Graves Disease

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]

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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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What was studied?
The study assessed thyroid function and oxidative stress in foundry workers occupationally exposed to lead (Pb) dust and fumes. It investigated the correlation between blood lead levels (BLL) and thyroid hormones, as well as markers of oxidative stress.

Who was studied?
The study involved 59 adult male foundry workers exposed to lead and a control group of 28 male subjects with no history of lead exposure or thyroid abnormalities.

What were the most important findings?

Foundry workers had significantly higher blood lead levels (16.5±1.74 µg/dl) compared to the control group (12.8±1.16 µg/dl).

The exposed group exhibited significantly increased levels of free triiodothyronine (FT3) and free thyroxine (FT4), and decreased levels of thyroid stimulating hormone (TSH).

Markers of oxidative stress showed a significant increase in malondialdehyde (MDA) and a significant decrease in glutathione (GSH) among exposed workers.

A significant positive correlation was found between BLL and duration of employment, while a negative correlation existed between BLL and both TSH and GSH levels.

Elevated thyroid hormones were observed in 32.76% of the occupationally exposed workers.

There was a significant positive relationship between GSH and TSH, and between MDA and FT3 and FT4 among exposed workers.

What are the greatest implications of this study?
The study suggests that occupational exposure to lead dust and fumes can stimulate thyroid function, resulting in increased thyroid hormone levels, which may contribute to an oxidative-antioxidant imbalance. This imbalance, indicated by increased MDA and decreased GSH levels, underscores the potential health risks associated with prolonged exposure to lead, highlighting the need for improved protective measures and monitoring in industrial settings.

September 7, 2018

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What was studied?
The study investigated the gut microbial composition in patients with Graves’ disease (GD) compared to healthy controls.

Who was studied?
The study involved 27 GD patients and 11 healthy controls, with fecal samples collected for analysis.

What were the most important findings?

The association between gut microbiota and host homeostasis is pivotal for understanding various diseases, including autoimmune disorders like Graves’ disease (GD), characterized by hyperthyroidism and ophthalmopathy. This study hypothesized that gut bacteria play a significant role in GD pathogenicity. To investigate this, the intestinal bacterial composition of 27 GD patients and 11 healthy controls was analyzed using PCR-DGGE of the 16S rRNA gene targeting the V3 region and Real-time PCR for specific bacterial groups. High-throughput sequencing of the 16S rRNA gene (V3+V4 regions) was performed on randomly selected samples using the Hiseq2500 platform.

The results revealed a lower diversity of intestinal bacteria in GD patients compared to controls. Statistical analyses indicated significant alterations in bacterial phyla, with a higher relative abundance of Prevotellaceae and Pasteurellaceae, and a lower abundance of Enterobacteriaceae, Veillonellaceae, and Rikenellaceae in GD patients. At the genus level, Prevotella_9 and Haemophilus were significantly increased, whereas Alistipes and Faecalibacterium were decreased in GD patients. Notably, the species Haemophilus parainfluenza was more abundant in GD patients.

What are the greatest implications of this study?
The findings support the hypothesis of gut microbial dysbiosis in GD, suggesting that changes in the gut microbiota may contribute to the disease’s pathogenesis. These insights could pave the way for novel therapeutic approaches targeting gut microbiota in GD treatment.

February 14, 2023

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What was studied?

This study investigated the bidirectional causal relationship between Graves’ Disease (GD) and the gut microbiome. Utilizing Mendelian randomization (MR), it examined how alterations in the gut microbiome might influence GD and vice versa, supporting the thyroid–gut axis (TGA) concept. Genome-wide association study (GWAS) summary datasets, which analyze millions of genetic variants across diverse populations to identify associations between genetic markers and specific traits, were sourced from international consortiums to evaluate these interactions.

Who was studied?

The study involved two large datasets. Gut microbiome data included 18,340 samples spanning diverse ethnic groups (European, Middle Eastern, East Asian, Hispanic/Latin American, and African American), while GD data included 212,453 samples of Asian ethnicity, sourced from Biobank Japan. These comprehensive datasets were analyzed to identify instrumental variables linking genetic variants to gut microbiome composition and GD susceptibility.

What were the most important findings?

