Cellular redox homeostasis depends on a dynamic equilibrium between prooxidant production and its elimination. Reactive oxygen species (ROS), together with reactive nitrogen species (RNS), represent the most important prooxidants whose excessive accumulation leads to oxidative stress (OxS) and molecular damage (1, 2). ROS are molecules with an oxygen atom, and unpaired electrons are primarily generated as by-products of ATP synthesis in mitochondrial respiratory chains (1) or during inflammation (3, 4). The concentration of ROS determines their physiological role (5). When present at low concentrations, ROS are involved in signaling processes essential for normal cellular functions (6, 7), whereas high ROS concentration leads to DNA, lipid, and protein damage and apoptosis (8).

ROS are crucial in thyroid function because they are essential in the initial stages of thyroid hormone synthesis during iodide oxidation (9). Also, the process whereby thyroid peroxidase (TPO) catalyzes thyroxine (T4) and triiodothyronine (T3) during its synthesis in thyroid follicles involves ROS (10). In addition, thyroid hormones affect the mitochondrial activity and modulate ROS production (10). The dependence of normal thyroid function on ROS implies that the thyroid is continuously exposed to ROS and, thus, particularly sensitive to oxidative damage (10). Therefore, to protect the integrity of the thyroid, it is mandatory that the thyroid antioxidant defence system effectively regulates and balances ROS production and elimination (11, 12).

Aerobic organisms have evolved multiple antioxidant and repair systems for protection against OxS. Enzymes that decompose ROS, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) provide the primary antioxidant defence (5, 7, 8, 13). In contrast, ROS-induced damage repair systems eliminate damaged cells through autophagy and apoptosis processes (14, 15). However, the capacity of intrinsic antioxidant systems is not always sufficient to prevent damage caused by excessive accumulation of ROS. Thus, non-enzymatic mechanisms based on the action of molecules with antioxidant properties such as glutathione (GSH), thioredoxin, coenzyme Q10, and exogenous antioxidants, including various polyphenolic compounds, ascorbic acid, tocopherol retinol, and β-carotene, that may also support antioxidant systems are essential. The use of nutritional antioxidants as supplementary substances that delay and/or prevent the oxidation of cellular components has shown the potential to protect human organs, including the thyroid gland, against oxidative damage by reinforcing the body’s antioxidant defence and increasing total antioxidant capacity (5, 16, 17).

Recently, a search for natural nutritional antioxidants from biological resources has gained substantial attention. Of particular interest are probiotics which represent live non-pathogenic microorganisms that can restore microbial balance in the gastrointestinal tract upon appropriate administration (18). Evidence demonstrates that probiotic bacteria exert significant antioxidant effects in vitro and in vivo (19–22), and the connection between the thyroid gland and gut microbiome is well-established. Furthermore, it has been documented that dysbiosis, an imbalance in gut microbiota, is associated with impaired thyroid function and pathogenesis of thyroid disorders such as Hashimoto’s and Graves’ disease (23). In this review, we discuss the protective role of exogenous nutritional antioxidants in the context of various thyroid disorders. We also review novel findings related to the connection between the thyroid gland and gut microbiome and analyze the effects of probiotics with antioxidant properties on thyroid diseases.

We searched MEDLINE and PubMed for all English and non-English articles with English abstracts published between 1977 and 2022. The leading search terms were: oxidative stress, reactive oxygen species, thyroid disease, nutritional antioxidants, thyroid-gut axis, gut microbiome, and antioxidant probiotics. The search retrieved original peer-reviewed research articles, which were further analyzed, focusing on the role of nutritional antioxidants in thyroid diseases. We specifically focused on including the most recent findings published in the past five years.

