Oral mucosal diseases and psychosocial factors: progress in related neurobiological mechanisms

Abstract

The aetiology of oral mucosal diseases, such as recurrent aphthous ulcer (RAU), oral lichen planus (OLP) and burning mouth syndrome (BMS), involves many factors, and it remains difficult for clinicians to effectively relieve disease symptoms and formulate coping strategies. With the rapid development of psychology, the role of mental and psychological factors in RAU, OLP and BMS has gradually attracted researchers attention, but the specific mechanism has not been completely determined. This narrative review describes the potential neurobiological mechanism of oral mucosal diseases and detailed psychological factors after introducing relevant research into psychological factors and oral mucosal diseases. Future research strategies and innovations needed to understand and treat oral mucosal diseases and psychological factors, as well as how to prevent oral mucosal diseases by regulation of the neuroendocrine system, are also discussed.

Introduction

Oral mucosal diseases are not only related to local mucosal damage, but also to systemic diseases, and they may be aggravated or induced by anxiety, depression, and stress. ¹ Oral mucosal diseases may be a direct manifestation of negative emotions or an indirect result of psychological abnormalities, ² but their psychosomatic causes have not been comprehensively clarified. There are few studies on the relationship between oral mucosal diseases, negative emotions, and potential pathogeneses, and due to contradicting research conclusions, the relationship between them is controversial. For the present narrative review, the PubMed, Web of Science and Chinese databases (China National Knowledge Internet, WANFANG DATA and Chinese Technical Periodicals) were searched for articles published before 1 July 2023, using the search terms (“oral mucosal disease” or “recurrent aphthous ulcer” or “oral lichen planus” or “burning mouth syndrome”) and (“psychological factors” or “anxiety” or “depression”). Randomized, quasi-randomized or prospective controlled clinical trials, reports, guidelines and letters to the editor, published in English and Chinese, were included. Relevant studies are discussed, focussing on the relationship between oral mucosal diseases and negative emotions, and potential neurobiological mechanisms, with the aim of providing suggestions for future research.

Negative emotions and oral mucosal diseases

Recurrent aphthous ulcer

Recurrent aphthous ulcer (RAU) is the most common ulcerative disease involving the surface of the oral mucosa. It often starts in childhood, and the prevalence rate in the general global population is about 20%. ³ Most lesions occur in non-keratinizing mucosae, such as those of the buccal cavity and tongue, with periodic and self-limiting characteristics. The clinical manifestations are recurrent, round, well-defined ulcers of different sizes on the surface of the mucosa, with a soft base in the centre, redness around the edge, and the upper part covered with yellow–white exudate, accompanied by burning symptoms.^4,5 The clinical classification includes minor, major, and herpetic types. The potential causes of RAU include trauma, body oxidation–antioxidation imbalance, genetic predisposition, the influence of systemic diseases, and stress. Stress is suggested to be the biggest factor inducing RAU, which mainly affects women, and compared with housewives and other professions, students are shown to be more susceptible to stress. Anxiety, stress, and depression are more common in patients with a history of RAU than in healthy people, which suggests that negative emotions may promote the recurrence of lesions. ⁶ One cross-sectional study that evaluated the clinical and demographic factors of RAU found that the condition was related to anxiety but not depression. ⁷ Conversely, by evaluating the relationship between salivary cortisol levels and anxiety and depression in patients with RAU, other researchers found RAU to be related to depression but not anxiety. ⁸ In another study, no correlation was found between RAU and stress, anxiety, and depression. ⁹ Thus, the conclusions of these studies are contradictory, and the relationship between RAU, anxiety, and depression deserves further exploration.

Oral lichen planus

Lichen planus (LP) is a chronic inflammatory disease that may occur in many parts of the body, in which the skin and oral mucosa are often involved. Worldwide, up to 77% of patients with LP have oral mucosal lesions, with oral lichen planus (OLP) prevalent in 5% of the general adult population (male-to-female ratio = 2:1).^10,11 The lesions often involve the buccal mucosa and have various morphologies. Clinically, lesions are divided into two types: erosive (including erosive, atrophic, and blister types) and non-erosive (including reticular, papular, and plaquing types). ¹⁰ Often, the lesions have a typical appearance of stripes and a reticular distribution on both sides of the oral mucosa, but clinical features and pathological examination need to be combined for an exact diagnosis.

