Sue, Eckstein, Anja, Salvi, Mario, Marchesi, Julian R. ORCID: https://orcid.org/0000-0002-7994-5239 and Ludgate, Marian 2023. Gut microbiome associated with Graves disease and Graves orbitopathy: the INDIGO Multicenter European Study. The Journal of Clinical Endocrinology & Metabolism 108 (8) , pp. 2065-2077. 10.1210/clinem/dgad030

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Abstract

Context Gut bacteria can influence host immune responses but little is known about their role in tolerance-loss mechanisms in Graves disease (GD; hyperthyroidism caused by autoantibodies, TRAb, to the thyrotropin receptor, TSHR) and its progression to Graves orbitopathy (GO). Objective This work aimed to compare the fecal microbiota in GD patients, with GO of varying severity, and healthy controls (HCs). Methods Patients were recruited from 4 European countries (105 GD patients, 41 HCs) for an observational study with cross-sectional and longitudinal components. Results At recruitment, when patients were hyperthyroid and TRAb positive, Actinobacteria were significantly increased and Bacteroidetes significantly decreased in GD/GO compared with HCs. The Firmicutes to Bacteroidetes (F:B) ratio was significantly higher in GD/GO than in HCs. Differential abundance of 15 genera was observed in patients, being most skewed in mild GO. Bacteroides displayed positive and negative correlations with TSH and free thyroxine, respectively, and was also significantly associated with smoking in GO; smoking is a risk factor for GO but not GD. Longitudinal analyses revealed that the presence of certain bacteria (Clostridiales) at diagnosis correlated with the persistence of TRAb more than 200 days after commencing antithyroid drug treatment. Conclusion The increased F:B ratio observed in GD/GO mirrors our finding in a murine model comparing TSHR-immunized with control mice. We defined a microbiome signature and identified changes associated with autoimmunity as distinct from those due to hyperthyroidism. Persistence of TRAb is predictive of relapse; identification of these patients at diagnosis, via their microbiome, could improve management with potential to eradicate Clostridiales.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	0021-972X
Date of First Compliant Deposit:	3 March 2023
Date of Acceptance:	17 January 2023
Last Modified:	13 Mar 2024 17:01
URI:	https://orca.cardiff.ac.uk/id/eprint/157477

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