Chronic periodontitis as a risk for chronic inflammatory diseases of human

Shynkevich V.I.

Проблеми екологц та медицини

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ENGLISH VERSION: CHRONIC PERIODONTITIS AS A RISK FOR CHRONIC INFLAMMATORY DISEASES OF HUMAN

Shynkevich V.I.

Department of postgraduate education for dentists, Higher State Educational Establishment of Ukraine "Ukrainian Medical Stomatological Academy", Poltava

Assessment of dental plaque and the host response provides an essential basis to understand the disease process and treatment rationale. This information will help the reader to understand not only the way that plaque may have an impact on oral tissues but also why regular effective cleaning may improve periodontal health and why some individuals appear to have a greater susceptibility to periodontitis than others, either intrinsically or in relation to various systemic factors. The paper analyzes the main trends of chronic periodontitis treatment, including dental plaque removal and an-tibioticotherapy as the first ine which can prevent of cardiovascular disease, diabetes, nosocomial pneumonia and adverse pregnancy outcomes iat the same time.

Key words: chronic periodontitis, systemic inflammation, treatment, prevention, microbial biofilm periodontopathogens, genetic dysbiosis

Chronic periodontitis (CP) is due to an aberrant response to periodontopathogenic members of the subgingival microbiota [9] and, together with its nondestructive partner condition, gingivitis, is one of the most prevalent chronic inflammatory conditions of humanity. A recent survey in an US adult population of 3,742 individuals revealed a prevalence of 47% for periodontitis [28]. Periodontitis has a multifactorial aetiology, where the combination of common genetic variants alters the

response to the sub-gingival microbiota, predisposing to disease onset and progression [9]. Periodontopathogenic bacteria include gram-negative bacteria such as Aggre-gatibacter actinomycetemcomitans, Porphyromonas gin-givalis and Tannerella forsythia. Periodontitis increases systemic inflammation, by means of bacteria entering the hemo- and lympho- virculation via periodontal pockets [4]. These bacteria activate an acute-phase response by the liver and activate immune cells, such as neutrophils,

To cite this English version: Shynkevich V.I. Chronic periodontitis as a risk for chronic inflammatory diseases of human // Problemy ekologii ta medytsyny. - 2014. - Vol 18, № 3-4. - P. 53 -57.

to generate 'oxidative stress' in the circulation. It appears that it is not the bacteria, but the inflammatory response to them that causes the mayhem. The reaction to the bacteri ticks over at a slow, low-grade, but relentless pace over many years, and in doing so contributes to the overall 'inflammatory burden' that drives many of the inflammatory diseases of ageing [2, 13].

European scientists predict increasing burden of severe periodontitis due to the growing world population associated with an increasing life expectancy and a massive decrease in the prevalence of tooth loss throughout the world from 1990 to 2010. These changes underscore the enormous public health challenge posed by severe periodontitis and are the epidemiologic transition to non-communicable diseases occurring in many countries [30].

The association between chronic periodontitis and systemic inflammatory diseases suspected long ago, but over 20 years ago periodontitis was seen as a consequence or even a manifestation of systemic diseases and/or conditions such as psycho-emotional stress, smoking, cardiovascular diseases, age. Today consistent evidences found that the CP affects general condition of patient with diabetes, and predisposes, for example, to atherosclerosis [2].

The evidence for an association between diabetes and periodontitis is as follows: Type-2 diabetes is preceded by systemic inflammation, leading to reduced pancreatic p-cell function, apoptosis and insulin resistance. Increasing evidence supports elevated systemic inflammation (acute-phase and oxidative stress biomarkers), resulting from the entry of periodontal organisms and their virulence factors into the circulation, thus providing biologically plausible mechanisms underpinning the adverse impact of periodontitis upon diabetes and its complications. Epidemiological data - consistent and robust evidence is available which demonstrates that severe periodontitis adversely affects glycaemic control in diabetes and glycaemia in non-diabetes patients. In addition, in patients with diabetes, there is a direct and dose-dependent relationship between periodontitis severity and diabetes complications. Emerging evidence indicates an increased risk for diabetes onset in patients with severe periodontitis. Randomised clinical trials consistently demonstrate that mechanical periodontal therapy associates with approximately a 0.4% reduction in HbAIC at three months, a clinical impact equivalent to adding a second drug to a pharmacological regime for diabetes [14].

