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Central European Journal of Immunology
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Review paper

Ghrelin and oral diseases

Sylwia Małgorzata Słotwińska
1

1.
Department of Oral Hygiene, Medical University of Warsaw, Poland
Cent Eur J Immunol 2020; 45 (4): 433–438
Online publish date: 2021/01/30
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Eating food is one of the most complicated behaviours in mammals, especially humans. It is modulated and controlled by a number of endogenous and exogenous factors. One of the key compounds regulating this process is ghrelin, a natural peptide hormone consisting of a chain of 28 amino acids. It occurs in all vertebrates, including fish, amphibians and mammals and in the human body. Ghrelin is produced mainly in the stomach by the parietal cells of the mucous membrane, which is the main source of endogenous ghrelin. Ghrelin was first identified in the stomachs of rats, as an endogenous ligand for the receptor releasing the growth hormone (GH) [1, 2]. The primary function of ghrelin is regulation of the appetite level and its stimulation. Ghrelin is not secreted into the gastrointestinal tract; instead it enters the blood vessels and is distributed throughout the body with blood. It is synthesized and secreted in the stomach, by endocrine X/A type cells. It is also secreted in smaller quantities in the smaller intestine, the pancreas and many other organs, such as kidneys, placenta, thyroid, pituitary gland and hypothalamus [1, 3, 4]. Ghrelin immunoactive cells have been found both in the small intestine and in the large intestine [3]. Ghrelin is also produced by cells of the central nervous system, but in much smaller amounts, as compared to gastric enteroendocrine cells [1]. It is commonly called the hunger hormone. It is also responsible for the body’s energy balance and glucose homeostasis [5]. In experimental animals, the level of ghrelin in the blood serum increases significantly during fasting and decreases after feeding or introduction directly into the stomach. Experimental administration of exogenous ghrelin to rodents causes a rapid increase in appetite and increased food intake, with a significant weight gain [6-8].

The production of ghrelin in the body of healthy people is inseparably connected with the eating process, and the amount of ghrelin in saliva increases during eating. When a body is starved for a long time, ghrelin is released, causing the feeling of hunger and the craving for food. Ghrelin levels decrease as a result of satisfying hunger and the effect of fullness. Daily fluctuations are observed in the case of concentration of this hormone in blood, with an increase before meals, and a sharp decrease after meals [8, 9]. This means that ghrelin is a key regulator of the initiation of eating activities, stimulating the cascade of events preparing the body for the upcoming meal. Ghrelin levels also rise during fasting and during sleep between 10 p.m. and 4 a.m., and decrease for about an hour or two after a meal. Sleep deprivation increases ghrelin levels, therefore increasing the risk of gaining weight. People with severe obesity and those with eating disorders, such as bulimia or anorexia, have consistently high levels of ghrelin, which means they feel hunger regardless of their actual need for food. Ghrelin has very diverse control and modulation effects throughout the body [10]. Its regulatory role is emphasized, both in the central nervous system, especially in the brain, and in peripheral nerves. In experimental studies and clinical observations, ghrelin has been shown to affect many brain structures, which confirms the presence of ghrelin receptors in the brain. Goldstein et al. demonstrated that ghrelin-stimulated secretion of GH in the pituitary gland is critical for protecting the body against hypoglycaemia caused by prolonged fasting [11], which is also associated with weight regulation by increasing body fat and, consequently, reducing energy expenditure [12, 13]. It has also been shown that ghrelin is involved in centrally regulated processes of learning, rewarding, stimulating mood and memory, and in response to stress [8, 14, 15]. However, its peripheral effects include gastrointestinal motility, functioning of the immune system, glucose homeostasis and bone formation [5, 16-21]. Ghrelin was also found in heart cells, which may suggest both its cardiovascular effects and cardioprotective properties. Its protective effect on rodent cardiomyocytes has been described [20, 22, 23]. Studies are also conducted to assess the possible role of ghrelin in anxiety states and in memory disorders and motor dysfunctions [8].

