The impact of metabolic disorders on management of periodontal health in children

Periodontitis is a chronic inflammatory disease caused by plaque biofilm which shares risk factors with systemic chronic diseases such as diabetes, cardiovascular disease, and osteoporosis. Many studies have found increased prevalence and rate of progression of periodontal disease in children with common metabolic disorders. Although the causal relationship and specific mechanism between them has not been determined yet. The aim of this paper is to progress on the impact of metabolic disorders on periodontal health in children and the underlying mechanisms, which provides new evidences for the prevention and intervention of metabolic disorders and periodontitis in children.

discomfort, impaired mastication, and eventual tooth loss.Not only that, periodontal diseases could even contribute to systemic inflammation.Recent studies have learned that not all individuals are at equal risk of developing periodontitis.Periodontitis with systemic diseases often has the characteristics of earlier onset, faster progression, more severe destruction, and worse response to treatment. 24][5][6] Due to the particularities of children's growth and development, fewer studies have focused on the relationship between periodontal health and systemic diseases at this stage.However, preventive interventions in early life were found to be more beneficial than those in adulthood. 7Current epidemiological works found early disease experience could influence the risk of developing the same diseases in adulthood, especially metabolic diseases and chronic infections. 8The effects of these chronic inflammatory diseases on pediatric patients may also be long-lasting.The aim of this review is to focus on the impact of common metabolic diseases on periodontal health in children, and to provide a theoretical basis for a better understanding of the potential mechanism of systemic metabolic diseases on periodontal disease.

| DEVELOPMENT OF PERIODONTAL TISSUES IN CHILDREN AND ADOLESCENTS
Compared with adult periodontal health, children's periodontal health receives less attention.Due to the complexity of growth and development in childhood and adolescence (i.e., the structural and functional changes of periodontal structure during the eruption and exfoliation of teeth, [9][10][11][12] the establishment and maturation of oral microflora, [13][14][15][16] and the gradual development of the immune defense system 17 ), which means more attention should be paid to distinguishing the pathological process and normal changes of periodontal tissue with age.
Periodontal tissue consists of periodontal ligament, cementum, and alveolar bone.Typically, children will go through primary dentition, mixed dentition, and young permanent dentition during the growth and development.Each stage has its own characteristic physiological condition of periodontal tissue.Periodontal tissue in deciduous dentition has several characteristics: 1.The color of gingiva is pale red for rich blood vessels (the color will become lighter with age).The epithelium is thin, the degree of keratosis is poor, and the connective tissue of the lamina propria is loose. 182.The free gingiva of deciduous teeth is slightly thicker than that of adults, with rounded edges.The width of the attached gingiva is wider in adults than in children. 193. The periodontal ligament is wider and the fiber density is lower than that of adults.The alveolar bone has less bone trabecula and calcification, more bone marrow space, and more blood supply and lymphatic drainage. 20,21e to the changes of hormone levels, the replacement of primary and permanent teeth and the rapid growth of maxillofacial bone in mixed dentition, there are diverse characteristics and individual differences: 1. Gingival may have a darker appearance 22 2. Root migration of junctional epithelium.It is generally believed that the distance between the cementum enamel junction and the alveolar bone crest (CEJ-ABC) is 1-2 mm in the deciduous stage, indicating that the height of alveolar bone is normal. 18When the alveolar bone is adjacent to the replaced primary teeth or erupted permanent teeth, the distance of CEJ-ABC greater than 2 mm is considered physiological.In the study of deciduous teeth in vitro, it was found that 94% of deciduous molars had attachment loss, with an average value of 0.26 ± 0.32 mm. 22his tiny loss of attachment has no clinical significance and does not necessarily prove the existence of periodontitis, as it may be physiological.Many scholars have their own understanding of this loss of attachment, which may be related to inflammation, marginal periodontitis, or tooth eruption.The apical migration of the junctional epithelium has been related to the physiological apical displacement of the dento-gingival junction during the eruption of human permanent teeth and the increase in the distance of CEJ-ABC. 22A non-linear increase in the distance from the CEJ to the ABC takes place with age, this phenomenon may be related to facial growth patterns. 23During facial growth, the maxilla and mandible are displaced in an anterior and inferior directions (primary displacement), a "space" is created and alveolar bone remodeling takes place with a consequent vertical drift of the teeth. 24Tooth eruption may take place at a faster rate than the ABC deposition.Another factor that should be considered is that the root migration of junction epithelium may be related to the loss of adjacent primary teeth or the eruption of permanent teeth. 25owever, in most cases, the 2 mm CEJ-ABC distance may be considered as the boundary of "healthy" alveolar bone height.In conclusion, due to the special nature of dental replacement in children and adolescents during growth and development, periodontitis cannot be defined as precisely as it is in adulthood.Therefore, the periodic examination of periodontal tissues is critical for children.