The study established a bidirectional causal relationship between Graves’ disease (GD) and the gut microbiome, identifying key microbial associations that act as either risk or protective factors. Risk factors for GD included the classes Deltaproteobacteria (odds ratio [OR] = 3.603) and Mollicutes, as well as the genera Ruminococcus torques group, Oxalobacter, and Ruminococcaceae UCG 011. Protective associations were observed for the family Peptococcaceae and the genus Anaerostipes (OR = 0.489). Furthermore, GD was found to alter gut microbiome composition, increasing the abundance of genera like Anaerofilum (OR = 1.584) and reducing taxa such as the Clostridium innocuum group (OR = 0.918) and Sutterella (OR = 0.953). These findings highlight the regulatory activity of the thyroid–gut axis (TGA) and provide strong evidence for its involvement in GD pathogenesis.

What are the greatest implications of this study?

The findings underscore the critical role of the gut microbiome in GD pathogenesis and its reciprocal interaction with thyroid health. Identifying specific microbial taxa as risk or protective factors offers actionable insights for microbiome-targeted interventions (MBTIs), such as probiotics or dietary modifications, tailored to mitigate GD risk or progression. The bidirectional relationship between GD and the gut microbiome highlights the need for integrated approaches addressing both thyroid and gut health. These results could guide the development of precision medicine strategies, leveraging the gut microbiome to modulate immune responses and improve clinical outcomes for patients with GD. This research also establishes a foundational understanding of major microbial associations (MMAs) within the TGA, paving the way for future therapeutic innovations. Further, this study establishes a methodological precedent for using Mendelian Randomization to discern causal effects in microbiome-related research.

What was studied?

This retrospective case-control study investigated the short- and long-term effects of a structured exercise program on euthyroid patients with Graves’ disease (GD). The primary outcomes included aerobic capacity, fatigue, thyroid hormone levels, time to anti-thyroid medication withdrawal, and relapse rates. Participants were divided into an exercise group (n=62) who completed a 3-week structured program involving daily supervised walking, stretching, and resistance exercises, and a control group (n=62) who engaged in unstructured leisure activities. Both groups were evaluated at admission and discharge, with long-term follow-up over 24 months.

Who was studied?

The study included 124 euthyroid patients (62 per group), aged 20–40 years, with previously diagnosed Graves’ disease, maintained on stable anti-thyroid medication for at least one month. All participants met inclusion criteria related to hormone levels, exercise tolerance, and clinical stability. Patients were selected from a pool of ~700 medical records at a Serbian thyroid rehabilitation institute. Gender was matched (31 men and 31 women in each group), and follow-up data on medication cessation and relapse were available for all.

Most important findings

Exercise significantly improved aerobic capacity, reduced fatigue, and favorably influenced the course of GD. The key findings are summarized below:

Parameter	Exercise Group	Control Group
Peak VO₂ (ml/kg/min, Admission→Discharge)	23.6 → 39.6 (+68%)	26.2 → 27.1 (NS)
T4 Change (nmol/L)	↓ from 117.4 to 105.7 (p=0.038)	↓ from 119.1 to 115.3 (NS)
TSH Change (mU/L)	↑ from 3.2 to 3.5 (trend, p=0.071)	No change
Severe Fatigue (Admission→Discharge)	71% → 0%	49% → 34%
Medication Withdrawal ≤6 months	84%	18%
Relapse within 12 months	29%	72%

Additionally, exercise reduced resting heart rate, extended exercise test duration, and showed parallel improvement in fatigue scores. The immunological discussion suggests exercise may favorably shift immune balance toward TSH receptor–blocking antibody dominance, similar to remission patterns seen in pregnancy.

Key implications

This study provides preliminary yet compelling evidence that structured exercise can improve physical function and immunological outcomes in GD beyond standard pharmacotherapy. The reduction in relapse and earlier medication withdrawal suggest a role for exercise in disease modification. Mechanistically, exercise may modulate the neuroendocrine-immune axis, potentially shifting the TH1/TH2 balance and promoting the production of TSH receptor–blocking antibodies. These findings support integrating supervised physical activity into the rehabilitative care of GD patients, though prospective randomized controlled trials are needed to confirm causality and optimize protocols.

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Irritable Bowel Syndrome (IBS) •

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.

July 5, 2023

•

What was studied?

