Graves & Crohn: Genetic Evidence for Microbiome-Mediated Crosstalk Original paper
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Autoimmune Diseases
Autoimmune Diseases
Autoimmune disease is when the immune system mistakenly attacks the body's tissues, often linked to imbalances in the microbiome, which can disrupt immune regulation and contribute to disease development.
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Graves Disease
Graves Disease
OverviewGraves’ Disease (GD) affects approximately 0.5% of the population, predominantly women. First-line treatment options—antithyroid medications, radioactive iodine, and surgery— often result in significant side effects, incomplete remissions, and frequent relapses. Further, current first-line treatment options focus on symptoms management, and reflect an inadequate understanding of the etiology of the condition. However, recent research reveals a […]
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Irritable Bowel Syndrome (IBS)
Irritable Bowel Syndrome (IBS)
Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder characterized by symptoms such as abdominal pain, bloating, and altered bowel habits. Recent research has focused on the gut microbiota's role in IBS, aiming to identify specific microbial signatures associated with the condition.
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was studied?
This original research employed bidirectional two-sample Mendelian randomization (MR) to test for causal relationships between Graves disease (GD) and inflammatory bowel disease (IBD). Genome-wide significant single-nucleotide polymorphisms (SNPs) for GD were taken from Biobank Japan (BBJ), while SNPs for IBD—including Crohn disease (CD) and ulcerative colitis (UC)—came from the International IBD Genetics Consortium. Multiple MR methods (inverse-variance weighted, MR-Egger, weighted median and MR-PRESSO) were applied to account for heterogeneity and pleiotropy, mimicking a randomized trial at the level of inherited genetic variation.
Who was studied?
The analysis drew on 2176 GD cases and 210 277 controls of East-Asian ancestry from BBJ, and 2824 IBD cases (1690 CD; 1134 UC) plus 3719 controls from East-Asian, Indian and Iranian cohorts within the IIBDGC panel. Mean age at GD diagnosis (not reported) typically peaks at 30-50 years, while mean CD and UC diagnosis ages were 27.6 ± 12.2 and 35.8 ± 13.7 years, respectively. Male representation was 27 % in GD versus 67 % in CD and 50 % in UC, ensuring sex-balanced causal inference.
Most important findings
| Direction (Exposure → Outcome) | OR (IVW) | 95 % CI | p-value | Interpretation |
|---|---|---|---|---|
| IBD → GD | 1.24 | 1.01-1.52 | 0.041 | Overall IBD increases GD risk |
| CD → GD | 1.30 | 1.06-1.59 | 0.010 | Crohn loci elevate GD risk by ~30 % |
| UC → GD | 0.71 | 0.58-0.86 | <0.001 | UC loci appear protective |
| GD → IBD | 1.04 | 0.88-1.23 | 0.62 | No overall reverse causality |
| GD → CD* | 1.33 | 1.15-1.53 | <0.001 | GD variants modestly raise CD risk |
| GD → UC | 0.82 | 0.62-1.09 | 0.18 | No effect on UC |
*after exclusion of pleiotropic SNP rs1569723. Forest and leave-one-out plots on pages 4-6 visually confirm these asymmetric effects, with CD-associated SNPs clustering above the null line and UC-associated SNPs below.
Key implications
The asymmetric genetic links suggest shared immune-microbiome pathways between GD and CD, but distinct mechanisms in UC. CD-associated variants intersect with HLA-DRB1, JAK-STAT and PTPN22 loci—genes also tied to microbial sensing and T-helper 17 regulation—supporting the view that dysbiotic Crohn-type microbiota may precipitate thyroid autoimmunity. Conversely, UC-specific variants (e.g., epithelial barrier genes) may foster microbial communities that dampen GD risk. Clinically, heightened vigilance for thyroid dysfunction in CD patients, and consideration of microbiota-targeted or JAK inhibition strategies, could improve interdisciplinary care. The results also provide candidate microbial signatures (e.g., reduced Haemophilus abundance previously noted in CD) for inclusion in microbiome databases tracking autoimmune overlap.
Microbiome Signatures Definition: A Conceptual Advancement for Translational Microbiome Science
Microbiome signatures are reproducible ecological and functional patterns—encompassing traits, interactions, and metabolic functions—that reflect microbial adaptation to specific host or environmental states. Beyond taxonomy, they capture conserved features like metal metabolism or immune modulation, enabling systems-level diagnosis and intervention in health and disease.