Selenium and Prebiotics as Adjunctive Therapies in Treatment of Graves’ Disease

Abstract

Graves’ disease (GD), also known as Basedow disease, is an autoimmune disorder leading to excessive production of thyroid hormones (hyperthyroidism). The prevalence of GD varies by region and sex, with the highest onset typically occurring between the ages of 30 and 50. Symptoms include a rapid heart rate, weight loss, heat intolerance, and goiter. Standard treatments involve antithyroid medications, radioactive iodine therapy, or surgery. Multiple studies have linked gut microbiota to the development of thyroid disorders. Recent research has focused on the potential benefits of nutritional interventions, particularly selenium and prebiotics, in managing GD. This chapter aims to provide new insights into the etiology and treatment of Graves’ disease through the administration of probiotics and selenium.

1. Introduction

Multiple studies suggest that inadequate blood and tissue levels of specific micronutrients in the nutrient-sufficient range promote and/or sustain autoimmune diseases such as GD [1] and that tumor necrosis factor is a key player in the regulation of microelements [2]. The rare micronutrient deficiency diseases demonstrate the dependence of the thyroid gland on various trace elements [3]; in the economically developed world, however, the widespread availability and the absence of overt deficiency states give little cause for most individuals and their caregivers to pay attention to these potentially pathophysiologic vulnerabilities [4]. Understanding the complex relationships between trace elements and preexisting diseases is crucial for developing targeted therapeutic strategies and improving patient outcomes. Copper and selenium are involved in the initial iodination event as cofactors of the thyroid peroxidase, managing iodine’s incorporation into tyrosine residues of thyroglobulin [5].

When GD is treated with thionamide antithyroid drugs (ATD), hypothyroidism develops in a certain percentage of patients after several weeks to months due to the TSH receptor–blocking effect of the thionamide, leading to a decrease in the titer of the newly released antibody [6, 7]. Hypothyroidism might also develop due to the destructive antibody effect on the gland’s follicular cells or the occurrence of concomitant Hashimoto’s thyroiditis. To alleviate the clinical symptoms of hypothyroidism and to decrease the risk of myxedema myocarditis, treatment is aimed at replacing thyroid hormone [8].

GD is an autoimmune disorder manifested mostly by hyperthyroidism, an increase in the metabolic rate, heat intolerance, weight loss, sweating, fine tremor, insomnia, palpitations, fatigue, goiter, lid lag, and stare due to lid retraction, ophthalmopathy, and dermopathy [9]. Most patients have IgG antibodies against the TSH receptor, stimulation of which leads to gland growth and hormone release. Graves’ hyperthyroidism typically fluctuates in severity and often spontaneously resolves, requiring indefinitely suppressive doses of ATD, radioactive iodine treatment, thyroidectomy, or, for carefully selected patients, no definitive therapy [10]. In opposition to the primum non nocere principle, a percentage of patients are unable to tolerate methimazole due to intolerance of the drug itself or its minor side effects, including allergic or cholestatic hepatic injury and hematologic toxicity [11]; a percentage choose and adhere to radioiodine therapy due to prior exposure to antithyroid drug side effects, a dislike for their fluctuating symptomatology, social or job-related constraints, or a preference for a single definitive treatment [12].

2. Physiopathology of Graves’ disease

Since GD is an autoimmune disease, its onset is usually related to increased intestinal permeability, which is an initiating factor for autoimmune diseases [13]. Increased intestinal permeability combined with an imbalance of beneficial bacteria and dysbiosis, or a subtle impairment of the intestinal immune barrier, might contribute to the onset of autoimmune processes in those who are genetically predisposed [14].

The immune system normally protects the body by patrolling the bloodstream and killing bacteria or viruses, but in individuals who have GD, the immune system produces a type of antibody called thyroid-stimulating immunoglobulin (TSI) [15]. TSI attaches to the surface of thyroid cells, inducing the gland’s overactivity. This overactivity of the thyroid leads to the characteristic symptoms of GD, such as an enlarged thyroid, rapid heart rate, nervousness, anxiety, fatigue, weight loss, muscle weakness, and tremors in the hands [9, 14].

The exact cause of GD is unknown, although current research suggests that GD is largely a result of genetic predisposition [16]. It is certainly a multifactorial disease, which involves the interaction between genetic susceptibility and environmental agents such as stress, infections, and certain drugs [14].

2.1 Autoimmune mechanisms

In autoimmune thyroid disease, increased levels of reactive oxygen species are implicated not only in the concept of establishing a proinflammatory effect but also in influencing the differentiation of precursor T-helper and T-regulatory cells into mature cells [17]. Finally, there is a suggestion that selenium is particularly central in influencing the action of the transcription factor TGF beta [18, 19, 20], helping to maintain gut barrier integrity and thus enhancing the differentiation of T-regulatory cells and reducing inflammation by decreasing IL-6 and enhancing IL-10 levels [21].