| PREVALENCE, DIAGNOSIS AND CLASSIFICATION OF CHILDREN'S PERIODONTAL DISEASES
Periodontal disease generally refers to chronic inflammation of periodontal supporting tissues including gingiva, periodontal ligament, and alveolar bone. 26Periodontal diseases are recognized nowadays as epidemics in children, adolescents, and adults, though they were often considered in the past to be a disease associated with aging.Periodontal health problems in children have not received as much attention as adult periodontal diseases.However, there is less evidence in prospective long-term studies that periodontitis symptoms in childhood strongly predict the risk of periodontal disease in adulthood.In a longitudinal study spanning 32 years, people with high levels of dental plaque as children and adolescents experienced the highest levels of dental caries and periodontal disease as adults aged. 27A study of adolescents with severe dental caries in early childhood found that they were more than four times more likely to develop dental caries than age matched controls.They have a higher prevalence of periodontitis, more likely to be overweight or obese, and have a poorer quality of life related to oral health. 28e classification system of periodontitis agreed at the 1999 International Workshop is generally used at present.It includes gingival diseases, chronic periodontitis, aggressive periodontitis, periodontitis related to systemic diseases, necrotizing periodontal diseases, abscesses of the periodontium, and periodontitis associated with endodontic lesions. 29The basic periodontal examination has been advocated to screen for periodontal diseases in adults.According to the American Academy of Pediatrics and Dentistry, 30 children and adolescents should have periodic periodontal assessments and records.It includes the community periodontal index and X-ray film observing the shape of alveolar bone edge for identifying early signs of periodontal destruction.The definition of periodontitis cases depends to a large extent on the disease degree (the number of affected teeth) and the specific threshold of the disease severity (the depth of periodontal pockets of affected teeth, degree of attachment loss and alveolar bone loss).Thus, the estimation of the prevalence of periodontitis in different populations is essentially different.The prevalence of periodontitis in children and adolescents ranges from 2.2% to 80%.In the majority of the population, more than 70% of children over 7 years old suffer from periodontitis. 31,32Loss of periodontal attachment and supporting bone can be found at one or more sites in 5%-9% of children aged 5-11 years and in 5%-46% of children aged 12-15 years. 33A study found that the prevalence of gingivitis among American teenagers reached 82.1%. 34Other studies around the world have reported similar results, with the high prevalence of periodontitis in children and adolescents. 35,36According to the epidemiological data, periodontal diseases in children and adolescents are mainly characterized by mild and chronic periodontitis, but at this stage, severe periodontal diseases involving the entire dentition can also occur, and most of the indications are related to systemic diseases.Next, we will summarize the common metabolic diseases in children related to periodontitis.

MANIFESTATIONS IN CHILDREN
Periodontitis, as a chronic inflammation, is epidemiologically linked to many chronic inflammation driven diseases. 37,38In recent years, there has been a growing body of research on periodontitis and systemic health.The systemic oral health connection is not only the result of common risk factors, but is driven in large part by a variety of microbeinduced immune mechanisms. 39,40Host immune responses are tightly intertwined with metabolism, and dysfunction of this integrated system may contribute to chronic metabolic inflammatory diseases such as obesity, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). 40Chronic low-grade inflammation is a unifying feature and contributing factor to these diseases.Thus, at least in principle, metabolic diseases may affect periodontal inflammatory conditions by increasing the systemic inflammatory burden. 41,42At the same time, periodontal diseases are a common manifestation of some systemic diseases and may have important diagnostic value and therapeutic implications.