Oxidative stress is a disbalance caused by excessive production of prooxidant substances such as ROS and RNS and/or the antioxidant systems working inefficiently (14, 24, 25). ROS include superoxide anion, hydroxyl radical, and hydrogen peroxide, which are produced in vivo primarily by the mitochondrial respiratory chain during aerobic metabolism (26). RNS family includes peroxynitrite, generated via a reaction between nitric oxide (NO) and superoxide, and nitrosoperoxycarbonate, generated via a reaction between peroxynitrite and carbon dioxide. Under physiological conditions, ROS plays a vital role in maintaining cellular homeostasis by regulating the endogenous antioxidant pool (27–30) and participating in host defence and hormone synthesis (31, 32). In thyrocytes, ROS production is essential for their functional role (33) since TPO-mediated hormone synthesis depends on the action of dual oxidases (DUOX), enzymes responsible for H₂O₂ production (34). However, when ROS and RNS are present in excessive amounts and/or in the form of highly reactive free radicals such as superoxide anion and hydroxyl radical, they oxidize susceptible biomolecules such as membrane lipids, cellular proteins, and nucleic acids, leading to disruption of normal cellular functions (35). Lipid peroxidation is a process in which oxidants such as free radicals or non-radical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) (36). The main lipid peroxidation products are hydroperoxides, such as propanal, hexanal, 4-hydroxynonenal, and malondialdehyde (MDA) (37). Phospholipids, cholesterol, and glycolipids are also targets of potentially lethal peroxidative modifications (38). ROS can also cause damage to DNA by oxidizing nucleoside bases (39). For example, guanine oxidation produces 8-oxo guanine (8-oxoG), which may lead to G-T or G-A transversions if unrepaired. The guanine and deoxyguanosine oxidation products 8-oxoG and its nucleotide 8-oxo-2′-deoxyguanosine (8-oxodG) are ROS-mediated DNA lesions considered the most significant biomarkers for oxidative DNA damage (40). Oxidized bases are usually recognized and repaired by the base excision pathway (BER). Still, when they co-occur on opposing strands, BER can lead to the generation of double-stranded DNA breaks (41). ROS accumulation also induces mitochondrial DNA lesions, strand breaks, and DNA degradation (42). In addition, increased ROS levels are responsible for protein oxidation that can rapidly contribute to the augmentation of OxS by directly affecting cell structure, cell signaling, and essential enzymatic metabolic processes. Several modes of ROS-mediated protein oxidation are reported, including metal-catalyzed oxidation, oxidation-induced cleavage, amino acid oxidation, and the conjugation of lipid peroxidation products (43).

Excessive ROS accumulation is an important factor in the pathogenesis of different diseases. For instance, an elevated ROS production by the respiratory chain is observed in obesity as a response to metabolic overload caused by excess macronutrients and increased substrate availability (44). Mitochondrial dysfunction and endothelial reticulum stress contribute to metabolic perturbances in the adipose tissue of obese patients (45). Consequent ROS accumulation leads to cell damage and pathogenesis of inflammatory and cardiovascular diseases (46). Furthermore, mitochondrial ROS acts as signaling molecules mediating pro-inflammatory cytokines’ production, further reinforcing the connection between OxS and inflammation (47).

Several enzymatic and non-enzymatic defence mechanisms that guard cells against free radical damage have been identified in different cellular localizations, including mitochondria, plasma membrane, endoplasmic reticulum, peroxisomes, and cytosol. For example, enzymes SOD, Cat, and GPx, and transition-metal binding proteins, such as transferrin, ferritin, and ceruloplasmin, inactivate free radicals (48). Three forms of SOD are known in mammals: cytoplasmic SOD (SOD1), mitochondrial SOD (SOD2), and extracellular SOD (SOD3) (49). SOD belongs to a group of metalloenzymes that catalyzes the dismutation of superoxide anion to hydrogen peroxide and molecular oxygen, while Cat decomposes hydrogen peroxide to water and molecular oxygen (50). In high H₂O₂ levels, GPx also participates in detoxification by converting lipid peroxides to the corresponding alcohols. Hydrosoluble molecules with free radical scavenging properties such as ascorbic acid, albumin, bilirubin, urates and thiols, liposoluble coenzyme Q10, and vitamin E interfere with the lipid peroxidation by neutralizing the free radicals. In particular, liposoluble scavengers in cellular membranes have high diffusion rates, enabling them to abolish the radical chain reactions by immediately converting them into more stable and less reactive molecules (46). Additional defence mechanisms that reconstruct damaged molecules involve using specific phospholipase that removes peroxidized fatty acids, allowing the reacylation of damaged molecules (51, 52).

Thyroid hormones have a considerable impact on the cellular oxidative stress processes which is ascribed to their role in cellular metabolism and oxygen consumption (53). Thyroid hormones are produced by thyroid gland, released into circulation, and transported to all organs and cells where they exert their effect. An important role in production of thyroid hormones has hypothalamic-pituitary-thyroid axis. Hypothalamus production of thyrotropin-releasing hormone (TRH) stimulates anterior pituitary gland to secrete thyroid-stimulating hormone (TSH), which affects thyroid gland and leads to production of thyroid hormones. Thyroid gland mainly produces T4, a prohormone which needs to convert to T3 to become biologically active. T4 comprises about 80% of secreted thyroid hormones, while the other 20% is T3. Increased plasma values of thyroid hormones in circulation activate negative feedback loop and inhibit release of TSH (54, 55).

