Numerous studies during the past 30 years suggest that periodontitis is associated with certain systemic diseases such as cardiovascular disease (CVD), diabetes, adverse pregnancy outcomes (APOs), respiratory diseases, rheumatoid arthritis (RA), certain types of cancer and mental disorders [1-5]. While the mechanisms by which periodontal disease may increase the risk of these systemic diseases are not completely understood, some data suggest that periodontal inflammation may spread to other parts of the body and contribute to the development of these disorders [5,6]. The plausible mechanisms connecting these diseases are based on 2 fundamental assumptions. First, bacteria and bacterial products found in periodontal pockets can enter the blood stream through the pocket epithelium and colonize other parts of the body, especially in patients with compromised immune function. Indeed, transient bacteremia occurs frequently resulting from daily activities such as tooth brushing or chewing, as well as during invasive dental procedures [7-9]. Secondly, periodontal pathogens induce inflammatory reactions in the affected tissues, thus stimulating the release of pro-inflammatory cytokines, chemokines, or acute-phase proteins, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, 6 and C-reactive protein (CRP), leading to systemic inflammation.

The focus of this mini-review is on the multi-faceted ‘mechanistic causality’ aspect of the link between periodontitis and systemic disorders. Understanding how specific systemic pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation may provide novel insight into the pathogenesis of systemic medical disorders and new therapeutic approaches to reduce the risk of periodontitis-associated ailments [5].

Periodontitis

Periodontitis is one of the most common infectious diseases affecting humans, leading to the destruction of the teeth supporting structures and ultimately tooth loss [10]. It has been established that dental plaque biofilm, consisting of more than several hundred oral bacterial species and their products, is responsible for the etiology of periodontitis. It is also widely accepted that immunological and inflammatory host responses to dental plaque, via host-parasite interaction, are manifested by signs and symptoms of periodontal disease. The outcome of this interaction is modulated by risk factors (modifiers), either inherent (genetic) or acquired (environmental), significantly affecting the initiation and progression of different periodontal disease phenotypes [10]. In this model, disease results not from individual pathogens but rather from polymicrobial synergy and dysbiosis, which perturbs the ecologically balanced biofilm associated with periodontal tissue homeostasis [11,12]. While definitive genetic factors responsible for either susceptibility or resistance to periodontal disease have yet to be identified, a significant number of environmental factors affecting the pathogenesis of periodontal diseases have been described, including smoking, diabetes, obesity, medications, and nutrition [10].

Cardiovascular disease

Numerous epidemiological and interventional clinical studies suggest that periodontitis is associated with CVD [13]. People with periodontitis are more likely to develop CVD, and periodontal treatment can reduce this risk, independent of confounding factors such as smoking and obesity [14-16]. It was observed that there were increased levels of subgingival bacteria and corresponding humoral immune response in patients with CVD [17], suggesting that the association between periodontitis and CVD is partly mediated by immunologic responses to periodontal pathogens [18]. Although the basis for this association is not entirely clear, plausible mechanisms have been proposed. First, periodontal bacteria can enter the systemic circulation through ulcerated gingival epithelium, ultimately leading to an atherogenic stimulus and accelerated atherosclerosis [19,20]. For example, crucial periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were detected in the bloodstream before and after scaling and root planning, and viable bacteria were identified in the atheroma samples [21]. More recently, it was found that these organisms can disseminate to distant tissues indirectly via intracellular survival inside phagocytes or dendritic cells [22]. Another mechanism involves locally produced pro-inflammatory cytokines originating from periodontal lesions [23] can induce an acute-phase response in the liver (including elevated CRP, fibrinogen and serum amyloid A), and thereby promoting atherogenesis mainly through oxidative stress and inflammatory dysfunction [24]. It was observed that patients with severe periodontitis have increased systemic inflammation, as determined by elevated cytokines and acute-phase markers such as IL-6 and CRP [25]. Last possibility is that periodontitis can induce platelet activation and aggregation, which can increase the risk of blood clots and blockages in the arteries, leading to CVD [26]. Numerous periodontal pathogens were detected in atherosclerotic lesions [15,21,27,28]. Human endarterectomy specimens contained DNA from these periodontal pathogens and viable A. actinomycetemcomitans and P. gingivalis bacterial cells [21].