In the light of the observations so far, ghrelin has become the subject of studies evaluating its usefulness in the treatment of many diseases, in particular metabolic syndromes. Shiomi et al. demonstrated the effectiveness of Z-505 (ghrelin receptor agonist) in the treatment of anore-xia after total gastrectomy in an animal model [24]. Drugs that block ghrelin receptors are believed to be useful in the treatment of eating and appetite disorders, especially in the treatment of obesity and anorexia. The development of effective anti-obesity therapy has become a priority in the context of the increase in the global incidence of this disease. According to the World Health Organization, there are currently over 2 billion adults worldwide who are overweight, and nearly 700 million are morbidly obese. Despite modern public health education campaigns, obesity is reaching the proportions of a serious social pandemic, an ever-increasing health problem that remains unsolved in modern society. This situation provides an important impetus to study the mechanisms underlying central appetite regulation with the aim of developing novel strategies for treating eating disorders. Literature on ghrelin contains a great deal of information regarding the role of this hormone in a wide variety of physiological processes. Therefore, many attempts have been made to use ghrelin in pharmacotherapy. However, more than 20 years after the discovery of ghrelin by Kojima and his colleagues, no effective anti-obesity drug related to ghrelin has been introduced into clinical practice; nor have any therapies to treat chronic starvation and cachexia based on knowledge of ghrelin been developed. It seems that the basic problem is the very frequent presence in the human body of the GHSR-1a receptor for ghrelin, which, apart from its typical location in the gastrointestinal tract, is also located in the cells of the pancreas, spleen, myocardium, bones, adipose tissue, thyroid gland, adrenal glands and in the vagus nerve afferents and cells of the immune system [1-4, 25, 26]. Due to the ubiquitous expression of the GHSR-1a receptor, administration of exogenous ghrelin or ghrelin ligand may lead to a cascade of uncontrolled and unintended physiological and pathological reactions. Thus, therapeutic administration of exogenous ghrelin or its derivatives not only does not guarantee effective control of food consumption and selective appetite modulation, but also results in exerting a significant effect on many other central and peripheral processes, which can significantly disturb the complex metabolic balance and homeostasis of the body [27-30]. Moreover, ghrelin plays a key role in central regulation by contributing to the functioning of the hypothalamic-pituitary-adrenal axis. The results of studies suggest that ghrelin acts both peripherally, modulating the function of the gastrointestinal tract via the vagus nerve, and by redistributing the ghrelin GHSR-1a receptor in the gastrointestinal tract, which paves the way for local activity [6-9, 31]. In selected situations, central and peripheral ghrelinergic signalling seem to be complementary, as is the case of glucose homeostasis and visceral pain, as well as gastrointestinal motility regulation, including ghrelin receptors located in the oral cavity [6-9, 14, 23-26, 32].

In the mouth, ghrelin was found in saliva and salivary glands, teeth and gums, and in the taste buds of the tongue epithelium; it is also secreted by mucosal cells and gingival fibroblasts [33-38]. The presence of ghrelin in developmental enamel, especially in odontoblasts and ameloblasts, may suggest its regulatory role in the development of teeth [35]. The concentration of ghrelin in saliva is comparable to the concentration of ghrelin in the peripheral blood serum and in the plasma, which may suggest its effect on the development and course of diseases of the oral cavity [37, 38].