This study investigated the causal relationship between Graves’ disease (GD) and the gut microbiome using a bidirectional two-sample Mendelian randomization (MR) approach. Researchers utilized genome-wide association study (GWAS) summary statistics to examine whether changes in the gut microbiome contribute to the development of GD and whether GD, in turn, alters the gut microbiome. The study was grounded in the concept of the thyroid–gut axis (TGA), which posits bidirectional regulation between thyroid function and gut microbial composition. By leveraging MR methods, including inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode, the study aimed to infer causality while controlling for confounding and reverse causation.

Who was studied?

The analysis was conducted using GWAS data from two large cohorts. The gut microbiome dataset (n = 18,340) was derived from 24 international cohorts spanning European, Middle Eastern, East Asian, Hispanic/Latin American, and African American populations, as part of the MiBioGen consortium. The Graves’ disease dataset (n = 212,453; including 2,176 GD cases and 210,277 controls) came from BioBank Japan, representing individuals of Asian descent. Taxonomic profiling in the microbiome dataset used 16S rRNA sequencing, capturing 211 taxa after quality control and rarefaction.

Most important findings

The study identified several taxa with significant causal effects in both directions:

Gut Microbiome → GD:

Taxon	Direction	OR	Method
Deltaproteobacteria (Class)	↑ Risk	3.603	MR-Egger
Mollicutes (Class)	↑ Risk	2.354	Simple Mode
Ruminococcus torques group (Genus)	↑ Risk	1.445	IVW
Oxalobacter (Genus)	↑ Risk	2.395	Wald Ratio
Ruminococcaceae UCG 011 (Genus)	↑ Risk	1.379	Weighted Median
Peptococcaceae (Family)	↓ Risk	0.536	IVW
Anaerostipes (Genus)	↓ Risk	0.489	Weighted Median

GD → Gut Microbiome:

Taxon	Direction	OR	Method
Anaerofilum (Genus)	↑ Post-GD	1.586	MR-Egger
Oxalobacteraceae (Family)	↑ Post-GD	1.085	IVW
Intestinimonas, Peptococcus, etc.	↑ Post-GD	~1.04–1.13	IVW/Median
Clostridium innocuum group (Genus)	↓ Post-GD	0.918	IVW
Sutterella (Genus)	↓ Post-GD	0.953	IVW

No evidence of heterogeneity, horizontal pleiotropy, or weak instrument bias was detected, strengthening the causal inference.

Key implications

This study provides robust evidence of a bidirectional causal relationship between Graves’ disease and specific gut microbial taxa, thereby supporting the existence of a thyroid–gut axis (TGA). The identification of microbiota such as Deltaproteobacteria and Anaerostipes as risk and protective factors, respectively, highlights candidate biomarkers and potential therapeutic targets. Moreover, the findings suggest that GD not only results from microbiome alterations but can itself induce compositional changes, potentially exacerbating autoimmune dysregulation. These results offer a strong foundation for incorporating Graves’ disease gut microbiome causality into both diagnostic algorithms and microbiome-targeted intervention (MBTI) frameworks.

•

What was studied?

This study investigated alterations in the intestinal microbiota composition of patients with Graves' disease (GD) to explore possible microbiome signatures associated with the condition. The researchers used a combination of denaturing gradient gel electrophoresis (DGGE), real-time PCR, and high-throughput 16S rRNA gene sequencing (V3–V4 region) to compare microbial diversity, composition, and abundance in GD patients versus healthy controls. The study aimed to evaluate both qualitative and quantitative differences in gut microbiota and determine whether dysbiosis may be implicated in GD pathogenesis.

Who was studied?

The study analyzed fecal samples from 27 GD patients (10 males, 17 females, aged 35–50) and 11 healthy age- and sex-matched controls (4 males, 7 females). All GD patients had a disease duration of 1.5 years and were medication-free for at least six months before sampling. None of the participants had recent antibiotic, probiotic, or prebiotic use. Samples were collected at Xi'an Jiaotong University’s affiliated hospital and processed under strict ethical guidelines.