| Obesity
Obesity is a chronic metabolic disease, which will lead to a systemic inflammatory state and insulin resistance.Obesity increases the risk of many chronic diseases, including hypertension, dyslipidemia, diabetes, cardiovascular disease and osteoarthritis, with a significant impact on children's physical and mental health.Overweight and obesity among children and adolescents have become one of the most serious global public health concerns in the 21st century.In the past 30 years, the global prevalence of childhood obesity has increased significantly. 43A study systematically estimated the prevalence of overweight and obesity among children (<20 years old) and adults in 195 countries from 1980 to 2015.It found that since 1980, the childhood obesity rate in more than 70 countries has doubled, and that in some developing countries, the childhood obesity rate has roughly tripled.In many countries, the growth rate of childhood obesity has been higher than that of adult obesity. 44n China, the latest national prevalence estimates for 2015-2019 were 6.8% for overweight and 3.6% for obesity in children younger than 6 years, 11.1% for overweight and 7.9% for obesity in children and adolescents aged 6-17 years, nearly double compared with 2005. 45eeves at al. found that a 1-kg increase in body weight may increase the risk of periodontal disease by 6% in the group of obese teenagers over 17. 46 A cross-sectional study found a significant increase in the values of periodontal disease indicators and a higher percentage of pockets with a probing depth exceeding 4 mm in obese children aged 6-13 compared to peers with normal body weight. 47Moreover, an increased expression of TNF-α existed in gingival crevicular fluid samples from the obese children. 48,49In conclusion, obese children and adolescents are at a higher risk of periodontal disease.

| Diabetes mellitus
Diabetes can be divided into type I and type II diabetes.Type 1 diabetes mellitus (T1DM) is a type of diabetes caused by destruction of pancreatic beta cells and absolute insulin insufficiency.It usually starts in adolescence and presents as a severe disease state with ketoacidosis.Type 2 diabetes is a type of diabetes mainly caused by insulin resistance or accompanied by insufficient insulin secretion for various reasons, accounting for more than 90% of diabetes patients.The patients were characterized by hyperglycemia, relative insulin deficiency, insulin resistance, etc. Type 1 diabetes is still the most common metabolic disease in children.The incidence rate of type 1 diabetes increases with age, reaching its peak around 10-14 years old, but this disease can occur at any age. 50[53] An increasing number of children, adolescents and young adults are being diagnosed with type 2 diabetes.In the United States, the prevalence of T2 DM among children and adolescents increased by 30.5% between 2001 and 2009. 54Data from China suggest that the prevalence of type 2 diabetes in children has increased dramatically over the past 20 years. 55Several studies have shown that diabetes (types 1 and 2) is an established risk factor for periodontitis and contributes to the increased prevalence, severity and progression of periodontitis.Importantly, accumulating epidemiological evidence suggests a positive association between obesity [56][57][58] and MetS [59][60][61] (both diseases are strongly associated with type 2 diabetes) and periodontitis.Children with diabetes had significantly more gingival inflammation and attachment loss than control children. 62The incidence of chronic gingivitis in patients with type 1 diabetes is significantly higher than that in the healthy population. 63Gingival index (GI) refers to a comprehensive evaluation of the degree of inflammation of the gums based on their color, shape, texture, and probing bleeding.GI was significantly higher in obese children with T2DM than in obese children without diabetes and children with normal body weight aged. 64A cohort study of 350 children aged 6-18-year-old found a strong positive association between mean hemoglobin A1c and periodontitis. 65These studies suggest that both type I diabetes and type II diabetes increase the risk of periodontal disease in children and adolescents.

| Metabolic syndrome
The "MetS" is a complex syndrome of metabolic disorders caused by overnutrition, sedentary lifestyle and obesity.Mets comprises a clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure.Mets is associated with other comorbidities, including a prothrombotic state,a proinflammatory state and nonalcoholic fatty liver disease (NAFLD). 66Since MetS is a cluster of different conditions, rather than a single disease, leading to the development of multiple concurrent definitions.Although there is no international common definition of the MetS in children and adolescents, all definitions include obesity as a prerequisite for the development of the MetS even in children.Obesity is one of the major cardiometabolic risk factors, which is closely related to other metabolic diseases such as hyperlipidemia, hyperinsulinemia, and hypertension.A consensus definition was published in 2007 by the International Diabetes Federation, which agreed that 10-year-old children met the criteria for MetS if they had at least three of the following risk factors: high waist circumference, hypertension, insulin resistance, and dyslipidemia. 67A Spanish cross-sectional study published in 2011 showed that Mets occurred in 8%-32% of prepubertal children and 9.7%-41.2% of adolescent children. 68urthermore, Reinehr et al. compared different definitions of MetS in a cohort of 1205 children and found a wide prevalence range from 6% to 39%. 69Notably, MetS increases the risk of development and progression of periodontitis. 70Boys diagnosed with MetS had significantly higher levels of gingival crevicular fluid tumor necrosis factor alpha (TNF-α) and more sites with gingival bleeding compared with healthy boys. 71What's more, the number of positive MetS parameters, and HDL-cholesterol parameter showed a significant association with gingivitis in adolescents.ediatric rickets caused by Vitamin D insufficiency and disorders of calcium and phosphorus metabolism is a major public health problem worldwide, with the reported prevalence of up to 70% in some developing countries. 75The Rochester Epidemiology Project reported that the incidence of rickets has been increasing substantially over the past 40 years (0, 2.2, 3.7, and 24.1 per 100,000 in the 1970s, 1980s, 1990s, and 2000s, respectively). 76