It has been shown that stressful situations, especially in patients suffering from bulimia nervosa (BN), increase the concentration of ghrelin in saliva [38, 39]. It has been proven that ghrelin significantly reduces the expression of proinflammatory cytokines, which may have an important impact on diseases with inflammatory reactions and the body’s response in the process of tissue healing [16, 40]. Warzecha et al. investigated the effect of ghrelin administration on the healing of oral ulcers in rats. Treatment with ghrelin accelerated the healing of oral ulcers in rats with intact salivary glands and in rats with decreased salivary production due to removal of the salivary glands. Increases in blood flow and in cell proliferation in the mucosa were achieved, as well as a decrease in local inflammation in conjunction with a significant decrease in the concentration of pro-inflammatory interleukin 1b (IL-1β) in the mucous membrane [41]. Similar results were obtained by administering exogenous ghrelin preparation to rats with gingival ulcerations for 6 days [42]. In both of these experiments, ghrelin acted as an inhibitor of the inflammatory reaction, in which IL-1β always plays a key role, being a well-known mediator of acute inflammation and the body’s systemic immune response, and a catalyst for the release of a cascade of other pro-inflammatory cyto-kines. IL-1β stimulates the production and release of further inflammatory mediators, such as tumour necrosis factor, platelet activating factor, prostaglandins and other pro-inflammatory interleukins [43]. Administration of the IL-1 receptor antagonist has been shown to slow down and ameliorate the systemic inflammatory response [44-46].

Many immunocompetent cells contain ghrelin receptors [47, 48]. The effect of ghrelin on the immune system is multidirectional and includes the alleviation of septic shock [49], the promotion of thymopoiesis in the course of aging [50], the inhibition of the phagocytic activity of macrophages [51] and blocking the expression of pro-inflammatory cytokines [16]. The local inflammatory response, which can induce uncontrolled production of pro-inflammatory cytokines, is characteristic of chronic periodontitis, a disease involving gradual destruction of the apparatus supporting the tooth in the alveolus, loss of connective tissue attachment, damage to bone structures and the formation of deep periodontal pockets, populated by periopathogenic microorganisms with a high degree of virulence. The cells that play the most important role in defence against microorganisms are the neutrophilic granulocytes. Ghrelin is one of the important mediators in the innate immune response regulated by neutrophils [16, 40]. Local inflammation such as chronic periodontitis has a huge impact on the overall health of the body. The relationship of periodontitis with many systemic and chronic diseases was proven, especially with type 2 diabetes, in the course of which low concentrations of ghrelin in peripheral blood serum were detected [52, 53]. However, when diabetes is accompanied by periodontitis, we often observe increased concentrations of ghrelin in plasma and peripheral blood serum, as compared to the control groups [54]. The level of ghrelin in the gingival pocket fluid and other biomarkers associated with diabetes increases significantly [40, 54, 55]. It is believed that the observed tendency to increased ghrelin concentrations in many patients with type 2 diabetes is caused by the synergy effect of chronic periodontitis and type 2 diabetes [54]. Patients with chronic periodontitis have significantly higher concentrations of ghrelin in the peripheral blood serum, as compared to the control group [55]. High concentrations of ghrelin are also found in many chronic inflammatory conditions, such as Leśniowski-Crohn disease and inflammatory bowel disease [56].

Very interesting studies concern the role of ghrelin in the process of angiogenesis. The results of these studies are inconclusive. Ghrelin has been shown to stimulate the formation of new capillaries in rat myocardium [57]. In contrast, other authors found that ghrelin inhibits in vitro angiogenic activity of brain cells [58]. The gradual inhibition of the angiogenesis process, progressing with age, is the result of ghrelin deficiency, caused by physiolo-gical changes occurring in the body aging process [59]. In turn, excessive angiogenesis is one of the elements of the pathogenesis of periodontitis. Already in the 1990s, it was demonstrated that the concentration of one of the angiogenic factors – vascular endothelial growth factor in saliva and gingival fluid – in people with periodontitis is higher than in the group of people with clinically healthy periodontium (p < 0.05), and correlates with the clinical periodontal condition [60, 61].

The relationship of decreased ghrelin concentrations with pathological conditions occurring in the oral cavity, such as changes in the mucous membrane, dental, gum and periodontal diseases, as well as abnormalities in the composition and secretion of saliva in the course of eating disorders, mainly in anorexia nervosa and BN, has been the subject of studies for many years. Patients with these diseases display low bone mass combined with ossification disorders, frequently including advanced osteoporosis, as well as mucosal atrophy and dental erosion, and frequent swelling of the salivary glands with accompanying pain [62-69]. The analysis of the aetiology and pathophysiology of eating disorders indicates that the dysregulation of the network controlling the processes related to the eating function causes aberrations in eating habits and may contribute to the development of many other diseases. Ghrelin, as mentioned earlier, increases the appetite because its active form, acylated ghrelin, may cross the blood-brain barrier and thus activate neurons that increase appetite [70-73].