A range of factors from genetics, gender, imbalances in pro- and anti-inflammatory cytokines, and intestinal flora to genetic and environmental factors, such as iodine, selenium, and infectious agents, have been implicated in the etiopathogenesis of Graves’ disease [14, 16]. Selenium exerts its antioxidant function by acting as an essential cofactor for the enzyme family glutathione peroxidase and thus reducing the cellular concentration of hydrogen peroxide and organic hydroperoxides, which if they accumulate to mirror levels in tissues, contribute to lipid, DNA, and protein damage, leading to extensive tissue damage and autoimmune conditions [22, 23].

2.2 Role of thyroid-stimulating hormone receptor

The thyroid-stimulating hormone receptor (TSHR) facilitates the action of TSH on the thyroid gland, promoting the growth and proliferation of thyrocytes as well as the production of thyroid hormones [24]. In Graves’ disease, thyroid-stimulating autoantibodies mimic TSH, stimulating thyroid cells and causing hyperthyroidism and excessive thyroid hormone production. The binding epitopes for TSHR antibodies on the receptor molecule are well-studied [24, 25, 26]. Therefore, the activation of TSH receptor signaling during postnatal development increases the proliferation of benign cells and greatly accelerates the formation of their cancerous offspring [27, 28]. Unlike the current paradigm, mutations of the GNAS1 gene reduce TSHR signaling and, by either inhibiting cAMP production or increasing the Gnαs activity (lack of regulation), slow down the proliferation. Furthermore, in case all three proteins were mutated (TSHR; GNAS1; GNM), TSHR signaling would lose all its meaning if, especially for an embryonic mouse, thyroid-stimulating hormone were necessary. In a recent study, it is alleged that TSHR signaling is preserved during the early stages of thyroid tumorigenesis and that the inability of TSHR-deficient mice to bear an ectopic tumor is unrelated to activation [29].

The thyroid-stimulating hormone (TSH) receptor is a G-protein-coupled receptor that is present in its precursor form during embryonic development and appears on the cell membrane of the thyroid follicular cell on the 19th–21st gestational days in the mouse. At the time of birth, the receptor is present on the surface of the cell and forms a complex mass with other components of the basement membrane [30].

3. Current treatment approaches

3.1 R1: risk factors of Graves’ disease; genetic testing for primary (or only) prevention

The 2nd ERA recommended that 11 children born to mothers with Graves’ disease, 4 children who have two first-degree relatives with Graves’ disease, irrespective of whether it is on the maternal or paternal side, 2 first-degree relatives with Graves’ disease (mother and sister), and 3 populations at increased risk of GD based on family history should be tested. However, in the majority, the disease appears unexpectedly [31, 32].

The first question that arises is whom to treat. Since the diagnosis and treatment of Graves’ disease are not as straightforward as one might think, many patients are treated without giving them a complete and necessary rundown of the potential risks and benefits of therapy. Additionally, Graves’ disease is a unique autoimmune disease, as it is one of the few in which the cause of the autoimmune response is known, as well as the main autoimmune pathogenesis—stimulation of the TSHR by autoantibodies, particularly thyroid-stimulating antibodies (TSAb), and B-lymphocyte hyperactivity. This knowledge has opened the door to numerous therapeutic candidate treatments which interfere with the pathogenesis. Furthermore, treatments of other autoimmune diseases frequently are retrospective observations of benefits or adverse effects of already established treatment strategies. The four Rs discussed herein provide a comprehensive approach for the treatment initiation and monitoring of Graves’ disease [33].

3.2 Antithyroid medications

Although the European Thyroid Association recommends consideration of definitive therapy for all patients, some subgroups may benefit from any antithyroid drug therapy, including intolerant patients to thionamides, patients with a large goiter, and young patients who may undergo additional exposure to radiation or surgery during a lifetime [34].

According to the latest American Thyroid Association consensus, long-term low-dose therapy is the recommended dosage plan, with 2–2.5 years of therapy post achieving a euthyroid state serving as the ideal minimum treatment duration. Long-term low-dose therapy is a marriage of withdrawal and short-term low-dose methods, including minimal drug administration with the required length of therapy to achieve a remission effect post achieving a euthyroid state. Long-term low-dose therapy can add 20% of Graves’ disease patients who may benefit from improvement in the relapse rate by achieving a prolonged therapy duration [35].

In the treatment of Graves’ disease, antithyroid medications can be used as a single therapy or as a bridge to definitive therapy. Four strategies can be employed in the administration of antithyroid medications: block-and-replace, withdrawal, and short-term or long-term low-dose therapy. Treatment with an appropriately low dose has a remission induction effect, while the higher doses influence this action [35].