In recent years, OLP has been categorized as a potentially malignant disease; consequently, patients with OLP have a high incidence of hypochondria (illness anxiety) and a fear of cancer, and their long-term negative stress responses may have an impact on lesions. The results of one study showed that the prevalence of anxiety and sleep disturbance was higher in patients with OLP compared with the rate in healthy people. ¹² Compared with patients with non-erosive OLP, patients with erosive OLP reported a higher degree of pain and a prevalence of depression. However, that study also found that in some patients with OLP, particularly those with multiple oral mucosal lesions, the subjective perception of pain emanated mainly from peripheral and/or central neuropathy and was not significantly associated with negative emotions. However, if a patient has psychological abnormalities and sleep disorders, their pain will be further aggravated with the development of the disease. ¹²

Burning mouth syndrome

Burning mouth syndrome (BMS) is defined as a chronic and painful orofacial disorder that is commonly seen in perimenopausal or postmenopausal women. It is characterized by a persistent burning pain in the oral mucosa (mainly the tongue, lips, and palate), a dry mouth, a subjective bitter/metallic taste, and numbness of the oral mucosa. There may also be other symptoms, such as subjective changes in the shape of the tongue. Clinically relevant examinations show no obvious positive features, and the symptoms, which are mostly moderate to severe, usually involve both sides. ¹³

The exact cause of most BMS cases cannot be found clinically, but it is speculated to involve the interaction between local, systemic, neuropathological, and psychological factors. A systematic review involving middle-aged and elderly subjects revealed a moderate association between BMS and anxiety disorder, but a lower correlation between BMS and depression disorder. ¹⁴ Women were shown to be at higher risk of developing BMS than men, and in addition to anxiety and depression, the study showed that personality characteristics, sleep disorders and bio-psychosocial changes worsened in middle-aged and elderly patients with BMS. ¹⁴ Because most of the results analysed by the researchers were from cross-sectional studies, the causal relationship between anxiety disorder, depressive disorder and BMS could not be determined. ¹⁴ Moreover, BMS is also frequently present in patients with Parkinson’s disease, characterized by dopamine dysregulation (confirmed by positron emission tomography) in the nigrostriatal dopaminergic pathway. ¹⁵ As a potential biomarker for diagnosis of Parkinson’s disease, pathological α-synuclein accumulates abnormally in the oral mucosa of patients with Parkinson’s disease. ¹⁶ Both the oral mucosa and nervous system are derived from ectodermal tissue, thus, Parkinson’s disease and BMS may have common specific characteristics.

Neurobiological mechanisms

Stress affects the neuroendocrine and immune systems

Psychological stress affects the normal nerve–endocrine–immune pathway of the human body, leading to over-activation of the hypothalamus–pituitary–adrenal (HPA) axis and sympathetic nerve–adrenal medulla. ¹⁷ The hypothalamus–pituitary–gonad (HPG) axis is regulated by the HPA axis, which can inhibit or overactivate endocrine and immune systems, and the secretion of corresponding hormones, cytokines and proteins changes accordingly. ¹⁸ This may damage the oral mucosa and induce OLP and RAU. Moreover, because erosive OLP easily ruptures repeatedly and RAU easily relapses,^5,19 patients are under pressure for a prolonged period of time, which may result in anxiety and depression, thus accelerating the disease progress (Figure 1).

Figure 1.

Schematic showing the effects of stress on the neuroendocrine and immune system of the body, and the associated induction of oral mucosal diseases. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; NK, natural killer; PRL, prolactin. Figure created with BioRender.com.

Neuroendocrine dysfunction

Under acute or chronic stress conditions, hyperfunction of the HPA axis may be the neurobiological basis of depression and anxiety. ²⁰ Studies observing brain imaging in patients with depression and anxiety disorders have found that the volume of the hypothalamus, and the interaction and coherence of the endocrine and autonomic nervous systems, are affected by stress. ²¹ The hypothalamus and marginal area, as key parts of the fine neuroendocrine circuit, release excessive corticotropin-releasing hormone after being affected by stress, and corticotropin-releasing hormone further regulates the secretion of adrenocorticotropic hormone. Inactivation of the HPA axis in response to corticotropin-releasing hormone and over-activation of the HPA axis may lead to the development of depression and anxiety. ²² In addition, patients with anxiety and depression usually exhibit sympathetic nerve–adrenal medulla axis hyper-responsiveness. Stress induces a considerable release of catecholamine hormones from the adrenal medulla, and the release of epinephrine, norepinephrine, and high levels of adrenal steroid hormones from the adrenal cortex are risk factors for major depressive disorder. ²³