Most important findings

Graves' disease patients exhibited reduced gut microbial diversity, evidenced by significantly lower richness indices (Observed Species, Chao1, ACE, and Good’s coverage) compared to controls, although Shannon and Simpson indices were not statistically different. The most pronounced alterations were seen in specific taxa:

Taxonomic Level	Increased in GD	Decreased in GD
Phyla	Bacteroidetes, Proteobacteria	Firmicutes (trend)
Family	Prevotellaceae, Pasteurellaceae	Enterobacteriaceae, Veillonellaceae, Rikenellaceae
Genus	Prevotella_9, Haemophilus	Alistipes, Faecalibacterium
Species	Haemophilus parainfluenzae (↑)	Bifidobacterium longum, Lactobacillus gasseri, Clostridium leptum (↓)Molecular Alteration An…

Real-time PCR confirmed significantly reduced copy numbers of Bifidobacterium and Lactobacillus in GD (P < 0.05), suggesting depletion of beneficial microbes. Meanwhile, Bacteroides vulgatus was slightly increased, and Clostridium leptum slightly reduced, although these changes did not reach significance by q-value correction.The dominant microbial phyla in GD were Bacteroidetes (57.6%) and Firmicutes (32.9%), with GD patients having a lower Firmicutes: Bacteroidetes ratio compared to controls.

Key implications

This study reveals that Graves' disease is associated with a distinct gut microbiota signature characterized by reduced microbial richness and altered abundances of both beneficial and potentially pathogenic taxa. The significant increase in Haemophilus parainfluenzae and Prevotella_9, along with the depletion of Faecalibacterium and Alistipes, suggests immune-related microbial imbalance. These taxa may serve as major microbial associations (MMAs) for GD and could be investigated as microbial targets for microbiome-based interventions. The depletion of Lactobacillus and Bifidobacterium also suggests potential for probiotic or prebiotic therapy. While causality remains unresolved, the findings reinforce the need to consider intestinal dysbiosis as a contributing factor in GD pathogenesis and therapy development.

July 24, 2015

•

Microbes •

What was studied?

The study investigated the role of cholestyramine as an additional treatment for refractory iodine-induced hyperthyroidism in a patient who did not respond to conventional therapies.

Who was studied?

A 52-year-old female patient with a history of goiter who developed iodine-induced hyperthyroidism following a CT scan with contrast. The patient had obstructive symptoms and was unresponsive to standard treatments, including dexamethasone, carbimazole, and propranolol.

What were the most important findings?

After adding cholestyramine, the patient’s FT4 levels decreased by 30% within 5 days and normalized by 12 days.

What are the greatest implications of this study?

Cholestyramine can be an effective adjunct therapy for managing refractory iodine-induced hyperthyroidism, suggesting a potential new treatment avenue for similar cases, such as Grave's Disease (GD). This case highlights the need for alternative treatments when conventional therapies fail and emphasizes the utility of cholestyramine in rapid thyroid hormone reduction.

Role of Cholestyramine in Refractory Hyperthyroidism A Case Report and Literature Review

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What was reviewed?

This narrative literature review comprehensively examines the roles of trace elements—including iron (Fe), copper (Cu), cobalt (Co), iodine (I), manganese (Mn), zinc (Zn), silver (Ag), cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se)—in thyroid physiology, hormone synthesis, and the pathogenesis of thyroid diseases. The review details the molecular mechanisms by which these elements affect thyroid hormone biosynthesis, metabolism, immune function, and oxidative stress within the thyroid gland. It further explores how imbalances in these elements contribute to the development and progression of various thyroid disorders, including Graves’ disease, Hashimoto’s thyroiditis, hypothyroidism, autoimmune thyroiditis, thyroid nodules, thyroid cancer, and postpartum thyroiditis. Special attention is given to the dual role of certain elements as both essential micronutrients and potential endocrine disruptors, and to their emerging roles as therapeutic targets or biomarkers.

Who was reviewed?

This review synthesizes findings from a wide range of studies involving diverse populations—adults and children, both healthy and with thyroid disease, from various geographic regions (including iodine-deficient and iodine-sufficient areas). It includes research on different subgroups such as pregnant women, patients with autoimmune thyroid diseases, those exposed to occupational or environmental heavy metals, and individuals undergoing specific thyroid treatments. Evidence is drawn from human epidemiological studies, clinical trials, animal experiments, and cellular/molecular investigations.

Most important findings

The review highlights that optimal concentrations of Fe, I, Cu, Zn, and Se are critical for healthy thyroid hormone synthesis and metabolism. Deficiencies in Fe, Zn, Se, or I, or toxic exposures to Cd, Hg, and Pb, disrupt thyroid hormone production, immune tolerance, and redox balance, predisposing individuals to hypothyroidism, autoimmune thyroiditis, and thyroid cancer. For example, Fe is essential for thyroperoxidase activity; Cu and Zn are components of antioxidant enzymes; Se is vital for deiodinase function; while both deficiency and excess I impact hormone synthesis through mechanisms such as the Wolff–Chaikoff effect. Heavy metals (Cd, Hg, Pb) promote oxidative stress, immune dysregulation, and oncogenic transformation. The review also notes gender-specific and age-dependent differences in trace element effects, and complex interactions between environmental exposure, genetic susceptibility, and thyroid disease risk. Recent research into ferroptosis and cuproptosis (forms of metal-dependent cell death) suggests potential for novel biomarkers and therapeutic strategies in thyroid cancers.