Thyroid hormones exhibit profound metabolic effects characterized by an increased rate of both catabolic and anabolic reactions, resulting in an overall acceleration of the basal metabolism which is associated with increased oxygen consumption, respiratory rate, energy expenditure, and heat production (56). In addition, altered thyroid hormones levels may cause changes in the number and activity of mitochondrial respiratory chain components which represent the principal cellular site of ROS production, ultimately leading to changes in the cellular redox environment and increased ROS generation (57, 58). For instance, it has been reported that hypothyroidism-induced dysfunction of the mitochondrial respiratory chain is associated with increased production of free radicals (59) Thus, excess TSH in hypothyroidism may modulate oxidative stress processes (60) by augmenting the accumulation of ROS that result from both increased generation of free radicals and diminished capacity of the antioxidative defense systems.

Hypothyroidism is associated with an increased risk of atherosclerosis due to its metabolic effects (61, 62). It is commonly accompanied by hyperlipidemia which results from a disbalance between the rates of fatty acids’ synthesis and degradation and is characterized by elevated total cholesterol and low-density lipoprotein-cholesterol (LDL-C), thus providing the substrate for ROS-mediated lipid peroxidation (63–66). Interestingly, products of lipid peroxidation may further increase overall cellular oxidative stress by facilitating the generation of free radicals through the formation of adducts with proteins, which increases direct free radical-induced protein oxidation (67).

In thyroid diseases, metabolic disorders associated with low-grade inflammation can also lead to an increased oxidative stress (68). For instance, chronic low-grade inflammation observed in Hashimoto’s thyroiditis causes endothelial dysfunction which represents an early step in the development of atherosclerosis. Endothelial dysfunction is characterized by the reduction of bioavailability of NO, resulting in impaired endothelium-dependent vasodilation (69) and increased oxidative stress (70). However, it should be mentioned that there is still no consensus in the literature regarding the connection between hypothyroidism and oxidative stress. Some studies report increased oxidative stress in hypothyroidism while other suggest that hypometabolic state that is prevalent in hypothyroidism may protects tissues from oxidative damage.

Thyroid diseases are considered the most commonly reported endocrine diseases in clinical practice, followed by lipid and carbohydrate disorders (71–73). The primary thyroid condition that affects thyroid functionality presents as hyperthyroidism or hypothyroidism ( Figure 1 .). Thyroid dysfunction could manifest fully (clinically) or latently (subclinically). Based on duration, thyroid dysfunction could be persistent or transitional (73–75). The natural history of thyroid disorders can negatively affect the morphology and function of target tissues if left untreated or improperly treated (55, 73, 76). Thus, the leading causes of death in patients with thyroid dysfunctions are the consequences of atherosclerosis acceleration and the worsening of pre-existing cardiovascular and central nervous system diseases (77, 78). Such endpoints depend on pronounced OxS and diminished antioxidant defense systems at the molecular level (79–81).

Different thyroidopathies have been shown to cause increased ROS production and evident OxS-induced damage to thyroid cells. This relationship is reciprocal since thyroid conditions can worsen OxS and increase ROS production, exacerbating oxidative damage. Thyroid hormones increase ROS release in the mitochondrial respiratory chain (25, 82, 83). Hypothyroidism contributes to OxS through an inefficient antioxidant defence system, opposite to hyperthyroidism, where increased ROS production promotes OxS and oxidative damage of thyroid cells ( Figure 1 ) (46). According to published research, preventive dietary antioxidant therapy may partially correct the redox imbalance, making it a viable method for preventing the onset of many chronic thyroidopathies (25).

Proper nutritional intake is mandatory for overall well-being and better human health. However, dietary habits have an impact on human health and can lead to the development of a variety of disorders and diseases. The most prevalent diet in the world is the Western-style diet, characterized by an increased intake of refined food with a high caloric index and an increased amount of sugars and salt, while the intake of vegetables, fruits, and fish is reduced (133). Negative consequences of nutritional habits associated with a Western-style diet may lead to inflammation and production of free radicals (134) through the secretion of numerous pro-inflammatory molecules such as interleukin (IL)- 6, IL-1b, IL-8, and C-reactive protein (CRP), leading to the development of autoimmune disorders either directly, due to inflammation or disturbed immune balance, or indirectly due to increased fat depositions and the development of obesity. Obesity has the most severe consequences since it is associated with systemic inflammation, hypertension, and hypercholesterolemia, which represent conditions that increase the risk of developing cardiovascular disease and T2DM.