The evidence for an association between cardiovascular diseases and periodontitis is as follows. The bacteria, entering into the blood stream et CP, activate the host's inflammatory-immune response by multiple mechanisms. Several animal models have demonstrated that the host's inflammatory response favours atheroma formation, maturation and exacerbation. Epidemiological data - there is consistent epidemiological evidence that CP imparts increased risk for future cardiovascular disease, independently of other confounding factors. Intervention studies - there is moderate evidence that perio-dontal treatment reduces systemic inflammation as evidenced by reductions in C-reactive protein and oxidative stress, and leads to improvements of surrogate clinical and biochemical measures of vascular endothelial function [4, 13].

The evidence for an association between adverse pregnancy outcomes and periodontitis is as follows. Oral microorganisms and their products enter the blood

circulation and travel directly to the foetal environment where they cause inflammatory and immune responses affecting the foeto-placental unit. These bacteria in the circulation may also circulate to the liver, where inflammatory agents are produced, which in turn then circulate to the developing foetus. In clinical studies, low birth weight, pre-term birth and pre-eclampsia have all been associated with the presence of periodontitis in the mother, when all other risk factors have been accounted for. However, the strength of the connection found between periodontitis and these pregnancy outcomes varies between studies, and some show no association. The heterogeneity of data is likely due to differences in the study designs, study populations and different methods used for assessing and classifying periodontal disease. Intervention studies - results from clinical trials have shown that, in general, scaling and root debridement carried out during the second trimester of pregnancy, with or without antibiotic therapy, does not significantly improve adverse pregnancy outcomes, such as preterm birth and low birth weight. However, some clinical trials did report a favourable effect overall and it is possible that certain populations of pregnant women may benefit from periodontal therapy, even though others will not. One reason for negative study results may be that the interaction between periodontitis and pregnancy outcomes is more complex than our current understanding and the study results may have been affected by the type and timing of treatment employed and by the types of patients selected.

Periodontitis and other diseases. There is emerging evidence for associations between periodontal diseases and chronic obstructive airways disease, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and some cancers. To date, the only evidence for causality is in relation to respiratory microorganisms that colonise the oral/periodontal biofilm and may subsequently cause a hospital-acquired pneumonia (nosocomial pneumonia) in ventilated patients. The evidence is that respiratory pathogens arising from oral/periodontal biofilm reservoirs may be aspirated in certain risk patients within hospital environments and result in a nosocomial pneumonia. Epidemiological data supports a role for the oral/periodontal biofilm acting as a reservoir for respiratory pathogens in patients with poor oral hygiene and periodontitis, which may cause nosocomial pneumonia. Randomised controlled trials strongly support a role for improving oral hygiene in the prevention of nosocomial pneumonias in acute care hospital environments [13].

Common inflammatory and destructive mechanisms at chronic periodontitis and systemic inflammatory diseases can be mediated by matrix metallopro-teinases (MMP), PMN-derived serine proteases, plasmi-nogen-dependent, phagocytic mechanism, mechanisms of RANKL-activation of osteoblasts [31], NFkB-dependent mechanisms [2] and others. Thus, clinically significant polymorphism are 5A (-1612) 6A) gene MMP-3 polymorphism C (-799) T MMP-8 gene polymorphism and C (-1562) T MMP-9 gene, are found significantly more often among patients with both cardiovascular diseases, rheumatoid arthritis and CP [8]. Certain gene polymorphisms of IL-1, is associated with both periodontitis and diabetes [10].