It was observed that experimental bacteremia induced by P. gingivalis promotes coronary and aortic atherogenesis in pigs [29]. Oral infection with P. gingivalis in mice fed a high-fat diet or of atherosclerosis-prone apolipoprotein E-deficient (ApoE–/–) on a standard chow diet causes localization of P. gingivalis DNA in the aortic wall and increased atherosclerotic lesions along with local alveolar bone loss and systemic inflammation [17]. In addition, P. gingivalis can promote atherothrombosis by recruiting and activating of neutrophils, inducing platelet aggregation [30,31]. Very recently, the unique role of P. gingivalis has been proposed that may induce enhanced systemic inflammation. It was found that swallowed P. gingivalis caused changes to the gut microbiota with increased gut epithelial permeability and endotoxemia, leading to systemic inflammation characterized by increased CRP, IL, and TNF [32]. It was also detected that polymicrobial infection induced by P. gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum led to an increased aortic plaque area with macrophage accumulation, enhanced serum amyloid A, and increased serum cholesterol and triglycerides levels, inducing accelerated atherosclerosis [20,22].

In summary, periodontal bacteria and their byproducts can enter the bloodstream, potentially triggering inflammatory and immune responses that contribute to the formation and progression of atherosclerotic plaque. Additionally, pro-inflammatory mediators produced from chronic periodontitis can induce the systemic inflammation, resulting in endothelial dysfunction, lipid oxidation and promoting atherosclerosis. Moreover, the presence of bacteria in atherosclerotic plaques may contribute to plaque instability and rupture, triggering acute cardiovascular events like heart attacks and strokes.

Diabetes

Diabetes mellitus is characterized by hyperglycemia, inflammation and high oxidative stress that can lead to systemic complications. It is well established that diabetes and periodontitis are closely associated and might have a bi-directional causal relationship [33]. Diabetes is a risk factor for periodontitis and increases disease severity of periodontitis. In type I diabetics, the severity of periodontal diseases is higher in most individuals [34-36]. It was shown that type II diabetes is also a risk factor for periodontal disease [37]. There is strong evidence that people with periodontitis have elevated risk for dysglycemia and insulin resistance. Epidemiological studies showed that diabetic patients demonstrate significantly higher HbA1C levels in patients with periodontitis compared to periodontally healthy subjects. Also, it was found that periodontal therapy could provide effective glycemic management in people with type 2 diabetes [38,39].

It is generally accepted that mechanistic links between periodontitis and diabetes are associated with chronic inflammation initiated by periodontitis, leading to insulin resistance. Virulence factors of these pathogens, such as lipopolysaccharide (LPS), can trigger immune responses and damage insulin-producing cells, ultimately leading to the development of diabetes. P. gingivalis LPS has been shown to increase inflammatory mediators including IL-8, and phosphorylated the c-Jun N-terminal kinase (JNK) production in neutrophils that is linked to insulin resistance, leading to the development of type 2 diabetes [40]. This change can cause elevations in inflammatory cytokines, such as IL-1β, TNF-α, IL-6, receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio, oxidative stress and Toll-like receptor (TLR) 2/4 expression [41].

There were significant differences in subgingival microbiota between type-II diabetes and non-diabetic subjects. In diabetic patients, certain groups of bacteria were more prevalent, including Aggregatibacter, Neisseria, Gemella, Eikenella, Selenomonas, Actinomyces, Capnocytophaga, and Fusobacterium [42]. It was found that diabetes causes a shift in oral bacterial composition and that the oral microbiota of diabetic mice is more pathogenic [43]. In this study, treatment with IL-17 antibody lead to the [44] decreased pathogenicity of the oral microbiota in diabetic mice, with reduced neutrophil recruitment, reduced IL-6 and RANKL and less bone resorption.