It is believed that the state after taking a meal (postprandial state) is pro-inflammatory and pro-oxidative, and the type of food mainly consumed affects the occurrence of OxS. As mentioned earlier, the increased intake of proteins (processed, red meats), sugars, salt, saturated and trans fat, and refined carbohydrates, which are characteristic of the Western-style diet, leads to the development of many diseases, which have their basis in the occurrence of OxS (135). Furthermore, a diet based on an increased intake of carbohydrates and fats leads to increased production of free radicals, directly affecting mitochondrial metabolism. Also, animals fed a high-fat diet have been shown to have increased OxS and dysfunctional mitochondria (136).

To reduce the development of obesity, cancer, diabetes, and cardiovascular diseases, WHO recommended a diet that includes an increased intake of fruits, vegetables, nuts, fish, and unsaturated fatty acids. This type of diet is represented in certain coastal regions of the world and has received the popular name Mediterranean diet. The natural antioxidants, as a result of proper nutritional habits, provide indirect protection by decreasing the production of cytokines and reducing OxS (134).

Numerous exogenous antioxidant molecules (nutritional antioxidants) have been shown to play an important role in excessive ROS accumulation in organisms. Here we will discuss several nutritional antioxidants with a confirmed protective antioxidant role. For instance, monounsaturated fatty acids (MUFA) such as oleic acid that are present in high amounts in olive oil and certain nuts decrease ROS production and exert protection against OxS (137). In addition, oleic acid showed anti-inflammatory effects by decreasing obesity and cytokine production and reducing cardiovascular mortality (134). The anti-inflammatory actions of MUFAs are based on their ability to counteract the effects of long-chain saturated fatty acids on hepatocytes, which include reducing endoplasmic reticulum stress, restricting lipotoxicity induced by accumulation of saturated fatty acids, decreasing ROS production, and inhibiting nuclear factor-κB (NF-kB) transcription factors by binding peroxisome proliferator-activated receptor γ (PPARγ) and G-protein coupled surface receptor 120 (GPR120) (138). In vitro, MUFA has shown the ability to induce the expression of the adiponectin gene via PPARγ activation, which would result in decreased production of pro-inflammatory molecules such as IL-6 and tumour necrosis factor (TNF)-alpha (139)

Polyunsaturated fatty acids, such as omega-3 fatty acids (n-3 PUFA), are mostly found in eggs, nuts, and fish, whereas omega-6 fatty acid (n-6 PUFA) is predominantly present in sunflower and other vegetable oils. The ratio of n-3 PUFA/n-6 PUFA is of the utmost importance since its disbalance may activate pro-inflammatory pathways (140) n-3 and n-6 PUFA exert opposite effects on the immune system, whereas n-3 PUFA have an anti-inflammatory effect while n-6 PUFA induces a pro-inflammatory action (141). The anti-inflammatory effects of n-3 PUFA are based on their ability to decrease endogenous concentrations of ROS and expression of NF-kB and promote activation of genes involved in antioxidant protection.

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a natural polyphenol nonflavonoid compound primarily found in grapes, red wine, berries, and peanuts. It has been shown that long-term treatment with reservatrol prolongs lifespan and reduces OxS (142). In addition, resveratrol was shown to possess cardiovascular protective capacity (143–145) and exhibit antidiabetic, anti-inflammatory, and antioxidant effects (146–150), as well as the ability to suppress the proliferation of a variety of tumour cells (151, 152). Also, resveratrol positively affects obesity, reducing triglycerides and glucose levels. The anti-inflammatory effects resulting from using resveratrol can be seen in the reduction of increased levels of interleukin and TNF in obese mice (15). The antioxidant effects of resveratrol were confirmed in many studies. For example, resveratrol significantly inhibited ROS production by polymorphonuclear leukocytes treated with formyl methionyl leucyl phenylalanine (153) and reduced OxS markers like glycated albumin levels in serum and 8-hydroxyguanosine in urine in stroke-prone spontaneously hypersensitive rats (154). Due to its lipophilic nature, resveratrol can bind to lipoprotein particles, which seems crucial for its antioxidant effects (155). Resveratrol consumption increases plasma antioxidant levels and decreases lipid peroxidation (156). It also reduces intracellular ROS and prevents LDL oxidation in endothelial cells (157) by inhibiting lipoxygenases (158). The mechanism by which resveratrol prevents LDL oxidation is based on its ability to chelate copper and scavenge ROS (159).

