Overview

Graves’ 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 strong causal relationship between GD and the gut microbiome.^[1] Thus, a microbiome-targeted strategy aimed at addressing the root causes of GD moves beyond mere symptom suppression and marks a significant advancement in medical history.

Associated Conditions

Graves’ disease is a complex autoimmune condition primarily affecting the thyroid gland, leading to hyperthyroidism, but it is also associated with a wide range of other conditions and symptoms, such as Inflammatory Bowel Disease (IBD), Crohn’s disease (CD), depression, and Rheumatoid Arthritis (RA). ^[2]^[3]^[4] These associated conditions can also influence the development or progression of GD. The shared microbiome alterations between Graves’ Disease and these other conditions underscore the interconnectedness of systemic health, particularly the interplay between the gut, immune system, and endocrine function. Understanding these overlaps opens new avenues for microbiome-targeted interventions (MBTIs) as potential therapeutic or preventative strategies for GD and its comorbidities.

What other conditions are associated with Grave’s Disease?

Complication	Description
Graves’ Ophthalmopathy (GO)	Symptoms include eye bulging (exophthalmos), irritation, dryness, swelling, and in severe cases, vision loss. Also known as Graves’ orbitopathy, this affects the eyes and can be worsened by smoking. ^[5] GO is the most frequent extrathyroidal manifestation of GD, affecting 25-50% of GD patients (Yang et al., 2025). The overall pooled prevalence of TED (Thyroid Eye Disease) among GD patients is 40% (Chin et al., 2020).
Insulin Resistance (IR)	Excessive thyroid hormones in GD can lead to IR and may cause diabetes.^[6]
Graves’ Dermopathy	Rare skin condition often characterized by thick, red skin on the shins or tops of the feet (pretibial myxedema).^[7]
Depression	GD is strongly correlated with an increased risk of depression. Overt hyperthyroidism is associated with depression, and subclinical hyperthyroidism is independently linked to depressive symptoms. GD can drive depression through autoimmune responses, hormonal disorders, and interactions with the thyroid-gut-microbiome-brain axis. ^{^[8]}
Atrial Fibrillation (AF)	Hyperthyroidism can lead to hemodynamic changes that cause cardiovascular diseases like AF, which is also a risk factor for depression.^[9]
Type 1 Diabetes Mellitus	Both are autoimmune diseases, and patients with Graves’ disease are at increased risk of developing type 1 diabetes. Other autoimmune diseases may frequently concur with GD, with about 16.7% of GD patients having another autoimmune disease.^[10]
Ulcerative colitis (UC)	Notably, genetically predicted UC may prevent individuals from developing GD. ^[11]
Inflammatory Bowel Disease (IBD)	Genetically predicted IBD may increase the risk of GD by 24%. ^[12]
Rheumatoid Arthritis	Observational studies have cited and discussed the frequent coexistence of GD and RA. Our sources indicate a bidirectional causal effect: the presence of RA may increase the risk of GD by 39%, and the existence of GD may increase the risk of RA by 30%. ^[13]
Thyroid cancer	An increased risk of thyroid cancer in GD has been observed, particularly when patients with GD have thyroid nodules. ^[14]
Plummer Disease (PD)	A form of thyrotoxicosis with multiple nodular enlargements. Butyricimonas and Lachnospira are protective. Dorea, Eggerthella, Odoribacter, Lactobacillus, Intestinimonas, and Phascolarctobacterium increased PD risk. ^[15]

Causes

Graves’ disease is an organ-specific autoimmune thyroid disorder characterized by hyperthyroidism driven by autoantibodies against the thyroid-stimulating hormone receptor (TSHR). Classic paradigms emphasize a genetic predisposition interacting with environmental triggers to precipitate a loss of immune tolerance. Indeed, genetic susceptibility, combined with factors like iodine excess, psychosocial stress, infections, and postpartum immune shifts, are known to contribute to GD development in susceptible individuals.^[16]^[17] However, these factors alone do not fully explain disease onset, as many exposed individuals never develop GD and the precise pathogenic mechanism is unclear. Emerging research has expanded the scope of inquiry to the “thyroid–gut axis,” investigating how gut microbiome dysbiosis and increased intestinal permeability (“leaky gut”) might instigate or amplify autoimmune processes. Notably, recent Mendelian randomization studies provide evidence supporting a causal link between gut microbial profiles and GD risk, underscoring the complex interplay between genes, immunity, and the environment.^[18] The table below summarizes prevailing causal theories of GD and highlights key limitations or criticisms for each, based on current (post-2020) evidence.