Other links of chronic periodontitis with systemic inflammatory diseases are suspected on basis of mi-crobial biofilm study and human responses before enter-

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ing through barrier skin and mucosa; namely local colonization, selection and accumulation of certain bacteria [26].

It is now recognised that humans are supra-organisms [32] with 90% of the cells in the human body being bacterial, termed the normal bacterial microbiota. It is estimated that in the human gut, the microbiome outnumbers the human genome by 150-fold. The traditional meaning of 'microbial disease' includes infections such as smallpox, tuberculosis or AIDS, caused by colonisation and infection by a specific pathogenic microbe, usually transmitted between individuals. Some microbes or even microbial strains may indeed be responsible for more than one disease state, an example being E. coli, associated with gastro-intestinal and urinary infections as well as meningitis. However, some bacterium, bacterial L-form, virus and so forth are the cause of many major idiopathic. An example of this is rheumatoid arthritis, which was thought to be caused by a wide variety of microorganisms [12].

Recent research has identified a group of conditions probably resulting from dysbiosis, or alternatively referred to as originating from a misrecognition or aberrant response to the normal microbiota, including inflammatory bowel disease, psoriasis, bacterial vaginosis and periodontal diseases (PD). These four diseases seem to cluster together from an epidemiological, pathogenic, genetic and microbial standpoint, with similarities between them being recently reported [19]. A common feature of the diseases described above is that they are not, like common infections, caused by individual bacterial species. Rather, they appear to be the result of a dysbiosis, which is a change in the normal microbiota, or of misrecognition of the normal microbiota within different body environments. A sensible hypothesis is that genetic defects in the recognition and response pathways that the host uses to identify microbial pathogens predispose to either altered microbial colonisation or to the misrecognition of normal microbiota that lead to these diseases. We could refer to 'genetic dysbiosis' to define this mechanism. This underpins the concept of infectogenomics [25], for which two distinct pathways have been recognised: bacterial recognition and bacterial proliferation.

Bacterial recognition. Mammals have a very wide variety of pattern-recognition receptors (PRRs), which recognise evolutionarily-conserved constituents of microbes called pathogen-associated molecular patterns (PAMPs). These include the toll-like receptors (TLRs), NOD-like receptors, RIG-I-like receptors, C-type-lectin like receptors, scavenger receptors, innate DNA receptor proteins termed AIM2-like receptors, members of the complement pathways and peptidoglycan-recognition proteins (PRPs). In addition to these proteins, which are mainly cell-bound, there are also a range of soluble PRRs including collectins, ficolins, pentraxins, galectins, CD14 and natural IgM. Each of these families of proteins contains multiple members. In addition, these various receptor-based and soluble PRRs generally interact with various accessory proteins to allow for selective cell signaling; and the target cell generates pro- and/or anti-inflammatory proteins such as cytokines.

Mutations in the promoter regions and coding segments of the individual PRR genes may result in either altered expression of PRRs or differences in the ability to recognise the microbial constituents that they bind to respectively. In addition to the influence of PRR production and PRR kinetics of binding, changes in the interaction

between the PRR and obligatory accessory proteins may be a factor in this 'binding/recognition' process. Initial evidence has recently been produced for the effect of microbial recognition genes on microbial presence in periodontal [17] and vaginal biofilms [18, 29]. Features of expression and signaling from oral mucosa TLRs are important for understanding the susceptibility to infection and disease; thus genes polymorphisms of TLR2 and TLR4 may cause susceptibility to infection by certain microorganisms [7]. In these conditions, a proposed hypothesis is that genetic factors which may determine an aberrant epithelial barrier (through defects in PRRs and innate immune signalling pathways) may induce microbial shifts and an inflammatory cascade which can give rise to chronic diseases and even cancer [24].