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a natural polyphenol derived from the rhizomes of the herbs from genus Curcuma, particularly from Curcuma longa (turmeric), Curcuma amada, Curcuma zedoaria, Curcuma aromatic and Curcuma raktakanta. (160–162). It has multiple positive effects on the organism, acting as an antioxidant and decreasing inflammation. Using macrophages, Lin et al. showed that curcumin treatment increased levels of SOD and Cat while decreasing levels of ROS (163). The anti-inflammatory effect of curcumin is most likely associated with its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS) (164). In addition, curcumin positively affects body weight and glucose, increases GPx activity (165), and decreases FFA, triglycerides, and cholesterol concentrations in diabetic rats (15).

Berberine (5,6-dihydro-9,10-dimethoxybenzo [g]-1,3-benzodioxolo [5,6-a] quinolizinium) is a plant alkaloid found and derived from numerous families of plants, such as Annonaceae, Menispermaceae, Papaveraceae, Ranunculaceae, etc. (166). Barberine has been shown to have numerous positive effects such as decreasing cholesterol levels and reducing weight and adipose tissue in obese mice. In addition, berberine decreases obesity- and diabetes-related inflammation (167). In the atherosclerotic mouse model, berberine activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway decreases OxS (15, 168). Ma et al. (169) showed diabetic animal models administered berberine activates the Nrf2 pathway and decreases OxS.

It is important to mention micronutrients with antioxidant properties, such as vitamins. Since the body cannot synthesize sufficient amounts of vitamins, it is necessary to take them through food or supplements. Vitamin E acts as a regulator of cellular metabolism, and its deficiency leads to anaemia, dysregulation of energy metabolism, irregular mitochondrial function, and tissue damage resulting from increased lipid peroxidation (16). Vitamin D deficiency affects muscle function and leads to irregular cardiovascular function. Also, a lack of Vitamin D is connected with disrupted mitochondrial function and thus increased inflammation and OxS (16). However, it should be emphasized that an increased intake of vitamins has the opposite effect, increasing OxS. For example, it is well known that vitamin C has antioxidant properties; it reacts with ROS creating a product with poor reactivity that does not have detrimental effects. On the other hand, vitamin C may undergo the Fenton reaction, in which a highly reactive free radical is formed (170).

Besides the impairment of cellular redox homeostasis in thyroid gland cells, thyroid diseases significantly contribute to systemic redox imbalance. In that way, thyroid diseases are organ-confined and promote histological changes in distant organs by disturbing the vital cellular pathways. Therefore, the simultaneous treatment of thyroid diseases and substituting of nutraceutical antioxidants could beneficially affect different molecular mechanisms enabling the recovery of disturbed redox balance. Se levels are lower in people with thyroid dysfunctions, such as subclinical or overt hypothyroidism (242). In order to determine whether Se supplementation may impact the progression of autoimmune thyroid disease, some trials carried out in regions where the population has a diffusely low or borderline Se status inconsistently suggest that Se supplementation may cause a decrease in thyroid autoantibodies (243, 244). The population heterogeneity, various Se formulations and the length of Se supplementation, as well as different thyroid function test and Se measurement strategies, are among the reasons for the study conclusions inconsistency (244). The benefit of Se supplementation could be expected in patients living in regions with low Se availability or who have low- or sub-optimal Se levels. The supplementation must be attentive as the reference ranges of Se blood levels are narrow, and the risk of insufficient or toxic supplementation is possible (245, 246).

Accumulating evidence support the existence of a thyroid-gut axis and displays important correlations between the composition of the gut bacteria and thyroid function. Dysbiosis, a common finding in thyroid disorders, not only promotes local inflammation of the intestinal membrane but also directly affects thyroid hormone levels via its own deiodinase activity and TSH inhibition. In addition, gut microbiota can modulate the absorption of trace minerals, such as iodine, selenium, and zinc, that are essential for thyroid function, including iron. For instance, iodine deficiency may lead to goiter, whereas high iodine intake may induce thyroid dysfunction in susceptible patients. Supplementation with antioxidative probiotics has shown beneficial effects in thyroid diseases thus representing a potential adjuvant therapy for thyroid disorders. The advances in the field of microbiome research envision the future possibility of personalized treatment with probiotics that are specifically adjusted to individual patients. Nevertheless, more data from adequately powered human studies are required for further evaluation of the impact of gut microbiota on thyroid diseases and the potential for possible therapeutic interventions.

MM wrote the article. ZG wrote the article. SZ wrote the article. ME wrote the article, XG wrote and critically reviewed the article and EI wrote and critically reviewed the article. All authors contributed to the article and approved the submitted version.