| Osteogenesis imperfecta, Ehlers Danlos syndrome, and Marfan's
syndrome-Hypophosphatemic chondropathy is a disorder of bone mineralization caused by excessive urinary phosphorus excretion. 779][80] Other less common causes of hereditary hypophosphatemia include autosomal dominant hypophosphatemia, autosomal recessive hypophosphatemia and hereditary hypophosphatemic chondropathy with hypercalciuria.Acquired hypophosphatemic chondropathy can be caused by tumor induced osteomalacia and Fanconi syndrome. 77Congenital X-linked hypophosphatemic rickets have more pronounced systemic symptoms and oral manifestations with marked skeletal and dental mineralization disorders. 81,82Baroncelli at al. found children with X-linked hypophosphatemic rickets had increased incidence of periodontal disease. 82teogenesis imperfecta, also known as brittle bone disease, is the most common inherited bone disorder with an incidence of 0.79 per 10,000 newborns. 83Osteogenesis imperfecta is a heterogeneous group of inherited connective tissue disorders associated with abnormal type I collagen leading to a variety of clinical manifestations. 84,85There are four categories of osteogenic defects.Type I; Mild phenotype, type II; Perinatal fatal, type III; Progressive deformity, most severe surviving form, type IV; Intermediate severity between types I and III. 86EDs are a group of inherited connective tissue disorders caused by collagen and elastin, leading to a variety of disorders.There are 13 types, many of which are associated with increased skeletal and capillary fragility in children and adults. 87MFS is an autosomal dominant connective tissue disorder with a reported incidence of 1 in 3000-5000 individuals. 88MFS has a wide range of clinical manifestations, including cardiovascular, musculoskeletal, cutaneous, and central nervous systems.

| Non-alcoholic fatty liver
NAFLD is the most common cause of chronic liver disease in western countries. 89,90In particular, there is an alarming increase in the number of children affected by NAFLD, which is supported by high prevalence data, ranging from 3% to 12% in the general pediatric population and up to 70%-90% in young obese individuals. 91Childhood NAFLD is associated with several factors of MetS, such as abdominal (central) obesity, dyslipidemia (hypertriglyceridemia and/or hypercholesterolemia), and insulin resistance. 92Thus, NAFLD can be considered a hepatic manifestation of MetS.The NAFLD shows a significant association with clinical microbial periodontal parameters. 93A similar association was observed between periodontal disease and NAFLD risk (OR = 1.19, 95% CI = 1.06-1.33). 46

| THE MECHANISM OF METABOLIC DISEASES AFFECTING PERIODONTAL HEALTH MANAGEMENT IN CHILDREN
The identification of etiology is critical for the prevention and treatment of periodontal diseases.However, the specific etiological mechanisms of periodontal disease have not been fully understood.Currently, the recognized etiologies are dysbiosis of oral microbiome and dysregulated host immune response. 40Metabolic diseases can not only affect the oral and intestinal microbiota balance, but also destroy the host immune function.A poorly controlled host immune response, in turn, can generate a self-perpetuating pathogenic cycle where dysbiosis and inflammation reinforce each other by forming a positive feedback loop. 94