What are the current causal theories of Grave’s Disease and their limitations?

Major Proposed Causes of Graves’ Disease and Their Limitations

Causal Theory	Limitations / Criticisms
Genetic Predisposition – Family clustering and twin studies indicate a strong hereditary component. Genome-wide studies have identified over 80 susceptibility loci (e.g. HLA-DR variants, CTLA4, PTPN22, TSHR) that confer increased GD riskpmc.ncbi.nlm.nih.gov mdpi.com. Monozygotic twins show a much higher concordance for GD than dizygotic twins, suggesting genetics account for ~60–80% of disease riskpmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov. These genes largely affect immune regulation, predisposing carriers to loss of tolerance and production of TSHR-stimulating autoantibodies.	Incomplete Penetrance: Genetic predisposition alone is not sufficient – even identical twins often remain discordant for GD (twin concordance only ~20–35%)pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov. The identified risk alleles each have modest effects; no single gene causes GD in a deterministic manner. For example, HLA variants contribute only ~5% of the genetic riskmdpi.com. Many people with “at-risk” genotypes never develop GD, indicating that environmental and epigenetic factors are required to trigger diseasemdpi.com mdpi.com. In sum, heredity explains much but not all of GD’s causation.
Environmental Triggers – Numerous external factors have been linked to precipitating GD in genetically susceptible individuals. Well-documented examples include excessive iodine intake, which can overstimulate the thyroid; severe psychological stress or trauma; certain infections (e.g. viral, with SARS-CoV-2 and others hypothesized); the postpartum period (immune rebound after pregnancy); and cigarette smoking, which significantly raises GD risk and worsens Graves’ ophthalmopathymdpi.com frontiersin.org. Some medications or immune modulators (e.g. interferon-α, immune reconstitution after HAART) have also been reported to trigger GDncbi.nlm.nih.gov ncbi.nlm.nih.gov. These factors are thought to act as catalysts that initiate autoimmunity in predisposed thyroid tissue.	Correlation vs Causation: The evidence for most triggers is observational. Many individuals with these exposures do not develop GD, so these factors are neither necessary nor sufficient on their own. It is challenging to prove a direct causal role due to confounding variables and retrospective study designs. For instance, vitamin D deficiency has been associated with AITD, yet a Mendelian randomization found that genetically lower vitamin D levels did not significantly increase GD riskfrontiersin.org. Similarly, while stress or iodine overload often precede onset, prospective data are limited. Overall, no single environmental factor explains a majority of cases, and the interplay of multiple triggers with genetic predisposition makes causality difficult to isolate.
Autoimmune Mechanism (Loss of Immune Tolerance) – GD’s defining pathogenic feature is an autoimmune reaction against thyroid antigens. B cells produce TSHR-stimulating immunoglobulins (TRAb/TSI) that bind the TSH receptor and drive unregulated thyroid hormone production. This arises from a breakdown in self-tolerance: autoreactive T-helper cells (e.g. Th17 and Tfh subsets) and antigen-presenting cells (like dendritic cells) escape normal regulation and activate B cells to target the thyroidmdpi.com mdpi.com. The result is glandular hyperthyroidism and inflammatory sequelae (such as orbitopathy) caused by cytokines and autoantibodies. Virtually all GD patients have detectable TRAb, supporting the central role of autoimmunity.	Mechanistic Gap: Describing GD as autoimmune is accurate but not a complete explanation of cause. It identifies the proximate mechanism (pathogenic autoantibodies) but not why immune tolerance failed initially. The “autoimmune theory” is broad – similar tolerance breakdown occurs in other diseases, so additional context is needed to explain specificity to the thyroid. In GD, multiple pathways and cell types are involved, and it remains unclear what tipping point triggers the anti-thyroid response in a given patientmdpi.com. In essence, autoimmunity is the disease process itself; the unanswered challenge is identifying the inciting events or factors that lead the immune system to attack the thyroid.