Key microbial and microbiome associations:

While the review centers on trace elements, it references the gut microbiome’s role in thyroid autoimmunity, especially its impact on trace element absorption (notably Fe and Se) and immune modulation. Dysbiosis may impair micronutrient status, influencing the risk and severity of autoimmune thyroid diseases. This emerging connection between trace element metabolism, the gut microbiome, and thyroid autoimmunity is a promising area for further investigation and may be relevant for microbiome signature databases.

Key implications

Clinical management of thyroid disorders should consider patients’ trace element status, exposure to environmental toxins, and dietary habits. Screening and correcting micronutrient deficiencies (Fe, Zn, Se, I) can help prevent or ameliorate thyroid dysfunction, while minimizing exposure to toxic metals (Cd, Hg, Pb) is crucial for thyroid health. Personalized approaches, considering genetic and microbiome influences, may optimize prevention and treatment. Some trace elements (Se, Fe, Cu) and related molecular pathways (ferroptosis, cuproptosis) hold promise as therapeutic targets or diagnostic/prognostic biomarkers in thyroid cancer and autoimmunity. Integration of trace element assessment into clinical and public health practice, alongside continued research into their interplay with the microbiome, could significantly improve thyroid disease outcomes.

What was reviewed?

This comprehensive literature review examines the role of trace elements—including iron (Fe), copper (Cu), cobalt (Co), iodine (I), manganese (Mn), zinc (Zn), silver (Ag), cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se)—in thyroid hormone synthesis, metabolism, and the pathogenesis of thyroid diseases. The review methodically synthesizes findings from a wide range of clinical and preclinical studies, focusing on the molecular mechanisms by which these elements modulate thyroid function and how imbalances contribute to diseases such as Graves’ disease, Hashimoto’s thyroiditis, hypothyroidism, autoimmune thyroiditis, thyroid nodules, thyroid cancer, and postpartum thyroiditis. Special attention is given to both the detrimental effects of toxic elements (e.g., Cd, Hg, Pb) and the therapeutic or protective roles of essential micronutrients (e.g., Se, Zn), with detailed tables summarizing the mechanisms and clinical implications of each element.

Who was reviewed?

The review encompasses studies involving diverse populations, including healthy individuals, patients with various thyroid disorders (autoimmune, nodular, neoplastic, and postpartum), and special groups such as pregnant women, children, occupationally exposed workers, and experimental animal models. Clinical data from cross-sectional, case-control, and cohort studies are integrated alongside experimental findings from in vitro and in vivo models. The reviewed literature spans geographic regions with variable environmental exposures and dietary practices, reflecting a global perspective on trace element influence in thyroid health and disease.

Most important findings

The review highlights that optimal levels of trace elements are crucial for maintaining thyroid hormone synthesis and homeostasis. Key findings include:

Iron (Fe): Essential for thyroperoxidase (TPO) activity and thyroid hormone production. Deficiency impairs hormone synthesis and increases risk for hypothyroidism and autoimmune thyroiditis.
Copper (Cu): Modulates TPO and antioxidant enzymes; imbalance linked to thyroid nodules and cancer.
Cobalt (Co): High exposure can inhibit iodine uptake, inducing hypothyroidism; used therapeutically in Graves’ ophthalmopathy.
Iodine (I): Both deficiency and excess are pathogenic—deficiency leads to goiter and hypothyroidism; excess can trigger autoimmune thyroiditis, hypothyroidism (Wolff–Chaikoff effect), and modulate thyroid cancer risk.
Manganese (Mn): Influences deiodinase activity and oxidative stress; elevated levels associated with hypothyroidism and thyroid cancer.
Zinc (Zn): Cofactor for thyroid hormone metabolism and antioxidant defense; deficiency impairs hormone production and may increase risk for nodules and hypothyroidism.
Silver (Ag): Accumulates in thyroid tissue; nanoparticles show anticancer activity in vitro.
Cadmium (Cd), Mercury (Hg), Lead (Pb): Accumulate in thyroid tissue, promote oxidative stress, disrupt hormone synthesis, and are linked to cancer and autoimmunity.
Selenium (Se): Integral to selenoproteins in thyroid hormone metabolism and antioxidant protection; deficiency exacerbates autoimmune thyroiditis and Graves’ disease, whereas supplementation shows therapeutic potential.

