Filippo Biscarini, Giulia Masetti, Ilaria Muller, Hedda Luise Verhasselt, Danila Covelli, Giuseppe Colucci, Lei Zhang, Mohd Shazli Draman, Onyebuchi Okosieme, Pete Taylor, Chantal Daumerie, Maria-Cristina Burlacu, Michele Marinò, Daniel George Ezra, Petros Perros, Sue Plummer, Anja Eckstein, Mario Salvi, Julian R Marchesi, Marian Ludgate
The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 8, August 2023, Pages 2065–2077
https://doi.org/10.1210/clinem/dgad030
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).
This work aimed to compare the fecal microbiota in GD patients, with GO of varying severity, and healthy controls (HCs).
Patients were recruited from 4 European countries (105 GD patients, 41 HCs) for an observational study with cross-sectional and longitudinal components.
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.
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.
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