Controversy remains on the optimal treatment regime for Graves’ disease, due to potential side effects with antithyroid medications and relapse after definitive therapy with radioactive iodine or surgery [34, 36]. Although better characterization of patients for the risk of relapse may aid in the decision for definitive therapy, identifying novel adjunctive therapies with this action, such as selenium and prebiotics, is of immense interest [35].

3.3 Radioactive iodine therapy

The use of radioactive iodine (131I) rituximab therapy for GD is often characterized by a rapid onset of hypothyroidism, due to the destruction of the thyroid tissue caused by the radiation emitted by the 131I, which is selectively absorbed by the cells expressing the sodium-iodide symporter. Hypothyroidism is associated with longer remission, higher patient satisfaction, and better overall outcomes, including the prevention of complications related to Graves’ disease.

When deciding the optimal therapeutic approach for the patient with newly diagnosed Graves’ hyperthyroidism, it is important to bear in mind the possible risks and benefits and present the case in a balanced way, perhaps offering the patient the choice between surgery, antithyroid medication, and radioactive iodine. Before treatment is offered, the patient should ideally be given written information on the aims, side effects, and risks of each treatment option and discuss the preferred options with experienced healthcare professionals (normally an endocrinologist and nuclear medicine physician). It is perfectly reasonable for patients to ask their physician who is not a specialist in the field of Graves’ disease of the best course of action to take, such as the GP [37].

3.4 Thyroidectomy

Thyroid carcinoma has an extensive usage of lymph node dissections, which can result in a visible external nerve injury. The patients are subjected to total thyroidectomy with isthmectomy and central neck lymph node dissection. This type of surgery decreases transient hypoparathyroidism, but functional LNT injury is frequently found. The loss of delta mRNA expression ratio (TPO/CDH1) can evaluate the LNT dysfunction compared to the contralateral nerve. The saliva is obtained preoperatively and postoperatively from the operated patients, and it is used to evaluate the delta mRNA expression ratio in the LNT. Synchronous saliva-serum samples are available, offering complementary comparisons for preoperative information on the thyroid gland’s malignant state. The saliva-serum comparison from the control group and after a 6-month follow-up indicated that energy metabolism, protein homeostasis, and cellular integrity represent potential biological process pathways.

Thyroidectomy is considered in the case of small or toxic multinodular goiter, in the presence of malignancy, or in the presence of an extensive LNT. The total or subtotal thyroidectomy impacts the LNT regenerating process. The level of mRNA expression of the selenoenzymes decreases progressively from 6 to 12 months post-total thyroidectomy. A scratch wound assay presented that the LNT isolated from patients subjected to total thyroidectomy migrates more slowly compared to cells isolated from healthy patients. Treatment with the concentration of selenium found in the serum of healthy people restored the wound healing ability of the LNT from patients subjected to thyroidectomy. Also, after 24 hours of L-selenomethionine treatment, the level of expressions of mRNA of selenoenzymes GPX1, 2, and 4 was restored [38, 39].

4. Rationale for adjunctive therapies

4.1 Limitations of current treatments

Treatments with iodine and corticosteroids can help control thyrotoxicosis before definitive therapy with antithyroid drugs but do not shorten the average time to remission [40]. Furthermore, all treatments for GD have the risk of side effects and potential drug adverse events, especially hepatic, neuropsychiatric, and hematologic side effects for MMIs and PTUs, and the limited choice in treatment options [41]. RDAs are lacking in the general population and may consequently leave GD patients more vulnerable to a myriad of detrimental effects that mediators released during the inflammatory response can have on the organism [42]. There is a growing interest in the use of supplements for patients with autoimmune disorders to mitigate the release of proinflammatory mediators by modulating oxidative and immune functions. In vitro and experimental trials with metal-based trace elements like selenium have shown some benefits from lower oxidative stress, reduced circulating proinflammatory cytokines, and increased circulating levels of interleukin 4, an anti-inflammatory cytokine [43]. The ecosystem within and surrounding the digestive tract can also influence the degree of reactivity of the innate and adaptive immune responses occurring in GD. This review aims to highlight the benefits arising from such a diet plan, namely a diet enriched in oligofructose, a prebiotic that can selectively stimulate the activity and growth of beneficial bacteria, acting as a sort of shield against the degree of the immune system’s protection from the onslaught of the mediators of the inflammatory response and elicited by an individual’s interference [44].

The spectrum of antithyroid drugs and permanent forms of surgical and ablative therapies (complicated with the risks of post-treatment hypothyroidism), currently available for hyperthyroid GD, points out that treatment strategies do not address the innate and adaptive autonomous immune responses that drive the disease [45]. The introduction of treatments that could target the mechanisms of progression of GD may allow earlier treatment efficacy over a long term. Indeed, the main drawbacks of pharmacological treatments with MMI and PTU antithyroid drugs are the lack of efficacy to deliver a lasting remission from the disease and the long time to reach remission [46]. The relentless rate of remission while on medication in antithyroid drugs and the high rate of recurrence of the disease after withdrawal are key factors of medication withdrawal failure [47]. The low remission rate and compliance are even more pronounced in adolescence with a smaller number of patients being in remission, frequent relapse of hyperthyroidism, and difficulties with access to care in this age group [48].