| Effects of metabolic disorders on host immunity
As previously mentioned, common metabolic diseases in children are most frequently associated with abnormal glucose and lipid metabolism.Therefore, we mainly focused on the effects of obesity and diabetes on host immunity here.Pediatric obesity has both short-term and long-term impacts as the physiological changes altered by obesity occur at critical developmental stages.These comorbidities are caused by obesity-related low-grade inflammation, characterized by abnormal cytokine production and macrophage infiltration into adipose tissue. 95Large differences in leukocyte numbers as well as in phagocytic and oxidative burst activity of monocytes, have been reported between normal and obese individuals (Figure 1). 96Not only that, insulin target tissues such as adipose tissue, liver, muscle, and pancreatic islets are under attack from chronic inflammation in children with obesity and diabetes. 97,98Adipose tissue-associated inflammation elicits a wide variety of immune responses, involving early neutrophil participation followed by macrophage involvement and mast cell polarization. 96These cellular adaptations lead to altered metabolic profiles in early life and premature death in adulthood. 99Studying the causes of obesity-related inflammation in pediatric populations may identify opportunities to prevent progression to serious comorbidities such as hypertension, abnormal glucose metabolism, and dyslipidemia.These observations have led to the term "immunometabolism," which encompasses the potential interplay between immune processes and metabolic defects. 100In the context of pediatric obesity, adipose tissue displays unhealthy expansion, with excessive accumulation of adipocytes, leading to hypoxic conditions in this tissue. 101The hypoxic environment in turn triggers the recruitment of monocytes that subsequently convert to mature adipose tissue macrophages (ATMs). 102Proinflammatory macrophage recruitment, accumulation, and activation in metabolic tissues are the ultimate drivers of chronic lowgrade inflammation.Although macrophages are the major effector cell type, other types of immune cells also participate in these inflammatory processes. 103,104The proinflammatory polarization state of ATMs leads to the release of a large number of inflammatory cytokines.Additionally, macrophages are capable of secreting chemotactic molecules such as TNF-α. 103In a cohort study of obese Mexican American children, alterations in blood plasma cytokines/chemokine levels among healthy weight, overweight, and obese children were found. 105Serum concentrations of interleukin-8 and TNF-a were higher in the obese children.The release of TNF-a not only recruits other inflammatory factors involving interleukin-1β (IL-1β) and interleukin-6 (IL-6) 106 but also can activate various intracellular signaling molecules, such as JNK and IKKB, which are key components of the inflammatory signaling system, leading to impaired insulin action. 107The adipose tissue of obese children expresses high levels of TNF-α and its inhibitor can improve insulin sensitivity and glucose tolerance abnormalities which are vital findings in establishing the link between immune cells and metabolic dysfunction. 104In a rodent model of obesity, normalization of TNF-α decreased insulin resistance. 104Another key component of inflammation activation is a multimeric protein complex called the "inflammasome," which is activated by cellular nutrients such as glucose and free fatty acids to induce IL-1β production (Figure 1). 107,108Interestingly, obesity has been demonstrated to exacerbate thymic senescence, reducing T-cell diversity, and therefore potentially affecting immune surveillance. 109 the other hand, obesity has a variety of impacts on adipose cells, particularly the endocrine effects of adipokines (Figure 1).The main immunomodulatory factors derived from adipose include leptin, adiponectin, and proinflammatory cytokines: TNF-α, IL-6, and IL-1β. 110,111The levels of adiponectin, declined during obesity, have been shown to affect natural killer cell cytotoxicity and cytokine production. 112At the same time, excessive proinflammatory cytokines produced by the white adipose tissue of obese individuals can be secreted into the blood and may have long-term effects.However, how the longterm production of these cytokines affects cellular immunity remains to be elucidated.Prolonged exposure to proinflammatory cytokines may decrease the sensitivity of immune cells to inflammatory responses during actual infections. 113Compared to proinflammatory cytokines, the pleiotropic effects of leptin on immune cell activity are highly diverse and complex. 114Almost all cells of the innate immune system express an isoform of the leptin receptor OBRb, which is required for leptin signaling. 115In monocytes, leptin upregulates the production of the proinflammatory cytokines IL-6, IL-12, and TNF-α, as well as phagocytic function. 116In neutrophils from healthy humans, leptin signaling induces chemotaxis, production of reactive oxygen species, and affects oxidative capacity. 117Natural killer cells are greatly influenced by leptin signaling, including differentiation, proliferation, and activation. 118Ob/ob mice, an animal model of obesity, provided important information about the role of leptin in host defense and immunity, with nearly all innate immune cells being impaired in mice lacking intact leptin signaling. 119In conclusion, the clinical observations and the results of animal experiments suggest that obesity impairs the normal functioning of the immune system.Similar to obesity, diabetes also leads to hyperreactivity of the body's immune system and immune cells.T1DM is a long-term and chronic autoimmune disorder, in which the immune system attacks the pancreatic cells. 120Early evidence in rats and humans suggested a defective neutrophil response in diabetes. 121Subsequent studies have shown that diabetic patients develop a hyperinflammatory, monocytic phenotype characterized by elevated levels of proinflammatory mediators in the periodontal sulcus fluid. 1224][125] An infiltration of macrophages into these tissues is seen in animal models of obesity and diabetes as well as in obese human individuals with MetS or T2DM. 126,127Therefore, diabetes may increase the local (infected site) and systemic inflammatory response to bacteria. 128Moreover, the production of IL-1 and TNF-α was raised in diabetes by increasing the polarization of M1 macrophages, which may exacerbate periodontal disease. 129Dendritic cells regulate adaptive immune response by activating lymphocytes.Diabetes may potentially affect dendritic cells, increasing the production of Th1 or Th17 lymphocytes or reducing the formation of regulatory T cells. 128Therefore, the role of the immune inflammatory response in the pathogenesis and relationship between periodontitis and metabolic disorders cannot be ignored.The chronic inflammatory environment caused by metabolic disorders not only increases the susceptibility of periodontitis, but also affects the regeneration of periodontal tissues.Regulation based on immune response is a hot topic and research direction in the prevention and treatment of periodontitis and metabolic disorders.