The review underscores distinct trace element–disease associations, including Fe deficiency in Hashimoto’s, excessive I intake in autoimmune thyroiditis, Cd and Pb accumulation in thyroid cancer, and Se supplementation reducing thyroid antibody titers.

Key implications

For clinicians, the findings reinforce the need to consider trace element status in the evaluation, prevention, and management of thyroid diseases. Deficiencies or excesses of Fe, Zn, Se, and I should be corrected to maintain thyroid health, especially in vulnerable groups (e.g., pregnant women, those with autoimmune thyroiditis). Environmental and occupational exposures to toxic metals (Cd, Hg, Pb) should be recognized as risk factors for both thyroid dysfunction and malignancy. The emerging roles of ferroptosis (Fe) and cuproptosis (Cu) in thyroid cancer open new avenues for targeted therapies. Se supplementation appears beneficial in autoimmune thyroid conditions and may mitigate some side effects of thyroid cancer treatment. Ultimately, integrating trace element assessment into clinical practice may improve disease outcomes and foster personalized management strategies.

[45]

•

What was reviewed?

This narrative review synthesizes epidemiological and mechanistic literature linking Graves’ disease (GD) to depression. The authors searched PubMed/MEDLINE, Cochrane Library and Web of Science up to 22 March 2023, retrieving 11 human population studies (5 cohort, 3 cross‑sectional, 3 case‑control) and multiple basic‑science reports that collectively explore immune, hormonal and microbiome pathways connecting GD and mood disorders.

Who was reviewed?

The clinical evidence base spans >30 000 participants from Asia, Europe, Africa and North America. Cohorts ranged from large national databases (e.g., 20 975 Asian patients; 2 200 000 Swedes) to smaller hospital samples, covering adults, pregnant women and paediatric cases. Collectively, these studies consistently show higher depression risk in overt or sub‑clinical hyperthyroidism compared with euthyroid controls. Key mechanistic papers include rodent models of hyperthyroidism, human cytokine profiling, and microbiota analyses in 263 GD versus 239 healthy controls.

Most important findings

Graves’ disease‑related hyperthyroidism is increasingly recognised as a biological driver of depressive symptoms. The mechanisms converge on immune–neuroendocrine crosstalk and gut‑brain communication, each amplifying neuroinflammation and neurotransmitter dysregulation. The table below delineates the three core pathways and the epidemiological evidence base.

Pathway / Evidence domain	Key mechanistic details and clinical observations
Auto‑immunity & neuroinflammation	Elevated IL‑1β, IL‑6, IL‑17A and TNF‑α degrade tight‑junction proteins, breach the blood–brain barrier and activate microglia. Resultant dopaminergic, serotonergic and glutamatergic imbalances underpin mood disturbances.
Endocrine dysregulation	Excess circulating T₃/T₄ suppress cortical dopamine–norepinephrine signalling, trigger oxidative stress, and promote insulin resistance and sex‑hormone imbalance—each independently linked to depressive phenotypes.
Thyroid‑gut‑microbiome‑brain axis	GD is marked by loss of short‑chain‑fatty‑acid‑producing Bacteroides and enrichment of Prevotella, Veillonella and Lactobacillus. These shifts distort tryptophan‑serotonin metabolism and skew Th17/Treg balance, further fuelling neuroinflammatory cascades.
Epidemiological risk	Across 11 clinical studies (>30 000 participants), GD or hyperthyroidism confers a 1.5‑ to 2‑fold increase in depressive symptoms; untreated disease and high free T₃ correlate with the greatest risk.

Key implications

Recognising GD as an independent driver of depression justifies routine mood screening in endocrine clinics and prompts integrative management. Potential interventions include early antithyroid therapy, β‑blockade, probiotics/synbiotics targeting SCFA restoration, and anti‑cytokine or HPA‑axis‑modulating strategies, though prospective trials remain scarce.

What was studied?