The level of selenium intake has a large contribution to public health [49]. The inadequacy of selenium can lead to a significant decrease in the immune response, which can make the host susceptible to various types of infectious agents [20, 50]. The role of selenium as an immunoregulator has been known for over 30 years and has been shown mainly by increasing the production of proinflammatory cytokines [51]. For decades, the link between thyroid dysfunctions and selenium has been studied [52]. It is known that selenium is the precursor of iodothyronine deiodinases, which determine the synthesis of active hormones. In addition, the antioxidant role of selenoproteins is often emphasized, in particular the antioxidant role in the thyroid. Consequently, the imbalanced intake of selenium plays a significant role in the occurrence of autoimmune thyroiditis and thyroid tumors and development of preconditions for antimicrobial conditions [53]. Thus, the use and dosage of selenium as a therapeutic agent is essential, especially given the different effects on cellular functions such as the endocrine, immune, or other specifically expressed ones [54].

4.2 Potential benefits of selenium and prebiotics

Formerly, selenium was shown to regulate the functioning of the immune system [55]. Since autoimmunity is related to the Th1 type and hyperplasia appears in the thyroid gland, the shift from Th1 to Th2 immune response could help in pathologies related to the immune response [56]. The regulation of the intestinal microflora, IL-10 level increase, and oxidative stress and inflammation suppression are the mechanisms underlying the Se immune modulatory effects [57]. Furthermore, selenium can also increase the level and action of the VIP, which is a potent anti-inflammatory regulator [58]. Thereby, by using prebiotics, it is possible both to alleviate the damage from GD and to build a defense against stimuli provoking the development of autoimmunity [42].

It is well established that a deliberate reduction of oxygen consumption rate is a key strategy of cell defense. Thus, reduction in individual metabolism is a vital role of selenium-containing proteins, such as 15-kDa selenoprotein [59]. In addition to the antioxidant effect, Se supplementation could reduce the inflammatory status [60]. It has been proven that Se has the ability to modulate cytokine profile making it shift from a Th1-mediated (γ-interferon) to a Th2-mediated (IL-10) immune response that is important during autoimmunity [58]. Moreover, it has been shown earlier that selenium-containing copolymers can increase in vitro production of IL-2 [42].

5. Selenium as an adjunctive therapy

Low selenium status (< 80 µg/L) is associated with increased risk of thyroid disease. Increased selenium intake may reduce the risk in areas of low selenium intake [61]. No significant correlation was found between serum selenium levels and the clinical activity and severity of GO, with the exception of the finding that lower serum selenium concentrations were associated with eyelid retraction [62]. It can be assumed that there is a specific concentration of selenium below which complications are likely to appear in patients with GD, particularly those predisposed to immune hypersensitivity due to lifelong selenium deficiency [43]. It is also likely that the use of selenium is recommended to maintain or restore the concentration of selenium in the THM above the critical concentration [63].

At the Institute of Endocrinology and Metabolism in Kiev, Ukraine, 104 patients with GD, aged between 42 and 45 years, were examined for the level of selenium in the serum, the median urinary iodine excretion, relationship between selenium and ioduria levels [64]. The study results show that the concentration of selenium in whole blood testing is a reliable prognostic criterion for the outcome of GD. Selenium supplementation could visibly reduce the serum levels of FT3, FT4, and TPOAb in patients with AITD, but no observable effects were detected on the levels of TSH and TGAb [65]. Decreased plasma selenium levels < 64.32 µg/L, and increased concentrations of Th2 chemokines (e.g., CCL2) < 190 pg/L, may reflect GO disease activity, shedding light on the diagnosis and evaluation of active GO [66].

In several studies, selenium has been shown to reduce oxidative stress in patients with GD. It also can reduce the concentration of antithyroid antibodies, and prevent or mitigate the appearance of its physical symptoms, or the progression of autoimmune thyroiditis [67]. Data on the toxic effects of increased selenium are not the same in vivo and in vitro. High plasma selenium levels are associated with a common cause of death [40]. With that, the clinical course of autoimmune thyroiditis and smoking is not recommended as a source of selenium [68].

Presently, there are not many factors that could change the progression of GD. Those used have undesirable side effects. The search for new preventive or adjunctive agents for the treatment of patients with GD is relevant. The thyroid gland contains a significant amount of selenium, and its effect on thyroid gland function is of interest in autoimmune thyroid [69]. Currently, the role of selenium as a therapy, which reduces inflammatory activity, can slow autoimmune aggression in GD, and may prevent associated diseases, such as heart disease, malignant neoplasms, and movements and maintain fertility, is the subject of research [70].