Interestingly, recent studies have proposed that the dissemination of periodontal pathogens into the intestinal tract that may induce systemic inflammation, metabolic changes, and fatty liver disease in non-diabetic mice models [32,45]. Oral administration of P. gingivalis in diabetic mice aggravated both fasting and postprandial hyperglycemia, and increased alveolar bone resorption [46] and induced gut microbiota changes, leading to entero-hepatic metabolic derangements, thus aggravating hyperglycemia in an obese type 2 diabetes mouse model [47].

Adverse pregnancy outcomes

Epidemiological and clinical studies suggest that periodontitis is associated with increased risk of APOs, such as low birthweight, pre-term birth, miscarriage and/or stillbirth [44,48,49]. Two major plausible biological mechanisms connecting periodontitis and APOs have been proposed: first, periodontal pathogens that disseminate systemically may cross the placenta into the fetal circulation and amniotic fluid, and inflammatory mediators produced locally in the periodontium could enter the systemic circulation and stimulate an acute-phase response and thereby adversely affect the placenta and fetus. The elicited systemic inflammatory response may exacerbate local inflammatory responses at the feto-placental unit and further increase the risk for APOs [49].

Adverse pregnancy outcomes are associated with oral bacterial changes. It was found that significantly higher levels of T. forsythia and Campylobacter rectus was associated with APOs [49,50]. Periodontal pathogens including F. nucleatum and A. actinomycemtemcomitans were also frequently identified from placental and fetal tissue, and amniotic fluid [50]. Interestingly, identical F. nucleatum clones were found in the subgingival biofilm of a mother with pregnancy-associated gingivitis and her stillborn infant [51]. However, the same strain was not present in the vaginal samples [52]. These results suggest that the bacterium can disseminate from the mother’s gingiva to her uterus, and lead to APO.

Several animal studies support that periodontal bacteria can cause pregnancy complications. It was observed that injection of P. gingivalis LPS resulted in intrauterine growth retardation and induce deleterious effects on the developing fetus [53-55]. A causal relationship between F. nucleatum and APOs has been demonstrated in mice. Injection of F. nucleatum into the tail vein of pregnant mice resulted in preterm and term stillbirths within 72 hours [56]. It was found that F. nucleatum attaches to and invades epithelial and endothelial cells via E-cadherin-binding FadA adhesin, allowing colonization in the placenta [55,57], accompanied by inflammation similar to intrauterine infections in humans, where it induces TLR4-dependent necroinflammatory response. FadA is uniquely encoded in F. nucleatum, but absent in most other species of Fusobacterium including those colonizing the vaginal tract [55]. FadA also can adhere to the vascular endothelial cadherins (VE-cadherin) and cause VE-cadherin to migrate away from the cell-cell junction, thus increasing the endothelial permeability allowing microorganisms to penetrate through the endothelium [58], penetrating to the placental barrier. It is plausible that the tight junctions loosened by FadA permit other bacterial species to disseminate and subsequent placental colonization [50]. An isogenic mutant lacking FadA is found to be deficient in colonizing the murine placenta, while its complement clone restores the colonization [57]. These data indicate that FadA may be responsible for APOs mediated by F. nucleatum.

Interestingly, P. gingivalis may also induce APOs via alternative mechanisms. Peptidylarginine deiminases (PADs) of P. gingivalis can degrade cardiolipin, leading to the release of neoantigens that can trigger an immune response. It seems that cardiolipin-specific antibodies are associated with APOs [59], as these autoantibodies could be induced in response to cross-reactive bacterial epitopes such as the arginine-specific gingipains of P. gingivalis and cause fetal loss when passively administered to pregnant female mice [60].

Rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disorder, although exact etiology of RA has not yet been elucidated [61,62]. Several studies suggest an epidemiological association between periodontitis and RA, even after adjusting for common risk factors such as smoking [63,64]. Many evidences suggest that microorganisms might play a role in the pathogenesis of RA [65], as microbial dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Crucial diagnostic markers of RA are anti-citrullinated protein antibodies (ACPAs) as they are detected in the serum prior to the onset of the disease and their serum levels correlate strongly with the disease severity [66,67]. A recent study showed that ACPA-positive RA patients have higher incidence of periodontitis than control subjects [68,69].