This original Mendelian randomization (MR) study evaluated the bidirectional causal relationship between Graves’ disease (GD) and rheumatoid arthritis (RA). Using genome‑wide association study (GWAS) summary statistics from BioBank Japan, the authors selected single‑nucleotide polymorphisms (SNPs) associated with each disease as instrumental variables and applied inverse‑variance–weighted, MR‑Egger, and weighted‑median models to infer causality.

Who was studied?

The analysis drew on 2,176 GD cases, 4,199 RA cases, and >208,000 population controls of East‑Asian ancestry. All participants were genotyped within BioBank Japan; supplemental RA data (4,873 cases, 17,642 controls) were included to test robustness. Because only East‑Asian datasets were used, findings chiefly reflect genetic architecture in this population.

Most important findings

The MR framework showed a 39 % genetically mediated increase in GD risk among individuals predisposed to RA (OR 1.39, 95 % CI 1.10–1.75; p = 0.007) and a 30 % increase in RA risk among those genetically predisposed to GD (OR 1.30, 95 % CI 0.94–1.80; p = 0.11). Sensitivity analyses (MR‑Egger intercept, leave‑one‑out, weighted median) indicated little horizontal pleiotropy, supporting a genuine bidirectional effect.

Autoimmune phenotype	Key microbiome signatures reported in literature*	Possible mechanistic links
RA	↑ Prevotella copri, ↓ Bifidobacterium, ↑ Th17‑skewing taxa	Mucosal priming, molecular mimicry
GD	↑ Prevotella, ↓ Lactobacillus/Bifidobacterium, altered Firmicutes/Bacteroidetes ratio	Enhanced gut permeability, T‑cell activation
Shared pattern	Enrichment of Prevotella spp.; depletion of butyrate producers	Convergent Th17 and NF‑κB signalling, systemic autoimmunity

*Derived from recent gut‑microbiome case‑control studies of RA and GD; not measured in the present MR analysis.

Key implications

The genetic evidence that RA and GD are causally linked in both directions suggests overlapping pathophysiology that extends from host genetics to immune regulation and, plausibly, to shared gut‑microbiome dysbiosis. Clinically, clinicians should (1) screen RA patients for thyroid dysfunction and vice versa, (2) anticipate that therapies modulating common immune checkpoints (e.g., CD40, JAK–STAT, IGF‑1R) could confer cross‑disease benefit, and (3) consider microbiome‑targeted interventions as adjunctive strategies. For microbiome‑signature databases, GD and RA may be grouped under a common “Prevotella‑enriched, butyrate‑depleted” autoimmune endotype, informing future diagnostic or therapeutic biomarker development.

•

What was reviewed?

This narrative review collates pre‑clinical and clinical data on Graves’ disease (GD) pathogenesis and evaluates emerging “precision” therapeutics that intervene at discrete immune‑molecular checkpoints—CD20, CD40/CD40L, BAFF, neonatal Fc‑receptor, HLA‑DRβ1‑Arg74—or directly antagonise the thyrotropin receptor (TSHR) via monoclonal antibodies, small‑molecule inverse agonists or CAR‑T strategies. It also summarises complementary insights from genetics, epigenetics and the gut microbiome that refine present pathogenic models and inform candidate drug targets.

Who was reviewed?

The authors executed a PubMed search (no end‑date; English language only) for mechanistic and interventional studies, excluding case reports, letters and abstracts. Included material spans animal models, phase I–II trials, population genetics and multi‑centre microbiome consortia (e.g., INDIGO). Clinical data predominantly involve adult GD patients (with or without orbitopathy), whereas immunobiology derives from both human biospecimens and murine thyroiditis/GD models. Overall, the synthesis integrates evidence from several hundred individuals across Europe and Asia plus complementary in‑vivo platforms.

Most important findings

Immune escape hinges on TSHR‑stimulating antibodies driven by aberrant T‑ and B‑cell costimulation (CD40/CD40L) and BAFF‑mediated survival of autoreactive B cells. Genome‑wide and epigenetic studies highlight HLA‑DR, CTLA‑4, PTPN22 and FOXP3 variants, while single‑cell RNA‑seq reveals expanded memory B‑cell and CD16⁺ NK‑cell compartments. Importantly for microbiome signature databases, GD exhibits a reproducible dysbiosis: reduced α‑diversity and phylum‑level shifts summarised below.