The main cause of the progression of autoimmune aggression in GD is an increase in its own antigenic stimulation. Factors that could prevent the progression of autoimmune aggression in GD have been studied. Some of them showed their effectiveness in reducing the symptoms of GD. The role of selenium and prebiotics aimed at normalizing the intestinal microflora in the treatment of GD is considered in this review [52].

Graves’ disease (GD) is an autoimmune disorder of the thyroid gland characterized by the overproduction of thyroid hormones, the presence of antithyroid peroxidase and antithyroglobulin antibodies, and typical symptoms [58]. Standard therapy for GD includes the use of thionamides, iodine agents, or corticosteroids, ablative therapy, or surgical thyroidectomy. These methods do not affect the basic pathogenetic processes of the autoimmune aggression against thyrocytes [70]. They are directed against the symptoms of GD.

5.1 Biological functions of selenium

Selenium is a nonmetal that is represented in the Periodic Table of the Elements by the chemical symbol Se [55]. It is an element that is rich in biological and economic significance and is a very important element in nutrition. For over 40 years, its importance in function and health has been understood and has been the focus of medical attention (Figure 1). Epidemiologic and laboratory studies support the participation of selenium in preventing infection, cancers, and endocrine, autoimmune, and digestive disorders [60]. Many human diseases are accompanied by low blood and tissue levels of selenium, and increased dietary selenium enhances selenium concentrations throughout the body [58]. Because of its capabilities, selenoproteins either play or are partly involved in more than one customarily glutathione-dependent enzymes [71]. As historically documented, selenium, as a medicinal food, has been applied extensively in China for approximately 1000 years [21].

Figure 1.

The selenium implication in vital pathways.

Selenium’s main function in the human body is as a component of the 25 selenoproteins, most of which have a strong antioxidative, anti-inflammatory, and antiviral effect [55]. Several selenoproteins have protective and detoxifying functions linked to excessive oxidative stress, which can damage cells and tissues and initiate an autoimmune response [60]. Selenoproteins play a role in the endoplasmic reticulum and in the regulation of the immune and inflammatory response, which might be of importance under inflammatory and autoimmune states [58]. The polyadenine and selenolate bond within the selenoproteins enable glutathione peroxidases and thioredoxin reductases to lower oxidative stress, and the other selenoproteins participate in redox-signaling pathways or work as molecular chaperones [71].

The selenium could exist in organic or inorganic forms. It is implied in many mechanisms such as immunological ones. Besides, disease such as Basedow or Graves’ disease is regulated under the selenium action.

5.2 Studies on selenium supplementation in Graves’ disease

The aim of this review is to summarize the data on the effectiveness of supplementation with selenium-iodine-laminina1, selenium, and “Revifort” prebiotic in Graves’ disease.

The mechanism of selenium in the treatment of Graves’ disease is generally believed to be due to its antioxidant effect [58]. An optimal selenium nutritional status in preventing oxidative damage is suggested by its incorporation into a range of selenoenzymes that function as potent intracellular antioxidants. They convert reactive oxygen species into less toxic forms. Therefore, selenium may inhibit inflammatory damage. However, some studies have suggested that selenomethionine and methyl selenocysteine are immunosuppressive agents [42]. The immunomodulatory effects of selenium supplementation may be the mechanisms responsible for the treatment of autoimmune thyroid disease [68].

The first study reporting beneficial results of selenium supplementation in Graves’ disease was conducted by Contempre et al. in 1991. It used a double-blind, placebo-controlled design in Central Africa. With 50 µg of selenium (as selenomethionine) daily, serum T4 concentrations decreased without a concomitant increase in serum TSH concentrations in the healthy children. Shortly after that, a Polish team reported the beneficial effects of selenium supplementation on oxidative stress by reducing lipid peroxidation. This was done in a randomized, double-blind, placebo-controlled design at a dose of 100 mg per day [72]. These two studies received abundant attention and became the classic papers that promoted the application of selenium supplementation in Graves’ disease.

6. Prebiotics as an adjunctive therapy

In autoimmune diseases, the hypothesis of the consumed antibiotics, excess sterilization, and reduced exposure to microbes in modern society is increasing in frequency at an alarming rate. Understanding the external factors that influence these conditions is of considerable interest for obtaining data on SCFA metabolites and improving protection against colitis. On the other hand, prebiotics, designed substrates, were usually fructans directly entering the colon to stimulate microflora to show positive effects [73]. In some or perhaps all other tissues, microflora is an essential factor in the regulation of T cell function. Hence, the more beneficial work in microflora disorders is promising in the treatment of autoimmune diseases, as well as intestinal microbiota [74]. In GD, antibiotics could be applied to treat gut dysbiosis, and the tendency aimed at normal restoration of the interaction between the microbiome, environment, and the intestine [48]. A nutritional additional supplementation has been used as encouragement to increase the total number of Lactobacilli with additional treatment of prebiotic-causing bacteria, in the primary therapy of Graves’ disease [75]. Dietary and pharmacological antithyroid therapies, such as methimazole, thiourea derivatives, and potassium iodide, have been used. However, the potential role of probiotics, individually or in combination with prebiotics, has not been sufficiently tested as treatments to either prevent or cure the autoimmune process.