Recent studies have suggested a potential link between periodontal infections mediated by P. gingivalis and the development of RA, as this microogranism has been found in the synovial fluid of RA patients, and antibodies against P. gingivalis have been detected in the serum of RA patients [69,70]. Citrullination is a post-translational modification in which arginine is converted into citrulline by the activity of enzymes called PADs. In RA patients, the immune system mistakenly recognizes citrullinated proteins as foreign, leading to the production of autoantibodies, such as ACPAs. These autoantibodies contribute to the inflammatory response and joint damage characteristic of RA. P. gingivalis can produce an enzyme called PAD that can citrullinate peptides and proteins [71-73], leading to the formation of citrullinated fibrinogen and α-enolase, 2 major RA autoantigens [74]. It was found that the citrullinating activity of P. gingivalis requires concerted action between PAD and arginine-specific gingipains in susceptible individuals. Specifically, the cleavage of fibrinogen or α-enolase by gingipains exposes C-terminal arginine residues that are subsequently citrullinated by PAD [74]. In animal models, P. gingivalis infections have been shown to induce the production of ACPA [72,75], suggesting a key-stone periodontal pathogen P. gingivalis may mediate RA pathogenesis.

Recently, it was also found that another crucial periodontal pathogen A. actinomycetemcomitans possesses the ability to citrullinate host proteins via PAD activity. Consequently, the citrullinated proteins can enter the bloodstream and potentially reach the joints, where they may contribute to the development or progression of RA [76].

Respiratory diseases

Several mechanisms for microbiological links between periodontitis and respiratory diseases have been identified [77]. First, periodontal pathogens can enter the respiratory tract through inhalation or macroaspiration, potentially colonizing the lungs. Second, periodontal bacteria can enter the bloodstream during the routine daily activities such as tooth brushing, chewing, or dental procedures. Once in the bloodstream, these bacteria can travel to the respiratory system. Third, periodontitis can trigger a chronic inflammatory response that can release pro-inflammatory cytokines and other systemic immune mediators. These systemic inflammatory molecules can circulate to the respiratory system, and contribute to the development or exacerbation of respiratory diseases. Finally, periodontitis can modulate the whole host immune responses, impairing the defense mechanisms against respiratory pathogens that can cause respiratory diseases.

Oral microbiome is likely a reservoir for respiratory infections, as oral anaerobic bacteria are commonly found in aspiration pneumonia and lung abscesses [78], and periodontitis is epidemiologically implicated as a mortality risk factor for aspiration pneumonia in the elderly [79]. It is likely that polymicrobial synergistic interactions might occur in the lung tissue. In a mouse model of aspiration pneumonia, mixed infection with P. gingivalis and T. denticola caused significant increased inflammatory responses, reduced bacterial clearance and more severe lung disease compared with single infection with either bacterium [80]. Furthermore, it was observed that reducing oral microbial burden effectively decreased the incidence of aspiration pneumonia in elderly patients [81].

Periodontitis is also associated with chronic obstructive pulmonary disease (COPD), a commom respiratory respiratory disease that affects millions of people worldwide [82]. It was found that individuals with COPD had a significantly higher prevalence of severe periodontitits compared to those without COPD [83,84]. Polymicrobial infections including the opportunistic pathogen Pseudomonas aeruginosa are associated with exacerbations of COPD increasing its morbidity and mortality [85]. P. gingivalis is readily detected with P. aeruginosa in tracheal aspirates of patients with acute COPD exacerbations [86], and can enhance the pathogenicity of P. aeruginosa in the lower airway infection [87]. Indeed, P. gingivalis promotes the ability of P. aeruginosa to invade respiratory epithelial cells and modulates its apoptosis-inducing capacity through activating the signal transducer and activator of transcription 3 (STAT3) signaling pathway [88]. Inhibition of epithelial cell apoptosis for a substantial time following P. aeruginosa and P. gingivalis co-invasion may provide the bacteria with a safe intracellular niche and the opportunity to proliferate and establish infection, leading to an exacerbation of COPD.