Gut Microbiota Dysbiosis – Growing evidence implicates the gut–thyroid axis in GD. Patients with GD show altered gut microbiome profiles compared to healthy controls, including reduced overall microbial diversity and shifts in key bacterial groupsmdpi.com (e.g. lower Firmicutes and higher Bacteroidetes proportions). Such dysbiosis may affect immune homeostasis: changes in the gut flora can modulate intestinal T-cell populations and cytokine production, potentially promoting autoimmune activity (e.g. an imbalance of regulatory T cells and pro-inflammatory Th17 cells). Recent two-sample Mendelian randomization studies strengthen the case for causality, identifying specific gut bacterial taxa that influence GD risk (some genera associated with higher odds of GD, others protective). These findings suggest that an imbalanced gut microbiome can act as a contributing cause of GD by altering systemic immune regulation.	Emerging and Complex: The dysbiosis–GD link is still under active investigation, and several caveats remain. Most studies are cross-sectional, so it is often unclear if gut microbial changes precede GD or result from the disease (or its treatment). Indeed, bidirectional MR evidence indicates GD itself can alter the microbiome, complicating cause–effect interpretation. Different studies have reported different “signature” microbes associated with GD (e.g. some identified increases in Prevotella and Veillonella, others highlighted Ruminococcus or Lactobacillus), reflecting inconsistencies and population differences. Factors like diet, medication, and hyperthyroidism-induced metabolic changes can also influence the microbiota. While genetic MR analyses support a contributory role of gut bacteria, these rely on statistical inference with certain assumptions. No clinical trial yet has shown that modifying the gut microbiota (via probiotics or other means) can prevent or cure Graves’ disease. Thus, the gut dysbiosis hypothesis, though compelling, requires further longitudinal and mechanistic studies to validate causality and identify actionable microbial targets.
Intestinal Barrier Dysfunction (“Leaky Gut”) – Another novel theory posits that increased intestinal permeability may underlie GD development. A “leaky” gut lining allows microbial products such as lipopolysaccharide (LPS) and other toxins to translocate into the bloodstream, potentially triggering or amplifying autoimmune inflammation. Recent studies show that patients with active Graves’ disease have significantly elevated circulating markers of gut barrier disruption and bacterial translocation (e.g. LPS, zonulin, D-lactate, and intestinal fatty acid-binding protein) compared to controls. These biomarker levels correlate with disease activity – for example, higher LPS and D-lactate associate with higher free T4 and TSH-receptor antibody levels, and worse hyperthyroid symptoms. Such findings suggest that loss of gut barrier integrity might contribute to the immunologic attacks on the thyroid by promoting systemic exposure to pro-inflammatory microbial factors.	Cause or Effect Uncertain: The leaky gut–GD association is based on correlation and has not established causation. Notably, in one study these gut permeability markers were elevated in patients with new-onset (active) GD but tended to normalize in treated euthyroid patients, suggesting that high thyroid hormone levels might themselves cause transient barrier disruptions. In other words, it remains possible that hyperthyroidism (or associated stress and dietary changes) leads to gut permeability changes, rather than leaky gut initiating the autoimmunity. The evidence so far is limited to cross-sectional data and a handful of biomarkers, so we may be seeing an epiphenomenon. More research – particularly prospective studies or interventions to restore gut barrier function – is needed to determine if a leaky gut is a primary driver of GD or a secondary effect of the disease.