Phylum (or genus)	Change vs controls	Principal cohorts	Putative link
Firmicutes	↓	Ishaq 2018; Chang 2021	Loss of butyrate producers diminishes T‑reg tone
Bacteroidetes	↑	Ishaq 2018; INDIGO 2023	LPS‑rich membrane may amplify Th17 skew
Proteobacteria	↑	Ishaq 2018	Enriches sulfate‑reducers driving oxidative stress
Actinobacteria	↑	Chang 2021	Associated with heightened BAFF levels

Therapeutically, anti‑CD20 (rituximab) and anti‑CD40 (iscalimab) achieve biochemical remission in 40‑50 % of early GD, especially when baseline TRAb < 20 IU/L. FcRn blockade (batoclimab) rapidly de‑tiers TRAbs; TSHR‑blocking mAb K1‑70 and small molecules (ANTAG‑3, VA‑K‑14, S37) normalise thyroid hormones in murine models. Peptide apitope ATX‑GD‑59 restores tolerance in 50 % of mild GD, and TSHR‑CAR‑T selectively deletes TRAb‑producing B cells in vivo.

Key implications

Targeted immunomodulators promise durable euthyroidism without ablation or life‑long levothyroxine, and microbiome data suggest adjunctive avenues such as microbial metabolite supplementation or dysbiosis‑directed probiotics. Integration of host genetics, microbiota and antigen‑specific therapy could enable precision stratification, minimising exposure to broad immunosuppression and its respective risks.

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Treatment with Myo-Inositol and Selenium Ensures Euthyroidism in Patients with Autoimmune Thyroiditis.. Nordio M, Basciani S.. (Int J Endocrinol. (Feb. 15, 2017))
Selenium in the Treatment of Graves' Hyperthyroidism and Eye Disease. . Lanzolla G, Marinò M, Marcocci C.. (https://doi.org/10.3389/fendo.2020.608428)
Selenium in thyroid disorders — essential knowledge for clinicians.. Winther, K.H., Rayman, M.P., Bonnema, S.J. et al.. (Nat Rev Endocrinol. (Jan. 30, 2020))
The potential prebiotic berberine combined with methimazole improved the therapeutic effect of graves' disease patients through regulating the intestinal microbiome.. Han Z, Cen C, Ou Q, Pan Y, Zhang J, Huo D, et al.. (https://doi.org/10.3389%2Ffimmu.2021.826067)
Vitamin B12.. Truswell, Arthur.. (Nutrition & Dietetics. (2007).)
Structured exercise program improves functional capacity and delays relapse in euthyroid patients with Graves’ disease.. Cutovic M, Konstantinovic L, Stankovic Z, Vesovic-Potic V.. (Disability & Rehabilitation. 2012;34(18):1511-1518.)
Effects of Trace Elements on Endocrine Function and Pathogenesis of Thyroid Diseases—A Literature Review.. Bryliński Ł, Kostelecka K, Woliński F, Komar O, Miłosz A, Michalczyk J, Biłogras J, Machrowska A, Karpiński R, Maciejewski M, et al.. (Nutrients. 2025;17:398.)

Graves Disease

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Overview

Associated Conditions

Causes

Major Proposed Causes of Graves’ Disease and Their Limitations

Diagnosis

Primer

Metal Homeostasis

Mineral Homeostasis

Interventions

Pharmacological

First-Line Pharmacological Treatments for Grave’s Disease

Nonthionamide antithyroid drugs (NTADs)

Drug Repurposing

Antibiotics

Supplements

Lifestyle Interventions

STOPs

Microbiome Signature: Graves Disease

Research Feed

What was studied?

Who was studied?

What were the most important findings?

What are the greatest implications of this study?

What was studied?

Who was studied?

Most important findings

Key implications

What was studied?

Who was studied?

Most important findings

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What was studied?

Who was studied?

Most important findings

Gut Microbiome → GD:

GD → Gut Microbiome:

Key implications

What was studied?

Who was studied?

Most important findings

Key implications

What was studied?

Who was studied?

What were the most important findings?

What are the greatest implications of this study?

What was reviewed?

Who was reviewed?

Most important findings

Key microbial and microbiome associations:

Key implications

What was reviewed?

Who was reviewed?

Most important findings

Key implications

What was reviewed?

Who was reviewed?

Most important findings

Key implications

What was studied?

Who was studied?

Most important findings

Key implications

What was reviewed?

Who was reviewed?

Most important findings

Key implications

References

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