Cancer

Cross-sectional and longitudinal epidemiologic studies suggest a positive association of periodontitis with cancer risk and certain specific types of cancer, including oral, lung, pancreatic, breast, and colorectal cancer [5,89,90]. The plausible mechanism for linking cancer and periodontitis may be the chronic stimulus from periodontal inflammation. Chronic inflammatory processes can generate free radicals and active intermediates causing oxidative stress that can lead to DNA mutations, ultimately resulting in aberrations of genetic structure and malignant transformation [4,91-93]. Additinally, the chronic inflammation associated with periodontal disease may weaken the immune system, making it more difficult for the body to fight off cancer cells. Several studies have shown that certain anti-inflammatory drugs may help prevent or decrease the risk of certain site-specific cancers, including those of the colorectum, esophagus, stomach, biliary tract, and breast [94,95]. These results suggest systemic inflammation can increase the cancer risk and related ailments [4,5].

In addition, proteolytic enzymes produced by periodontal pathogens including P. gingivalis, T. forsythia, and T. denticola, may devastate host immune system, resulting in the onset and progression of tumors. These bacterial enzymes, as well as other bacterial components such as endotoxins, and metabolic by-products that are naturally toxic to tissues, may cause direct DNA damage to neighboring epithelial cells. They can induce mutations in proto-oncogenes and tumor suppressor genes, or interfere with the molecular pathways involved in cell proliferation and/or survival [96].

A key-stone periodontal pathogen P. gingivalis is associated with oral squamous cell carcinoma (OSCC) [97,98], orodigestive cancer [99,100], and pancreatic cancer [101,102]. Certain immune subversive mechanisms of P. gingivalis are consistent with a role in cancer development. P. gingivalis promotes invasion of OSCC via inducing the expression of pro-matrix metalloproteinase-9 (MMP-9) by triggering proteinase activated receptor-2-mediated NF-κB activation (extracellular mechanism involving gingipain secretion) or by activating the extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases pathways (intracellular mechanism requiring β1-integrin-dependent invasion [103]. In addition, the gingipains additionally cleave the secreted proenzyme into mature MMP-9 (gelatinase), which promotes carcinoma cell migration [103]. It was found that P. gingivalis invasion of epithelial cells suppresses apoptosis and stimulates cell proliferation by inhibiting the p53 tumor suppressor [104].

Gastrointestinal cancer risk increases in individuals with periodontal disease or tooth loss [105]. Oral bacteria may activate alcohol and smoking-related carcinogens locally or systemically, through chronic inflammation [106,107]. A history of periodontal disease and the presence of circulating antibodies to selected periodontal pathogens, such as P. gingivalis and A. actinomycetemcomitans, have been associated with increased risk of pancreatic cancer [102]. It was also found out that important periodontal pathogen T. forsythia in the oral microbiota is associated with esophageal adenocarcinoma and depletion of the oral microbiome of the commensal Neisseria genus, and that Streptococcus pneumoniae were associated with a lower risk of esophageal adenocarcinomassion. Recently, it was observed that intratumoral P. gingivalis promoted pancreatic cancer progrevia elevating the secretion of neutrophilic chemokines and neutrophil elastase [101].

It was observed that F. nucleatum is associated with colorectal cancer [108,109], and can stimulate the growth of colorectal cancer cells [110]. This activity depends upon interactions between E-cadherin and the F. nucleatum adhesin FadA, in which expression is elevated in the cancerous colon tissue and is correlated with the expression of oncogenic and inflammatory genes [110]. In mouse models, it was found that F. nucleatum can specifically attract tumor-infiltrating myeloid cells and create a proinflammatory condition that promotes colorectal carcinogenesis [111]. It was also demonstrated that F. nucleatum potentiates intestinal tumorigenesis by suppressing cytotoxic and effector T cells [111,112]. F. nucleatum, in combination with P. gingivalis, can promote carcinogenesis by upregulating the IL-6/STAT3 pathway via the activation of toll-like receptors on oral epithelial cells [113].