| Disrupted equilibrium of the oral microbiome in metabolic disorders
The oral cavity is the second largest microbiota in the human body.Currently about 500 different bacteria have been identified in the oral cavity. 129The microbiome and the host's immune system are interdependent and co-develop from birth.Thus, the microbiota shapes the development of the immune system, which in turn determines the composition of the microbiota.The composition of the oral microbiota varies according to different life events: dietary diversification, hormonal changes (puberty and menstrual period), administration of drugs such as antibiotics, and age. 130Another source of alterations in the oral microbiota is changes in the balance of systemic health, generally associated with systemic diseases such as metabolic disorders. 131vels of several bacteria are higher in the oral cavity of obese individuals than in nonobese controls, and these bacterial species appear to serve as biological indicators for the development of overweight conditions.Obesity is linked to subgingival microbiota disturbance in adolescents.Previous study has demonstrated that traditional periodontal pathogens such as Porphyromonas gingivalis, A. actinomycetemcomitans, and P. micra, 132,133 are present a threefold increase in the dental biofilm of obese adolescents compared with the normal weight controls.A significantly higher number of bacteria from the Streptococcus genus were found in the group of children with well-controlled diabetes mellitus when compared to the healthy children. 134Glycemic control of childhood type I diabetes was also associated with the complexity and abundance of microbial communities in dental plaque, as discovered by 16S rRNA sequencing.Besides, several studies have reported diabetes induced changes in the oral microbiota.Examples of these bacterial changes include: (1) increased phagocyte function in patients with diabetes 135 ; and (2) P. gingivalis, Tannerella forsythia, 136,137 Capnocytophaga, Pseudomonas, bergeria, Sphingomonas, Corynebacterium, Propionibacterium, and Neisseria were increased in hyperglycemic individuals. 138Compared with the healthy population, the salivary bacterial spectrum of MetS patients has changed with decreased diversity of bacterial species. 139hen further stratified, both the MetS healthy periodontium and MetS periodontitis subject groups exhibited relatively distinct microbial profiles from each other and from those of healthy subjects.In addition, the MetS periodontitis group showed greater enrichment of canonical periodontal "Red complex" pathogens, namely forsythia, spiral hilum, and Treponema.However, for P. gingivalis, no significant difference was detected between the MetS patients and healthy people. 140Periodontopathic bacteria, particularly P. gingivalis, have been associated with the pathogenesis and progression of NAFLD on the basis of clinical research and immunology. 141The oral derived bacterium P. gingivalis can be detected in both liver and feces of patients with NAFLD.Studies have identified a possible oral-gut-liver axis in NAFLD patients. 142,143Similarly, an American study showed the transfer of oral bacteria into atherosclerotic plaques. 144Furthermore, they described the potential role of oral microbiota biomarkers in the development of vascular diseases. 144,1457][148] It suggests translocation of oral bacteria into the systemic circulation.
The close interaction between oral microbes and metabolic diseases have also been found in animal experiments.Oral microflora of diabetic mice was transferred from diabetic hosts to germ-free mice and compared with bacteria transferred from normoglycemic mice to similar hosts.Compared with bacteria from the normoglycemic control group, the transfer from the hyperglycemic mice stimulated more infiltration of neutrophils and the expression of bone resorbing cytokines (IL-6 and RANKL), increasing the number of osteoclasts and more periodontal bone loss. 149Moreover, inoculation of P. gingivalis to the mouth of ApoE-deficient mice caused an increase in the number of Bacteroides and a decrease in the number of Scleroderma, which were closely related to endotoxemia and systemic inflammatory responses. 150Many clinical studies have found that the development of atherosclerosis can be suppressed correspondingly after periodontitis is controlled in patients. 151,152By inducing obese mice with a high-fat diet, the researchers found that obese mice developed alveolar bone resorption and alterations in oral microbiota similar to those induced by actinomycetes.Obesity-induced alveolar bone resorption was effectively improved by oral topical application of antibacterial agents in mice with a high-fat diet. 153tabolic diseases can not only affect the colonization of oral microbiota, but also break the balance of intestinal microecology, which is closely related to the development of children's immune system. 154The dysbiosis of oral microbiome cannot be improved solely through antibiotic treatment, but requires adjustments to the systemic immune system.In conclusion, metabolic diseases affect the whole-body microbiome to a certain extent.Such changes may break the balance between the host immunity and the microbiome, causing chronic inflammation and aggravating periodontitis.This implicates a guiding direction for future research on the treatment of metabolic diseases complicated with periodontitis, but it still needs further research.