Oral ghrelin comes primarily from the salivary glands, where it is produced. Saliva production is controlled by the sympathetic and parasympathetic autonomic nervous systems. Thus, the central regulation of saliva production by the neural network may affect the production of ghrelin in saliva [74]. Based on many years of studies and observation, Ohta et al. argued that oral ghrelin is one of the important regulatory factors of the innate immune response to inflammation [75]. Reports of a relationship between ghrelin and periodontitis are contradictory. A positive correlation of blood concentrations (r = 0.708; p < 0.05) was demonstrated between ghrelin and IL-1β in experimental periodontitis in female rats, but only in the postmenopausal period [76].

Nokhbehsaim et al. demonstrated the important role of Fusobacterium nucleatum – bacteria causally associated with periodontitis – and IL-1β in the modulation of ghre-lin GHS-R1a receptor expression in the course of perio-dontitis [77-79].

There are numerous reports indicating the participation of ghrelin in the pathogenesis of many neoplastic diseases [80-84]. Ghrelin is believed to play a special role in the proliferation of cancer cells and in the development of neoplastic metastases [85, 86]. Ghrelin receptors have been discovered in oral cancer [87]. The assessment of serum ghrelin concentration and the degree of ghrelin receptors’ expression in tissues may aid in the diagnosis and differentiation of oral cancers [87-89]. The numerous presence of ghrelin receptors in cancer cells is considered an important target in the treatment of neoplasms [89].

Ghrelin is a hormone whose multidirectional mechanism of action is not yet fully understood. For years, experimental studies on the diagnostic and therapeutic use of ghrelin have been carried out [90]. However, its ubiquitous occurrence in the human body and its very diverse participation in metabolic processes may prove to be a significant obstacle in achieving the expected clinical effect of ghrelin as an effective drug in selected disease units.

Notes

[1] Conflicts of interest The author declares no conflict of interest.

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Jeffery PL, Herington AC, Chopin LK (2002): Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines. J Endocrinol 171: 7.

85 

Tsung CL, Hsiao M (2017): Ghrelin and cancer progression. Biochim Biophys Acta Rev Cancer 1868: 51-57.

86 

Chopin L, Walpole C, Seim I, et al. (2011): Ghrelin and cancer. Mol Cell Endocrinol 340: 65-69.

87 

Alnema MM, Aydin S, Ozkan Y, et al. (2010): Ghrelin and obestatin expression in oral squamous cell carcinoma: an immunohistochemical and biochemical study. Mol Cell Biochem 339: 173-179.

88 

Lou J, Liu L, Zhang W, et al. (2019): Differential expression of ghrelin and GHSR via the Mtor pathway during the dynamic carcinogenic process involving oral, potentially malignant disorders. Biosci Rep 39: BSR20192102.

89 

Nikolopoulos D, Theocharis S, Kouraklis G (2010): Ghrelin: a potential therapeutic target for cancer. Regul Pept 163: 7-17.

90 

Collden G, Tschop MH, Muller TD (2017): Therapeutic potential of targeting the ghrelin pathway. Int J Mol Sci 18: 1-29.

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88. Lou J, Liu L, Zhang W, et al. (2019): Differential expression of ghrelin and GHSR via the Mtor pathway during the dynamic carcinogenic process involving oral, potentially malignant disorders. Biosci Rep 39: BSR20192102.
89. Nikolopoulos D, Theocharis S, Kouraklis G (2010): Ghrelin: a potential therapeutic target for cancer. Regul Pept 163: 7-17.
90. Collden G, Tschop MH, Muller TD (2017): Therapeutic potential of targeting the ghrelin pathway. Int J Mol Sci 18: 1-29.
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