Bacterial proliferation. As well as affecting bacterial recognition, common human genetic variants are likely to be responsible for creating a favourable environment for fostering the growth of specific pathogenic bacteria within biofilms. The hypothesis is that genetic variants predisposing to an excessive inflammatory response create a favourable environment for the selective growth of specific bacteria within the human biofilms, which, due to specific characteristics in their metabolism, grow well in more inflamed environments. Initial evidence in periodontitis suggests that cytokine gene polymorphisms may select and favour the growth of certain components of the sub-gingival biofilm. Periodontitis studies confirm that some cytokine gene polymorphisms are associated with selective and predominant growth of certain types of microorganisms in subgigival biofilm [17]. Similarly to perio-dontitis, other human diseases might be affected by the overgrowth of certain components of the biofilms upon stimulation by a more or less 'inflamed' environment. It has been hypothesized that mutations in genes involved in immune regulatory mechanisms or pro-inflammatory pathways could lead to unrestrained inflammation in the intestine and that inflammation can influence the composition of the microbiota, skewing it in favour of pathological microorganisms. However, doubts still exist on whether the inflammatory deregulation is the cause, or actually the consequence of a microbial shift in such cases.

Genetic dysbiosis in periodontitis. A recent study has shown that specific genetic variants that violate the inflammatory response (eg, IL-1, IL-6 genes) associated with periodontopathogenetic bacteria (eg A.actino-mycetemcomitans and P.gingivalis) in sub-gingival plaque [19]. This adds to the evidence suggesting that periodontal 'dysbiosis' or a shift towards a more pathogenic microbiota (including A.actinomycetemcomitans) that may be due to specific genetic variants in the host [27].

Thus, the concept of infectogenomics highlights the macroorganism/host genetic predetermination in control microbial biofilm composition. According to conditional division of immunity to innate and adaptive it may be to consider similarly host mechanisms of biofilm restriction. Receptor innate mechanisms of recognition and response to microbial composition represented numerous families and PRRs mentioned above. But aberrant specific immune response to periodontopathogenic bacteria in biofilm also contributes to tissue destruction in periodontitis: host sensitivity to periodontopathogenic microflora of about 50% is due to genetic characteristics of adaptive immune mechanisms [15, 33]. Genetic features of cell-mediated immune response is closely associated

with the development of CP [16, 23]. Polymorphisms that lead to lower levels of antibody-mediated responses, in particular to Porphyromonas gingivalis, are also associated with more severe forms of CP [11]. Obviously, the mechanisms described as 'sensitivity' to periodontopa-thogenic microorganisms in biofilm also takes part in microbial selection and colonization, even regardless of the virulence.

Thus, genetic dysbiosis is considered by leading Ukrainian scientists [2] as a mechanism that links diseases that involve multiple barrier surfaces and/or mucous membranes. So, the combination of some diseases of gastrointestinal tract and chronic catarrhal gingivitis previously explained by intestinal dysbiosis [5]. As we was look on dysbiosis like genetically predetermined, the role of microbial biofilms become secondary, and limited efficacy of probiotics become clear [1].

In practical terms, information about complex relationships, continuous circle in systemic pathogenesis of chronic inflammatory diseases and PD may lead to the paradox conclusion about predetermination of disease, but it is not quite true. The main conclusion - is the need for constant maintenance and complex treatment of PD. Periodontal treatment and prevention is both the prevention of systemic inflammatory diseases. Factors which modify risk, such as cigarette smoking, stress, drugs or sex hormones, and some systemic inflammatory diseases, such as diabet, HIV can affect the course of all types of periodontal disease. It was concluded that there was insufficient evidence that there is a specific periodontitis associated with these diseases. In contrast, periodontitis as a manifestation of systemic disease includes various haematological disorders such as acquired neutropenia and leukaemia; various genetic disorders such as familial and cyclic neutropenia, Down syndrome, leukocyte adhesion deficiency syndrome, Papil-lon-Lefevre syndrome, Chediak-Higashi syndrome, histiocytosis syndromes, hypophosphatasia and others [22].

