Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study

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Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
Authors
Biscarini F, Masetti G, Muller I, Verhasselt HL, Covelli D, Colucci G, Zhang L, Draman MS, Okosieme O, Taylor P, Daumerie C, Burlacu MC, Marinò M, Ezra DG, Perros P, Plummer S, Eckstein A, Salvi M, Marchesi JR, Ludgate M
Journal
The Journal of clinical endocrinology and metabolism
Year
2023
Keywords:
Firmicutes:Bacteroidetes ratio, Graves disease, Graves orbitopathy, autoimmunity, gut microbiota, hyperthyroidism
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.

Experiment 1


Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Subjects

Location of subjects
Belgium
Germany
Italy
United Kingdom
Host species Species from which microbiome was sampled. Contact us to have more species added.
Homo sapiens
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Graves disease Basedow disease,Basedow's disease,exophthalmic goiter,Flajani-Basedow-Graves disease,grave's disease,Graves disease,Graves' disease,Graves' hyperthyroidism,parry disease,toxic diffuse goiter,graves disease
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Controls
Group 1 name Corresponds to the case (exposed) group for case-control studies
Graves’ disease (GD)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with Graves’ disease (GD)
Group 0 sample size Number of subjects in the control (unexposed) group
41
Group 1 sample size Number of subjects in the case (exposed) group
59
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
Three months

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V1-V2
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
T-Test
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes
Matched on Factors on which subjects have been matched on in a case-control study
age, sex
Confounders controlled for Confounding factors that have been accounted for by stratification or model adjustment
age, smoking behavior, geographic area, sex


Signature 1

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 1A and 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: increased abundance in Graves’ disease (GD)

NCBI Quality ControlLinks
Actinomycetota
Bifidobacterium sp.
Fusicatenibacter sp.

Revision editor(s): Aleru Divine

Signature 2

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 1A and 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: decreased abundance in Graves’ disease (GD)

NCBI Quality ControlLinks
Bacteroidota
Bacteroides sp.

Revision editor(s): Aleru Divine

Experiment 2


Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Graves ophthalmopathy Congestive Ophthalmopathy,Dysthyroid Ophthalmopathy,dysthyroid/thyroid-associated orbitopathy (TAO),Edematous Ophthalmopathy,Graves' ophthalmopathy,Graves' orbitopathy,Myopathic Ophthalmopathy,thyroid eye disease (TED),Thyroid-Associated Ophthalmopathies,Thyroid-Associated Ophthalmopathy,Graves ophthalmopathy,graves ophthalmopathy
Group 1 name Corresponds to the case (exposed) group for case-control studies
Graves’ ophthalmopathy (GO)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with Graves’ ophthalmopathy (GD)
Group 1 sample size Number of subjects in the case (exposed) group
46

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 1A

Description: Distributions of the main phyla Bacteroidetes, Firmicutes, and Actinobacteria in controls (HCs), GD, and Graves orbitopathy (GO) patients.

Abundance in Group 1: increased abundance in Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Actinomycetota

Revision editor(s): Aleru Divine

Signature 2

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 1A

Description: Distributions of the main phyla Bacteroidetes, Firmicutes, and Actinobacteria in controls (HCs), GD, and Graves orbitopathy (GO) patients.

Abundance in Group 1: decreased abundance in Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Bacteroidota

Revision editor(s): Aleru Divine

Experiment 3


Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Mild Graves’ ophthalmopathy (GO)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with mild Graves’ ophthalmopathy (GD)
Group 1 sample size Number of subjects in the case (exposed) group
36

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: increased abundance in Mild Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Bifidobacterium sp.
Fusicatenibacter sp.

Revision editor(s): Aleru Divine

Signature 2

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: decreased abundance in Mild Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Bacteroides sp.

Revision editor(s): Aleru Divine

Experiment 4


Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Severe Graves’ ophthalmopathy (GO)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with severe Graves’ ophthalmopathy (GD)
Group 1 sample size Number of subjects in the case (exposed) group
10

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: increased abundance in Severe Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Roseburia sp.

Revision editor(s): Aleru Divine

Experiment 5


Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Graves’ disease (GD)
Group 0 sample size Number of subjects in the control (unexposed) group
59

Lab analysis

Statistical Analysis

Matched on Factors on which subjects have been matched on in a case-control study
Not specified


Signature 1

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: increased abundance in Severe Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Roseburia sp.

Revision editor(s): Aleru Divine

Experiment 6


Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Mild Graves’ ophthalmopathy (GO)
Group 0 sample size Number of subjects in the control (unexposed) group
36

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: increased abundance in Severe Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Roseburia sp.

Revision editor(s): Aleru Divine

Signature 2

Needs review

Curated date: 2025/07/24

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 2

Description: Significantly different genera across eye-disease severity (distributed as control, no sign/Graves disease [GD] only, mild, moderate-severe according to the EUGOGO guidelines).

Abundance in Group 1: decreased abundance in Severe Graves’ ophthalmopathy (GO)

NCBI Quality ControlLinks
Bifidobacterium sp.

Revision editor(s): Aleru Divine