Prebiotics are fermentable, non-digestible fibers that are used to stimulate the growth and/or activity of beneficial bacteria in the colon, leading to improvements in host health [76]. Much interest in prebiotics as adjunctive therapies in the treatment of GD stems from the observation that individuals with thyroid conditions are more likely to have gut dysfunction. Therefore, the idea of using dietary intervention in diseases as a way of mitigating the effects of these diseases is very appealing [73]. Using trivial benign metabolic diseases and non-absorbed dietary products as therapeutic tools seems to be an ideal situation. Their role encompasses detoxification of potential toxin producers, their involvement in nutrient metabolism, substitution, and inhibition of other microflora, or “selective stimulation” [77]. There is a lot of hope in dietary therapy of different functional states and diseases. Supplementation with a non-digestible oligosaccharide is the way to selectively change the colon microflora.

6.1 Role of gut microbiota in autoimmune diseases

The gut mucosal immune system comprises both innate and adaptive immune compartments and is finely regulated by an intricate signaling network [78]. This delicate equilibrium of tolerance and immunity can be perturbed by a variety of exogenous factors, including pathogens, commensal microbiota, drugs, or diet. The onset and progression of gut-related immune-mediated diseases such as asthma, multiple sclerosis, obesity, diabetes, rheumatoid arthritis, depression, and mood disorders are closely related to aberrant changes in the composition or function of the intestinal microbiota [79]. The rapidly increasing global incidence of autoimmune disorders warrants a deeper understanding of the underlying causes, including the environmental factors that may modulate the gut microbiota and, subsequently, the immune system. Up to now, factors contributing to the development of autoimmune diseases have only been partially explained. Initial evidence has highlighted the importance of gut microbiota in disease development and raised the possibility of using bacteria and prebiotic treatments to prevent their onset [74].

The gut microbiota is an integral entity of the human body, both with respect to quantity and diversity, and the microbiome profile is the repertoire of microbial genes present in the microbiota [73]. A highly diverse and stable gut microbiota is a key factor in maintaining good health. Both local (affecting gastrointestinal mucosa) and systemic effects of gut microbiome influence efficient gut functioning and protection [74]. However, possibly the most relevant effect of the gut microbiota on human health is related to the fact that the intestinal microbiota contributes to the regulation of immune homeostasis, maintaining a balanced state of a healthy immune system.

6.2 Evidence for prebiotic use in Graves’ disease

A beneficial role for prebiotics, in which some are indigestible oligosaccharides, soluble non-digestible fibers, indigestible sugars, but also anti- and honey drink cutaneous bacteria with the honey-producing lactobacilli and other lactobacilli, is evident by the overall protection offered [78]. Perhaps this explains the transcendent advice of ancient Egyptian texts to drink honey or a mixture of milk and honey to protect the mouth and throat from infection, including inflammation. Both prebiotics, in the form of oligofructose-enriched inulin supplement, and oligofructose act as both pre- and probiotics to decrease the severity of celiac disease, with the former combatting dysbiosis and the latter down-regulating duodenal macrophage activity [74].

The rationale for this intervention lies in the known anti-inflammatory properties of prebiotics, which include the ability to inhibit the growth of unhealthy bacteria such as Escherichia coli and the promotion of a beneficial community dwelling of Firmicutes and Bacteroidetes [73, 74]. Specific benefits of prebiotics have been observed in preventing or modifying the manifestations of several autoimmune diseases and Graves’ disease, where there is direct evidence for a role for type 1 helper (T-h) and/or other inflammatory cytokines. Enhanced levels of pathogenic bacteria, including E. coli, have detrimental effects such as the increased ability of the immune system to promote the deposition of inflammatory and oftentimes pathogenic immunoglobulins in affected organs.

7. Combination therapy

Prospects for the near future: The combination of relatively low-harmful (for the body) doses of SS and several PRTs, which are at the stage of completion of clinical trials, with SS at the treatment stage of GD can provide the highest target therapeutic effect with the minimum harm to the body.

1. It is possible to combine the use of relatively low doses of ATDs with SS and PRTs that can correct the main misconceptions of ATD action [73].

2. It is possible to combine the use of relatively low doses of ATDs with the prescription of therapeutically acceptable amounts of ST without side effects [74].