Mental disorders

Recent research has indicated a potential relationship between periodontitis and mental disorders. Periodontal pathogens and/or pro-inflammatory cytokines and other inflammatory mediators can enter the bloodstream and reach the brain, affecting brain function and contributing to the development or worsening of mental disorders [114].

Major depression is frequently associated with systemic inflammatory diseases/conditions where pro-inflammatory cytokines, such as IL-1β, IL-2, IL-6, and TNF-α are overexpressed [115]. The pro-inflammatory cytokines communicate with neurons and microglia in the brain via the communication pathways, resulting in neuroinflammation [116]. A number of animal studies demonstrate that administration of LPS increases the expression of pro-inflammatory cytokines in microglia and perivascular macrophages in the brain, and causes abnormal behavior similar to major depression [117,118].

Recent epidemiological studies imply that periodontitis is a risk factor for such a neuroinflammatory and neurodegenerative disorder as Alzheimer’s disease (AD) [119,120]. Pathological hallmarks in AD are brain accumulations of amyloid-beta and neurofibrillary tangles consisting of aggregated and hyper-phosphorylated tau protein. The molecular mechanisms for the pathogenesis of AD have not yet been elucidated. One proposed mechanism is that periodontal pathogens can enter the bloodstream through inflamed periodontium and travel to the brain via weakened blood-brain-barrier, potentially triggering or exacerbating the neuroinflammation and involving pathogenesis of AD [121,122]. Several studies have found higher levels of periodontal pathogens, such as P. gingivalis, T. denticola, T. forsythia, F. nucleatum, and Prevotella intetmedia in the brains of individuals with AD compared to those without the condition. These bacteria have been detected in the amyloid plaques and neurofibrillary tangles [123]. In addition, elevated antibodies against these pathogens were found to be associated with AD [124,125]. Additionally, studies have shown that these periodontal pathogens can induce inflammation, oxidative stress, and damage to neurons in laboratory settings [126].

A keystone periodontal pathogen P. gingivalis has been associated with the pathogenesis of AD. P. gingivalis and its virulence factors, such as gingipains and LPS, are frequently detected in the brains of subjects with AD [127,128]. In experimental animal study, P. gingivalis infection was found to result increased pro-inflammatory mediators in the brain, increased production of β-amyloid substance, and cognitive impairment [129,130]. Moreover, gingipains (the cysteine protease Kgp) produced by P. gingivalis play critical roles in neuroinflammation and cognitive decline in mice [131,132]. Since gingipains can break down the beta-amyloid protein, the activity of P. gingivalis can lead to producing smaller fragments of the amyloid protein that are more toxic to the brain. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function [133]. It was observed that gingipain inhibition by small-molecule inhibitor reduced the bacterial load of an established P. gingivalis brain infection, blocked-amyloid production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipains in the brain play a central role in the pathogenesis of AD and gingipain inhibitors could be effective for treating P. gingivalis brain colonization and neurodegeneration in AD [127].

Epidemiological, clinical interventional and experimental studies provide numerous evidence that periodontitis adversely affects systemic health through biologically plausible mechanisms. These mechanisms are mediated by direct activity of periodontal pathogens and/or systemic inflammatory/immune responses triggered by local periodontal infection. It is well established that periodontal pathogens can enter the bloodstream and reach to distant tissues, inducing systemic inflammation that can contribute to the development or exacerbation of various systemic diseases. Recently, the novel roles of a key periodontal pathogen P. gingivalis and its crucial virulence factors including gingipain, LPS, and other enzymes have been suggested in the development of systemic diseases, such as CVD, RA, pancreatic cancer, and AD. These data may shed light on developing new therapeutic approaches to reduce the risk of periodontitis-associated comorbidities.

It is evident that by reducing bacterial load in the periodontium and subsequent systemic inflammation thorough good oral hygiene control can help reduce the risk of developing or worsening systemic diseases that are associated with periodontitis, eventually promoting systemic health.

None.

The author declares no competing interests.