| CONCLUSION AND FUTURE DIRECTIONS
As mentioned before, systemic metabolic diseases are closely related to the periodontal health of children and adolescents, giving some advice to the clinicians in the treatment.For physicians, enough attention should be paid to whether the patient has periodontal diseases when treating systemic metabolic diseases.The risk of systemic disease should be considered for oral practitioners in periodontitis patients with poor therapeutic effect of topical treatment.In conclusion, concurrent therapy with control of infection and inflammation should be used in adolescents and children with both metabolic and periodontal conditions.For example, screening for HbA1c is recommended at the time of the children's oral examination, with the aim of selecting patients at high risk for periodontitis and tooth loss or for incidental findings of an underlying cause of disease.6][157] The study found that non-surgical periodontal treatment resulted in a 0.24%-1.21%point decrease in glycated hemoglobin after 3 months of intervention. 158However, the effect of hypoglycemic agents on periodontal status remains unclear.Studies have shown that only in animal experiments can the application of rosiglitazone improve tissue damage associated with periodontitis in diabetic rats. 159,160The effect of the diabetes drugs on periodontitis may mainly depend on its anti-inflammatory potential, rather than the reduction of glycosylated hemoglobin.
Certainly, based on epidemiological data, the incidence of periodontal disease is not as high in children or adolescents as it is in adults.2][163] More importantly, the available literature does not strongly support the idea that the periodontal pathogens causing periodontitis in adults have their onset later in life.Indeed, these potential pathogens appear to be acquired early in life and at low levels in the oral microbiome of children and adolescents. 164Once an individual's native oral microbial ecology is established, it seems difficult for alien bacteria to gain a foothold for permanent colonization.What seems to occur is that changes in the oral environment contribute to the selection of the emergence of various taxa, genera and species that may initiate the disease process. 161Thus, alterations in oral microbial communities and predominant bacterial genera may result in the acquisition of a "dangerous microbial ecology" early in immune system development when children and adolescents have metabolic disorders. 30Therefore, we may have underestimated the long-term effects of gingivitis in children and adolescents.It can be expected that in obese and even overweight children and adolescents, these altered systemic responses may be reflected in gingival tissue early in life and "seed" the long-term risk of periodontal tissue destruction.Thus, initiating oral bacterial translocation in response to systemic challenges at a younger age may have long-term consequences. 165These chronic oral infections in children, combined with obesity and altered general health status, may have a significant cumulative impact on the risk of cardiovascular disease, diabetes onset, and other chronic inflammatory diseases.The influence of disorders in lipid and glucose metabolism on periodontal inflammation.Leptin and pro-inflammatory cytokines are released from adipose tissue in obesity to recruit and activate pro-inflammatory immune cells.These pro-inflammatory cytokines and immune cells will follow the blood into metabolic organs, such as the liver, causing chronic inflammation and affecting the process of glucose and lipid metabolism.Glucose and free fatty acids in the blood, among others, activate the inflammasome, which releases IL-1β, creating a highly pro-inflammatory environment in periodontium.IL-1 β, interleukin-1β.