3. The combined use of organic Se + prebiotics with not exceeding the recommended maximum EC level and increasing the intake of the most favorable ones may be accompanied by a significantly better management of GD compared to monotherapy. The most important advantage of the proposed hypothesis is not only the achievement of the therapeutic goal in managing GD but also the practically complete absence of side effects from the drugs used, which is very significant.

Hypotheses: According to the scientific data discussed above, we can formulate the following hypotheses.

7.1 Synergistic effects of selenium and prebiotics

Correlation studies showed that certain types of beneficial gut bacteria, particularly a group of bacteria in the Firmicutes phylum, can utilize dietary selenite directly or indirectly and turn toxic selenite into a non-toxic form [78]. Prebiotic compounds cannot be absorbed into the blood because the body does not have the metabolic enzymes to degrade or utilize them. They can be hydrolyzed and degraded in the colon and produce a lot of beneficial metabolites, such as short-chain fatty acids, which provide energy for the epithelium [73, 80]. $The activity of short-chain fatty acids (butyrate) on colonocytes is considered an environmental inducer-regulator of apoptosis and proliferation (Figure 2) [81].

Figure 2.

The impact of microbiota on the thyroid gland.

Intestinal dysbiosis: leading to impaired gut barrier function and increased intestinal permeability, facilitating antigen entry into circulation and immune system activation. Antibodies: in circulation may react with bacterial antigens, enhancing the activation of inflammatory foci within the thyroid. Short-Chain Fatty Acids (SCFAs): The main factor influencing Graves’ disease through the gut microbiota, increasing attention is being paid to the immunomodulatory effects of short-chain fatty acids (SCFAs).

Fecal SCFAs technology can be used as a treatment for radiation enteritis in clinical settings (Figure 3). Therefore, it is important to explore the interaction of prebiotics and enteritis associated with antithyroid drug treatment. More research on the synergistic effects of selenium and prebiotics is essential.

Figure 3.

Short-chain fatty acids (SCFAs) functions.

The supplementation of probiotics with prebiotic fiber elicits a stronger probiotic effect in the treatment of disease [81]. Despite studies supporting the benefits of integrating selenium and prebiotic nutrients into diets, the synergistic effects of these nutrients in the treatment of autoimmune diseases may be due to modulating the integrity of the GIT [73]. Selenium has been associated with the increase in the concentration of beneficial bacteria while reducing the inflammatory response. Selenium compounds can improve gut immunity by modulating the gut microbial composition. On the other hand, prebiotics also have the capacity to change the microbiota profile by promoting the proliferation of beneficial bacteria [78]. Although there is limited work on the simultaneous supplementation of selenium yeast and prebiotic fiber in association with the gut, future work might unmask the full potential of this combination.

SCFAs can serve as an energy source for epithelial cells, maintain intestinal barrier integrity, and reduce gut permeability and circulating lipopolysaccharides levels.

8. Safety and adverse effects

Selenium might be effective in reducing thyroid volume in Graves’ orbitopathy. While the combination of selenium and probiotics may improve the quality of life in patients with autoimmune thyroiditis. The role of L-selenomethionine in mild Graves hyperthyroidism and the effect of selenium supplementation on antithyroid treatment—results of a prospective, randomized, double-blind, placebo-controlled clinical study. The role of selenium and prebiotics as adjunctive therapies in the treatment of Graves’ disease. Adjuvanta: they represent an alternative in the adjuvant treatment of diseases like hyperthyroidism. They are safe medications with a strong anti-inflammatory and protective action of the thyroid. The most common adverse effects are minor allergies for probiotics and gastrointestinal symptoms for selenium [82].

8.1 Potential risks and monitoring

The geographical location of natural habitats of selenium-enriched plants should be kept in mind in the differential diagnosis, including the patient dietary history. In cases of new thyrotoxicosis occurrences treated with selenium monotherapy, the possibility of contamination of selenium-containing tablets with other substances should be considered. Similar signs and symptoms may also occur if the initial loading and maintenance doses are miscalculated or overdosed. In these instances, measuring serum selenium levels is unlikely to expedite the diagnostic process. In countries where a transitory oversupply of selenium has occurred, in vitro fertilized human egg donors may have been exposed and the thyroid of future generations should be monitored [83, 84].

While many patients have had safe treatment using oral selenium as monotherapy at 100–200 mcg per day and long-term intakes from food and supplements of approximately 800 mcg per day are rated as safe, it is important to exclude selenium as a contributing factor to type 2 hyperthyroidism due to ingestion of high dietary selenium levels, for example, from overuse of sports nutrition supplements. A recent meta-analysis suggests that the high level of both selenium content in maternal blood and breast milk is associated with an increased risk of thyroid autoantibodies in neonates and in Graves’ disease, which may also bear relevance for Graves’ disease generally. Patients with recent onset of symptoms of thyrotoxicosis together with a palpable goiter and characteristic signs of selenium excess, such as garlic breath and a metallic taste, should have the metabolic consequence of any organic selenium determined [85, 86].