The European Federation of Periodontology (EFP) has recently launched a manifesto for a paradigm shift: 'periodontal health for a better life' for all dental and health professionals that reasonably proven by links between CP and cardiovascular diseases, diabetes, adverse pregnancy outcomes [13]. The manifesto promotes a fundamental shift in the role of dental healthcare professionals and encourages orderly work towards prevention, early diagnosis and effective treatment of inflammatory periodontal diseases in order to reduce harmful dental and overall impact on human health and society in general. The dental team's role emphasises in promoting behaviour change in their patients aimed at reducing smoking and obesity levels, by promoting healthy nutrition and exercise. So knowledgeable in this area dentist engages fully in preventive medicine in support of medical colleagues in the best interests of public health. The main evidence is presented above and known quite wide, but are used primarily for internal.

Various host modulatory therapies have been developed or proposed to block pathways responsible for periodontal tissue break down. The newer drugs like bor-tezomib, infliximb, etanercept, vasoactive intestinal peptide, nitric oxide synthase inhibitors and denosumab are developed as a result of better understanding of pathogenesis of inflammatory tissue destruction and may represent [20]. However, the complexity of immune disorders in periodontitis indicates that it is unlikely cytokine ther-

apy or therapeutic immunoregulation become routine of periodontal treatment soon. Obviously, with the number of microbial biofilms and periodontopathogens in them today, we really can control them only with antibiotics (in the case of microorganisms penetrated) [6] and by mechanical and antiseptic removal of microbial dental plaque (decontamination [3]) as periodontal therapy.

A certain problem arises when we realize that most dentists are rather general practitioners, than experts in periodontology. Therefore, it should be noted that the most complex and the best prosthetic, restoration or orthodontic forces will not have full success without proper periodontal maintenance treatment.

The future strategy of periodontal therapy is aimed at improving of host ability to prevent microbial colonization and eliminate certain microorganisms. An appreciation of dental plaque and the host response provides an essential basis from which to understand the disease process and treatment rationale. This information will help the reader to understand not only the way that plaque may have an impact on oral tissues but also why regular effective cleaning may improve periodontal health and why some individuals appear to have a greater susceptibility to periodontitis than others, either intrinsically or in relation to various systemic factors [21].

Conclusions.

Chronic periodontitis requires lifelong treatment, with regular intervals, - an approach that is simultaneously preventing for systemic inflammatory diseases. Microbial biofilm control in chronic periodontitis is now really possible evidently only by systemic antibiotic therapy.

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16. Exploring the genetic basis of chronic periodontitis: a genome-wide association study / K. Divaris, K.L. Monda, K.E. North [et al.] // Hum Mol Genet.-2013.-Vol.22, N 11.-P.2312-2324.

17. Gene polymorphisms and the prevalence of key periodontal pathogens / L. Nibali, D.R. Ready, M. Parkar [et al.] // J Dent Res.-2007.-Vol.86.-P.416-420.

18. Gene polymorphisms of toll-like and related recognition receptors relation to the vaginal carriage of Gardnerella vaginalis and Atopobium vaginae / H. Verstraelen, R. Ver-helst, L. Nuytinck [et al.] // J Reprod Immunol.-2009.-Vol.79.-P.163-173.

19. Genetic dysbiosis: the role of microbial insults in chronic inflammatory diseases / L. Nibali, B. Henderson, S.T. Sadiq, N. Donos // J Oral Microbiol.-2014.-Doi: 10.3402/jom.v6.22962.

20. Gokhale S.R. Future prospects of systemic host modulatory agents in periodontal therapy / S. R. Gokhale, A.M. Padhye // British Dental Journal.-2013.-Vol.214.-P. 467-471. http

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www.nature.com/bdj/journal/v214/n9/full/sj.bdj.2013.432.ht ml WT.mc_id=EMI_BDJ_1410_Perio1 - a2