The role of glutamine

Glutamate participates in the transmission of excitatory neurotransmitters in the central nervous system. In this process, glutamic acid can be converted into glutamine and γ-aminobutyric acid, the latter of which is an inhibitory neurotransmitter. Dysregulated levels of these two central neurotransmitters, and related receptor balance, is the pathophysiological basis of diseases such as depression and anxiety. ²⁴ Glutamine participates in synthesis of the antioxidant glutathione, resulting in increased levels of intracellular antioxidants, thus promoting the scavenging of excessive oxygen free radicals via glutathione and protecting cell membranes and proteins from oxidative stress damage to improve cellular antioxidant capacity. Researchers have also found that glutamine levels in the saliva of patients with OLP is inversely correlated with anxiety and depression scores. ²⁵

In addition, glutamine can specifically induce the expression of heat-shock protein 70 (HSP70), a type of stress protein that plays a non-specific protective role in tissue cells against stress injury, while its deletion leads to an increase in apoptosis. One study found that specific concentrations of cortisol, oestrogen, and other stressors reduced the expression of HSP70 in normal oral mucosa, reduced cell activity, and even led to cell necrosis. ²⁶ This may increase the incidence of RAU and OLP. Therefore, glutamine deficiency may aggravate stress injury in patients with oral mucosal diseases and promote the development of such diseases.

Effects of cortisol and dehydroepiandrosterone

Cortisol is a glucocorticoid secreted by the adrenal cortex that has a variety of biological effects, including anti-inflammation and mood regulation, and it can affect the stress response of the body. However, under a state of chronic stress, despite the excessive secretion of cortisol, inflammatory damage and emotional disorders are aggravated. This suggests dysfunction of the glucocorticoid receptor in the body, so that anti-inflammatory effects cannot be exerted. One study found that cortisol–norepinephrine interactions were associated with underlying anxiety and depression. ²⁷ In addition, dehydroepiandrosterone (DHEA), an endogenous antagonist of cortisol, can be secreted by the adrenal cortex, the central nervous system, and the gonads. Its sulfated form is DHEA sulfate, and DHEA has been shown to be involved in the regulation of brain perception processes, such as neuropathic pain. ²⁸

Because levels of salivary DHEA and cortisol are closely related to levels of serum free DHEA and cortisol secretion, detection of DHEA and cortisol in saliva is often used to measure stress levels, anxiety, and depression. ²⁹ By detecting salivary cortisol and DHEA in patients with RAU, researchers found that the average level of salivary cortisol increased, the average level of salivary DHEA decreased, and the ratio of salivary cortisol to DHEA increased relatively. ³⁰ In addition, salivary DHEA level was inversely correlated with anxiety and depression scores. ³⁰ Stress states, such as anxiety and depression, will stimulate the HPA axis and increase salivary cortisol secretion, thus reducing salivary DHEA secretion and increasing the prevalence of RAU. Oral mucosal epithelial mucin 1 (MUC1) can protect mucosal epithelial cells and then interfere with physiological activities. The expression level of MUC1 has been shown to positively correlate with the level of DHEA, and to be inversely correlated with cortisol and the cortisol/DHEA ratio. ³¹ Another study detected serum cortisol levels in patients with erosive and non-erosive OLP and evaluated the anxiety and depression status of those patients. The comprehensive average serum cortisol levels of the patients with OLP were found to be higher than those of healthy controls, and negative emotions were a related factor for the occurrence and prognosis of OLP. ³² Generally, compared with healthy people, patients with BMS have lower levels of DHEA and higher levels of cortisol.^33,34 Therefore, salivary cortisol and DHEA can be used as saliva biomarkers to evaluate stress in patients with oral mucosal diseases.