Each theory above offers insights into the potential causes of Graves’ disease, yet none is fully sufficient on its own. The current consensus is that GD arises from an integration of genetic susceptibility, environmental/behavioral exposures, and aberrant immune responses. New methodologies like Mendelian randomization and microbiome analysis are helping to untangle these contributions by identifying which associations are likely causalfrontiersin.org. Ultimately, a comprehensive understanding of GD’s etiology will require synthesizing these theories – classical and emerging – to explain how a specific trigger (or combination of triggers) in a predisposed host leads to the cascade of autoimmunity that defines Graves’ diseasemdpi.com mdpi.com.

Diagnosis

Primer

Understanding metal homeostasis and mineral homeostasis is essential for fully elucidating Graves’ Disease, and helps us grasp the broader implications of the condition’s unique microbiome signature.

Metal Homeostasis

Data reveals that elevated levels of cadmium (Cd), lead (Pb), and chromium (Cr) are associated with an increased risk of hyperthyroidism, as these metals can disrupt endocrine functions and cause oxidative damage to the thyroid gland. These toxic elements pose significant health risks due to their cumulative nature. Conversely, higher cobalt (Co) levels are associated with a decreased risk of hyperthyroidism, highlighting its complex role in thyroid metabolism. Additionally, deficiencies in copper (Cu) and zinc (Zn), essential for thyroid hormone synthesis, are also associated with hyperthyroidism and GD. ^[19] While these findings certainly aid in understanding occupational risk factors for GD, further research provides alarming new insight on metal toxicity and carcinogenicity occurring in thyroid cells when chronically exposed to metal concentrations that are slightly increased, even within what is considered the “normal” range. ^[20]

What occupations are risk factors associated with Grave’s Disease due to exposure?

Occupation	Findings
Electroplating Workers	A study on electroplating workers found that occupational cadmium exposure significantly increased levels of thyroid hormones, anti-TPO antibodies, IL-6, MDA, and TNF-α, indicating a link between cadmium exposure and elevated inflammatory and oxidative stress markers. ^[21]
Battery Manufacturing	Lead, cadmium, and arsenic exposure in battery manufacturing workers was significantly higher than controls, with lead levels being the most prominent. This exposure correlates with altered thyroid function and increased oxidative stress, highlighting occupational hazards and potential implications for thyroid diseases like Grave’s disease. ^[22]
Paint Workers	Paint workers exposed to lead (Pb) and solvents are at risk for hyperthyroidism. Studies have shown that T3 (triiodothyronine) and T4 (thyroxine) levels are significantly higher in these workers compared to controls. This suggests that occupational exposure to lead and solvents can disrupt thyroid function, leading to increased thyroid hormone production and the potential development of hyperthyroidism. ^[23]

Mineral Homeostasis

Extensive research shows the thyroid-gut axis (TGA) significantly influences thyroid function. Gut health regulates thyroid roles and pathologies through nutrient intake and microbiota. Essential minerals like iodine and selenium are critical for thyroid hormone synthesis and overall health. The gut-immune interaction affects autoimmune diseases, including Graves’ disease and thyroid cancer.

What minerals are involved in Grave’s Disease and what are their functions?

Mineral	Details
Iodine	Iodine is essential for the synthesis of thyroid hormones (thyroxine [T4] and triiodothyronine [T3]). The thyroid gland absorbs iodine from the bloodstream and incorporates it into these hormones. In Graves’ disease, the thyroid is overstimulated by autoantibodies that mimic thyroid-stimulating hormone (TSH), leading to excessive production of thyroid hormones. Adequate iodine levels are necessary to sustain this increased hormone production, but excessive iodine can exacerbate hyperthyroidism in susceptible individuals. (Frontiers)
Selenium	The thyroid gland has the highest concentration of selenium in the human body, highlighting the element’s significance in thyroid health. This high concentration underscores the potential impact of selenium levels on thyroid-related disorders like Graves’ disease. [x] Selenium is a component of selenoproteins, including glutathione peroxidase and thioredoxin reductase, which protect the thyroid gland from oxidative damage during hormone synthesis. It is also involved in the conversion of T4 to the more active T3. Selenium deficiency has been linked to autoimmune thyroid diseases, including GD.
Zinc and Copper	These trace minerals are important for various enzymatic processes in the body, including those related to thyroid hormone metabolism and immune function. Deficiencies in copper (Cu) and zinc (Zn), essential for thyroid hormone synthesis, are also associated with hyperthyroidism and GD.