9. Future directions

Facilitation of dietary modification for GD is important as the ingestion of Se, through foods or supplements and/or prebiotics as components of healthy diets, is an important adjunctive treatment as discussed in this review. Exploration of the treatment and nutritional complications of comorbid GD found in a large European cohort would provide valuable insights into the practicalities of integrating adjunctive diet and bacterial re-balancing therapies [82]. Tools for the clinical assessment of gastrointestinal health and prompt adjunctive treatments for many patients and their carers would be beneficial. Clinical questions related to the onset differential to insidious and prompt medical therapy and adjunctive therapies in relation to dietary and bacterial precautions warrant further investigation [87].

As discussed in this chapter, innovative approaches to the management of GD which recognize the impact of gastrointestinal microbiota and the importance of nutritional co-factors such as Se are emerging. Research targeting the gut environment and the interaction of the bacteria on optimum functioning of the HPT axis and resultant immune adaptations for thyroid homeostasis support the pursuit of novel, biologically plausible, and cost-effective treatments. To capitalize on the full therapeutic benefits of adjunctive treatment by including Se or prebiotic therapy in the medical management of GD, more well-designed, appropriately powered clinical trials are required. Flow-through research studies that explore the significant clinicogenomic interactions that are so important for Se and gut health need to be identified in GD patients [76, 82].

9.1 Research gaps and opportunities

The concept of co-existence and/or interaction between these two agents, as well as other factors within the GI tract that help in shaping and maintaining the microbiome in disease, is an important theme of current research. Studies done under controlled conditions provide valuable information about the individual effects of the given agent on the microbiome, while early stages of GD are mostly examined in in vitro and animal models. However, real progress is achieved when results obtained in separate studies are put together and new, more advanced hypotheses are drawn. To better understand this complex problem, certain issues regarding the application and usefulness of selenium and prebiotics need to be resolved. It is doubtful whether studies presented so far, based mostly on subjective and state-dependent symptoms and signs of severe GD that have not been identified in the very early stages of GD, may suggest that these agents might have potential benefits in the treatment of the entire spectrum of GD. The determination of the optimal and appropriate duration of selenium supplementation for GD, as well as the proper selection of the most appropriate prebiotic compound and the required Prebiotic Index (PI), which could at best be obtained by matching certain prebiotics with certain probiotic species, optimized in each patient. The implementation of such a program would require the determination and validation of standard molecular and microbiological methods, as well as the extended cost-utility analyses in collaboration with other professionals, including dietitians, microbiologists, and industry [88, 89].

In this review, we described clinical evidence that might suggest the use of selenium and prebiotic fibers as adjunctive therapy during GD as both agents may be of some benefit to patients with GD. However, these effects, observed at a very early disease stage, probably by affecting autoimmunity, may not be so prominent and of substantial advantage in the advanced stages of GD when symptoms are present and first-line therapy might be applicable. Now, both agents are considered as nutritional supplements. However, in our opinion, they should be treated as substances that interact with the gastrointestinal tract environment, which should be taken systematically at the proper time, in the proper dose, by the proper subgroup of patients [90].

10. Conclusion

Prebiotics and dietary fibers can have a unique positive effect on the course of Graves’ disease due to the lack of side effects. However, it must be remembered that the flora of the intestine is specific for each person, and expenses can grow quickly. Therefore, the use of fiber polymers from various sources and combinations of several sources (so-called prebiotic combinations) in the prevention and complex therapy of Graves’ disease is the goal of further scientific search. A sufficiently profitable method, with the maximum specified therapeutic effect, could be the use of low or medium doses of single strains of probiotics, with the selection of the desired strains, and then a special phase that cannot be avoided: “personalized” to the sensitivity of the strain. At this point, the patient should initially benefit from the participation of a nutritionist, a gastroenterologist, and a laboratory for personalized medicine, cooperating during the preclinical phase of this therapeutic model.

Graves’ disease can cause a significant reduction in the quality of life and an increase in the costs of medical care. Conventional therapy using antithyroid drugs, radioactive iodine, and thyroid surgery is not suitable for some patients due to ineligibility, intolerance, or concerns about the side effects of therapy. Currently, the search continues for new methods of comprehensive treatment and means to improve traditional methods known for many years. This chapter proposes a combined treatment that includes the pathogenetic use of microelements, including selenium, Zn, and prebiotics, using drugs and functional food products based on dietary fibers, probiotics, and trace elements. Administering these methods can improve the efficacy of basic therapy aimed at eliminating the thyrotoxicosis syndrome, autoimmune inflammation, and the restoration of euthyroid function.