Regulatory effect of dual hormones

High cortisol levels enhance the negative correlation between depression, testosterone, and DHEA in women. Testosterone is also inversely correlated with anxiety, albeit not sharply. ¹⁸ The effect of cortisol is based on the fact that stress and cortisol inhibit the secretion of oestrogen and testosterone, and stress is closely related to mood disorders. ³⁵ The interactions of cortisol with the DHEA–depression association in girls suggest that there is an effect modification within the HPA axis. ¹⁸ Furthermore, the interaction between cortisol and testosterone supports the dual-hormone hypothesis, in which the HPA axis regulates the HPG axis and the relationship between human cognition and behaviour. HPG is the neuroendocrine axis that regulates the reproductive function of the body. Gonadotropin-releasing hormone, synthesized and secreted by the hypothalamus, enters the pituitary through the pituitary portal system and regulates the secretion of gonadotropins, such as luteinizing hormone, follicle-stimulating hormone and prolactin, thereby promoting gonadal secretion of sex hormones, such as oestrogen and testosterone. ³⁶ Long-term pressure inhibits this axis, and the levels of oestrogen and testosterone secreted by the gonads decrease, which may lead to the occurrence and development of oral mucosal diseases.

One study showed that mean serum testosterone levels were lower in premenopausal women with RAU than in healthy premenopausal women, and lower testosterone levels increased the risk and frequency of RAU. ³⁷ RAU is associated with the onset of menstruation or the luteal phase of the menstrual cycle, which is also the period when MUC1 expression in oral mucosa decreases. Salivary cortisol can affect the course of RAU by affecting the expression of MUC1. ³¹ In addition, a reduction in the oestrogen levels of perimenopausal women can easily lead to a decrease in the degree of keratinization of the squamous epithelium of the oral mucosa and a decrease in the anti-friction ability of the mucosa; consequently, normal oral activities may cause excessive stimulation of the mucosa, leading to BMS. ³⁸ Decreased levels of oestrogen may also lead to an enhancement in the nerve growth factor signalling pathway, an increase in the activity of transient receptor potential vanillin 1, or a reduction in the oestrogen-dependent regulation of P2X purine receptor 3 in sensory neurons, which will enhance the body’s sensitivity to pain and aggravate BMS symptoms. ³⁹ At the same time, low oestrogen levels in patients with BMS may lead to a disorder in monoamine neurotransmitters (including norepinephrine, serotonin, and dopamine), which, in turn, causes depressive symptoms and may accelerate the development of BMS. Therefore, the emotional disorders of patients with oral mucosal diseases may be affected by regulation of the HPA axis by the HPG axis.

Dual hormones affect immune function

In a stress state caused by oral mucosal diseases, hyperfunction of the HPA axis and regulation of the HPG axis by the HPA axis can affect the stability of the immune system. Patients with RAU who have negative emotions also have elevated levels of cortisol, ⁴⁰ while levels of testosterone are decreased. ³⁷ Testosterone inhibits the cyclooxygenase pathway of arachidonic acid metabolism, inhibits the synthesis and release of prostaglandins, increases the expansion of suppressor T cells, exerts anti-inflammation effects, and inhibits the autoimmune response. ⁴¹ One study demonstrated that the percentage of CD3+ and CD8+ peripheral blood lymphocytes was higher in patients with RAU than in healthy controls, and the levels of immunoglobulin (Ig)G, IgA, and complements C3 and C4 were considerably higher versus healthy controls, indicating that the pathogenesis of RAU may be related to the hyperactivity of cellular and humoral immunity. ⁴² Due to the inhibition of testosterone secretion by stress and cortisol, the immune function of the body may be overactivated, and RAU may be induced.

In addition, the interaction mechanism between OLP, anxiety, and depression may be mediated by the common immune activation state of these two diseases. Three-motif protein 21 (TRIM21) belongs to the three-motif protein family. As a common target for autoantibodies, it plays an important role in the regulation of autoimmunity, and can promote the activation of nuclear factor-kappa B (NF-κΒ), thereby triggering the production of immune factors and various pro-inflammatory cytokines, such as interleukin (IL)-6 and type-I interferon.^43,44 One study showed high expression of the TRIM21 gene in buccal lesions in OLP. Levels of TRIM21/NF-κΒ in the supernatant of CD3+ and CD4+ T cells under normal conditions were significantly reduced after treatment with oestradiol and testosterone compared with controls, suggesting that the expression of TRIM21 was inhibited, which led to the regulation of IL-6. The decreased expression of cytokines, such as type-I interferon, improves the immune imbalance of T cells. ⁴⁵ Therefore, testosterone and oestradiol can correct the imbalance of the autoimmune system and delay the occurrence and development of OLP via TRIM21-mediated signal transduction. This may confirm the dual-hormone hypothesis to some extent.