Interventions

Researchers involved in the microbiota analyses of GD predict that microbiota-targeted therapeutics will emerge as the new strategy for managing GD/GO in the coming years. ^[24] The section covers interventions for Grave’s Disease, such as pharmacological treatments, drug repurposing, and dietary supplements. It explores ASAPs, utilizing emerging science to find new treatments, and STOPs, which suggest reassessing standard practices. Here we suggest other microbiome-targeted interventions (MBTIs) for the management of GD.

Pharmacological

The therapeutic approach to Graves’ disease (GD) comprises thionamides, radioiodine ablation, or surgery as first-line therapy, and cholestyramine and oral iodine as second-line therapies.

First-Line Pharmacological Treatments for Grave’s Disease

Methimazole: Methimazole up-regulates the levels of Bifidobacterium and Collinsella which are decreased in GD, and down-regulates the levels of Prevotella and Dialister, which are increased in GD. ^[x]

Serum from patients with untreated Graves’ disease had a significantly higher concentration of Cu, Zn-SOD and higher SOD-like activity than those from normal subjects. This is likely due to the presence of Haemophilus parainfluenzae, which is significantly increased in Grave’s Disease, that has a rare Copper-zinc superoxide dismutase ([Cu, Zn]-SOD) encoding. [25]^[x]

It is noteworthy that methimazole treatment produced no significant change in SOD-like activity and Cu, Zn-SOD concentration in patients with Graves’ disease.^[26] Thus, it is likely that a patient not responding to Methimazole treatment has an increased level of H. parainfluenzae.

What are the risks associated with first-line therapies for GD?

Treatment	Associated Condition
Methimazole, Propylthiouracil (PTU)	Methimazole is associated with Antithyroid drug (ATD)-induced severe hepatotoxicity. ^[27]
Methimazole, Propylthiouracil (PTU)	Agranulocytosis
Propylthiouracil (PTU)	Vasculitis
Propylthiouracil (PTU)	Liver Failure
Methimazole	Teratogenic Effects
Methimazole, Propylthiouracil (PTU)	Skin Rash/Allergic Reactions
Methimazole, Propylthiouracil (PTU)	Arthralgia
Methimazole, Propylthiouracil (PTU)	Gastrointestinal Disturbances
Radioactive Iodine Therapy	Thyroiditis
Radioactive Iodine Therapy, Surgery	Hypothyroidism
Radioactive Iodine Therapy	Radiation Thyroiditis
Thyroid Surgery	Permanent Hypoparathyroidism
Thyroid Surgery	Recurrent Laryngeal Nerve Damage

Nonthionamide antithyroid drugs (NTADs)

Although thionamide antithyroid drugs are the cornerstone of hyperthyroidism treatment, some patients cannot tolerate this drug class because of its serious side effects including agranulocytosis, hepatotoxicity, and vasculitis. Therefore, non-thionamide antithyroid drugs (NTADs) play an important role in controlling hyperthyroidism in clinical practice.

What NTADs have been investigated for Grave’s Disease and hyperthyroidism?

NTAD	Findings
Cholestyramine	Cholestyramine enhances the enterohepatic excretion of thyroxine, and has been suggested as a monotherapy in case studies and subsequent reviews due to notable symptom improvements and “complete normalization” within one week of starting the intervention when first-line approaches were contraindicated. ^[28][29]
Lithium carbonate	The role of lithium (Li) as a primary or adjunctive therapy remains contentious. Nonetheless, recent studies suggest that a low therapeutic level of lithium (Li), combined with oral iodine, can effectively suppress thyroid overactivity without any adverse effects. Low-dose lithium carbonate is a safe and effective adjunctive antithyroid medication, particularly when primary therapies for hyperthyroidism are unavailable. ^[30] Use of low doses of carbonate lithium (900 mg/ per day) renders a significant decrease or normalization of thyroid hormones concentration within 7–14 days. ^[31] Lithium carbonate has also been used successfully as a monotherapy for GD. ^[31]
Perchlorate
Glucocorticoids

Drug Repurposing

Metformin: Metformin has shown promising benefits for treating Graves’ ophthalmopathy (GO) by activating the AMPK/mTOR pathway, which reduces inflammation and fibrosis in orbital tissues. ^[31] This suggests metformin could improve symptoms and reduce reliance on antithyroid drugs and other treatments with serious potential side effects. Additionally, metformin increases the abundance of Akkermansia muciniphila— ^[32] a beneficial bacterium that is decreased in GD— and reduced orbital pathology in GO patients has been positively correlated with higher levels of Akkermansia. ^[33]

Rituximab: Research suggests that roughly 70% of GD patients have evidence of Graves’ orbitopathy (GO). ^[34]

Antibiotics

The oral administration of the antibiotic vancomycin reduced the severity of GD/GO in mouse models. ^[35]

Supplements

Vitamin D: Research has increasingly highlighted the significant role of vitamin D in the pathogenesis and management of Graves’ Disease (GD). Numerous studies have observed that patients with GD often exhibit lower levels of vitamin D compared to healthy individuals. Vitamin D is known to modulate the activity of immune cells, such as T and B lymphocytes, dendritic cells, and monocytes, which are crucial in the autoimmune response seen in GD. By regulating these cells, vitamin D can help reduce the production of proinflammatory cytokines and enhance anti-inflammatory cytokines, thereby possibly mitigating the autoimmune attack on the thyroid. [36]^[x] Clinical trials and meta-analyses also suggest that vitamin D supplementation reduces the relapse rate of GD after antithyroid drug (ATD) treatment. ^[37]

Inositol: Research findings indicate that a significant proportion of Anaerostipes species, which are decreased in the Mircobiome Signature of Grave’s Disease, can convert inositol into propionate. [38] Another study highlighted that Myo-inositol and selenium (Myo-Ins-Se) supplementation effectively normalized thyroid-stimulating hormone (TSH) levels and improved overall thyroid function in hyperthyroid and hypothyroid patients. This combined therapy showed promise in restoring euthyroidism, potentially offering a new, effective treatment for Graves’ Disease and other forms of hyperthyroidism and hypothyroidism. ^[39]

Selenium: Selenium deficiency has been linked to autoimmune thyroid diseases, including GD. Adequate selenium levels help mitigate the oxidative stress associated with thyroid hormone production and can support overall thyroid health. Supplementation of selenium has been shown to improve thyroid function and reduce symptoms in patients with GD. ^[40] For patients with Graves’ disease, especially those with mild thyroid eye disease, selenium supplementation may lead to faster remission of hyperthyroidism, improved quality of life, and better eye involvement outcomes.^[x]

Glutathione: Exposure to lead, a redox inactive metal, depletes the cell’s major antioxidant reserves of glutathione.

Berberine: Methimazole combined with berberine achieves a better effect on GD than methimazole alone, and the changes in the gut microbiome include changes in levels of Lactococcus lactis, Enterobacter hormaechei, and Chryseobacterium indologenes. ^[42]

B-12: Vitamin B-12 (B-12) has the largest and most chemically complex structure of all of the vitamins. Also called cobalamin, B-12 is the only active substance in the body containing an atom of cobalt. ^[43] As mentioned previously, higher cobalt (Co) levels are associated with a decreased risk of hyperthyroidism, and may have protective effects.

Lifestyle Interventions

A structured exercise program in euthyroid Graves’ disease patients improved aerobic capacity, reduced fatigue, normalized some thyroid hormones, accelerated anti-thyroid medication withdrawal, and reduced relapse rates, highlighting exercise’s clinical and potential immunological benefits. [44]

STOPs

While probiotics often hold potential in managing GD/GO, careful selection and optimization of microbial strains are crucial. Probiotic formulas should exclude strains such as Lactobacillus, Prevotella, and Veillonella, which are often found in increased abundance in GD patients.

Microbiome Signature: Graves Disease

Research Feed

August 19, 2020

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