Influence of cytokine disorder

Cytokines are mainly produced by immune cells. Microglia in brain regions, such as the hypothalamus and basal ganglia of the central nervous system, and other central nervous system cells, such as neurons and astrocytes, release pro-inflammatory cytokines. There is evidence that the immune system of patients with depression is imbalanced, with immune activation (increased release of cytokines, such as IL-1, IL-6, tumour necrosis factor [TNF]-α and acute reaction proteins) and immunosuppression (decreased lymphocyte proliferation or natural killer-cell activity of T cells and decreased number of helper T cells). ⁴⁶

The HPA axis can be activated by IL-1, IL-6, and TNF-α. High cortisol levels in the blood directly stimulate indoleamine 2, 3-dioxygenase in immune cells, such as macrophages and dendritic cells. Interleukins and interferons stimulate indoleamine 2, 3-dioxygenase to increase its activity, leading to most of the tryptophan metabolism in the tryptophan–kynurenine pathway, significantly reducing serotonin synthesis, and affecting both sleep and emotional regulation. High tryptophan–kynurenine levels also trigger the glutamatergic system, with excitatory glutamatergic projections to a subset of neurons in the lateral hypothalamus/perifornical area strongly associated with anxiety disorders dependent on corticotropin-releasing hormone cells. ⁴⁷ An increase in tryptophan–kynurenine levels can also lead to the production of reactive oxygen species and nitrogen free radicals, causing oxidative stress, which, in turn, leads to local tissue damage and the activation of inflammatory reactions. Patients with OLP have been shown to exhibit significantly increased oxidative stress markers and decreased antioxidant markers in saliva and serum/plasma. ⁴⁸ In patients with RAU, the levels of TNF-α, IL-2 and total oxidation state is shown to be increased, while the level of IL-10 is decreased. ⁴⁹ Abnormal cytokine activity may accelerate lipid peroxidation and lead to the increase of serum oxidative stress, which plays an important role in oxidative/antioxidant defence in patients with RAU. ⁴⁹ In addition to the central nervous system, pro-inflammatory cytokines, such as IL-6, TNF-α, and type-I interferon, may also be released from the periphery of the body to induce a local inflammatory response. This demonstrates that hyperfunction of the HPA axis may enhance local inflammatory responses and induce oral mucosal diseases.

Summary and prospects

Emotional disorders, such as anxiety and depression, can cause dysfunction of the nervous, endocrine and immune systems, which may be risk factors for oral mucosal diseases, such as OLP, RAU and BMS, but there remains a paucity of relevant studies. Future investigations should include larger prospective studies with longer follow-up periods, based on different age groups in different countries/regions, to evaluate the relationship between oral mucosal diseases and depression and anxiety disorders. In addition, more research on the correlation between oral mucosal diseases and other systemic diseases is required, possibly deriving insight from the treatment of systemic diseases. Moreover, attention should be paid to investigating the biomarkers of psychological factors of oral mucosal diseases, as the discovery such biomarkers may facilitate exploration of the pathogenesis of diseases from the molecular level.

There has been close cooperation between multidisciplinary teams that include stomatologists, psychiatrists, neurologists and psychologists to evaluate multiple diseases and individualized treatment for patients with oral mucosal diseases such as RAU and BMS. In the prevention and control of diseases, timely drug treatment of dysregulated hormone levels in the body is required to regulate autoimmunity and maintain the homeostasis of oral mucosa. In addition, various simple and easy non-drug treatments should be encouraged, such as avoidance of alcohol and tobacco, overwork, lack of sleep and other factors leading to sympathetic hyperactivity. Optimizing the diet, such as by supplementation of antioxidant vitamins (vitamin A, C, and E) and minerals (zinc and iron), may enhance oral mucosal resistance. Appropriate physical exercise not only utilizes part of the blood sugar produced by diet, controls cortisol levels, and reduces inflammation, but also improves autoimmunity and reduces psychological stress. The balance between the neuroendocrine and immune systems may be improved by optimizing diet and exercise to reduce the prevalence of oral mucosal diseases.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231218619 - Supplemental material for Oral mucosal diseases and psychosocial factors: progress in related neurobiological mechanisms

Supplemental material, sj-pdf-1-imr-10.1177_03000605231218619 for Oral mucosal diseases and psychosocial factors: progress in related neurobiological mechanisms by Huirong Zhou and Xiaoping Lin in Journal of International Medical Research