Clinical periodontitis is associated with an increased risk for cardiovascular diseases (CVDs) through systemic inflammation as the etiopathogenic link. Whether the oral microbiota, especially its quality, quantity, serology, and virulence factors, plays a role in atherogenesis is not clarified. Patients with periodontitis are exposed to bacteria and their products, which have access to the circulation directly through inflamed oral tissues and indirectly (via saliva) through the gastrointestinal tract, resulting in systemic inflammatory and immunologic responses. Periodontitis is associated with persistent endotoxemia, which has been identified as a notable cardiometabolic risk factor. The serology of bacterial biomarkers for oral dysbiosis is associated with an increased risk for subclinical atherosclerosis, prevalent and future coronary artery disease, and incident and recurrent stroke. In addition to species-specific antibodies, the immunologic response includes persistent, cross-reactive, proatherogenic antibodies against host-derived antigens. Periodontitis may affect lipoprotein metabolism at all levels, and all lipoprotein classes are affected. Periodontitis or its bacterial signatures may be involved not only in increased storage of proatherogenic lipids but also in attenuation of the anti-atherogenic processes, thereby putatively increasing the net risk of atherosclerosis. In this review we summarize possible molecular mediators between the dysbiotic oral microbiota and atherosclerotic processes.

Lipopolysaccharide is an important virulence factor of gramnegative bacteria. It is often referred to as endotoxin, which is used synonymously with lipopolysaccharide, although there are a few endotoxins that are not lipopolysaccharides. 1 Virulence is determined as the strength of the pathogenic potential, referring to the relative capacity of a microbe to cause damage in the host and the ability to overcome host defenses. 2 Several virulence factors or characteristics contribute to the ability of a microbe to cause disease. For example, fimbriae, adhesins, and invasins promote colonization, growth, attachment, and invasiveness. Other factors, such as toxins and proteases, are more immunoinhibitory or immunosuppressive and contribute to tissue-destructive capacity and evasion of host responses. Also, the susceptibility of the host plays a role in infections.Lipopolysaccharide resides in the outer membrane of the bacteria, where its hydrophobic structures composed of fatty acid chains anchor the molecule into the bacterial membrane, and the hydrophilic portion (ie the rest of the molecule) projects from the membrane. Lipopolysaccharide is a potent activator of innate and adaptive immune responses, as well as of tissue destruction cascades. It plays a major role in the pathogenesis of periodontitis, where an abundant number of gram-negative species is a typical determinant of the periodontal microbiota.Translocation of lipopolysaccharide to the bloodstream causes endotoxemia (ie, lipopolysaccharide activity present in serum/ plasma). An approximate twofold increase of lipopolysaccharide activity in apparently healthy subjects is considered 'metabolic endotoxemia,' which has been associated with unhealthy nutrition. 3 Circulating endotoxin is alternatively called 'intestinal endotoxemia,' referring to its presumed source, the gastrointestinal tract. The levels reported, for example, among healthy blood donors, middle-aged subjects, or healthy elderly subjects have been 0.3 pg/ml, 1.2 pg/ml, and 6.7 pg/ml, respectively. [4][5][6] The corresponding level may reach 850 pg/ml in gram-negative septic shock caused by lipopolysaccharide. 7 Human cells expressing the lipopolysaccharide receptor complex are highly sensitive and can respond in minutes to picograms per milliliter of lipopolysaccharide. Chronic endotoxemia is involved in the pathogenesis of many inflammation-driven conditions, especially cardiometabolic disorders, including atherosclerotic cardiovascular diseases, obesity, liver diseases, diabetes, and metabolic syndrome,e 8 and thus it is regarded as a risk factor.Periodontitis patients are known to have increased circulating lipopolysaccharide activity and metabolic disturbances, which may be either the cause or effect of endotoxemia. Observations that bacteria disseminate into circulation after toothbrushing and periodontal procedures 9,10 and assumptions that endotoxin may disseminate through inflamed periodontium and bleeding gums support the This is an open access article under the terms of the Creative ...

Background Translocation of lipopolysaccharide from gram‐negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome‐wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high‐performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis‐related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome‐wide significant association with 741 single‐nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included KNG1 , KLKB1 , F12 , SLC34A1 , YPEL4 , CLP1 , ZDHHC5 , SERPING1 , CBX5 , and LIPC . The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism. Conclusions The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.

Genetic factors play a role in periodontitis. Here we examined whether the risk haplotype of MHC class III region BAT1-NFKBIL1-LTA and lymphotoxin-α polymorphisms associate with salivary biomarkers of periodontal disease. A total of 455 individuals with detailed clinical and radiographic periodontal health data were included in the study. A 610 K genotyping chip and a Sequenom platform were used in genotyping analyses. Phospholipid transfer protein activity, concentrations of lymphotoxin-α, IL-8 and myeloperoxidase, and a cumulative risk score (combining Porphyromonas gingivalis, IL-1β and matrix metalloproteinase-8) were examined in saliva samples. Elevated IL-8 and myeloperoxidase concentrations and cumulative risk scores associated with advanced tooth loss, deepened periodontal pockets and signs of periodontal inflammation. In multiple logistic regression models adjusted for periodontal parameters and risk factors, myeloperoxidase concentration (odds ratio (OR); 1.37, P = 0.007) associated with increased odds for having the risk haplotype and lymphotoxin-α concentration with its genetic variants rs2857708, rs2009658 and rs2844482. In conclusion, salivary levels of IL-8, myeloperoxidase and cumulative risk scores associate with periodontal inflammation and tissue destruction, while those of myeloperoxidase and lymphotoxin-α associate with genetic factors as well.

The use of systemic antibiotics may influence the oral microbiota composition. Our aim was to investigate in this retrospective study whether the use of prescribed antibiotics associate with periodontal status, oral microbiota, and antibodies against the periodontal pathogens. The Social Insurance Institution of Finland Data provided the data on the use of systemic antibiotics by record linkage to purchased medications and entitled reimbursements up to 1 year before the oral examination and sampling. Six different classes of antibiotics were considered. The Parogene cohort included 505 subjects undergoing coronary angiography with the mean (SD) age of 63.4 (9.2) years and 65% of males. Subgingival plaque samples were analysed using the checkerboard DNA-DNA hybridisation. Serum and saliva antibody levels to periodontal pathogens were analysed with immunoassays and lipopolysaccharide (LPS) activity with the LAL assay. Systemic antibiotics were prescribed for 261 (51.7%) patients during the preceding year. The mean number of prescriptions among them was 2.13 (range 1–12), and 29.4% of the prescriptions were cephalosporins, 25.7% penicillins, 14.3% quinolones, 12.7% macrolides or lincomycin, 12.0% tetracycline, and 5.8% trimethoprim or sulphonamides. In linear regression models adjusted for age, sex, current smoking, and diabetes, number of antibiotic courses associated significantly with low periodontal inflammation burden index (PIBI, p < 0.001), bleeding on probing (BOP, p = 0.006), and alveolar bone loss (ABL, p = 0.042). Cephalosporins associated with all the parameters. The phyla mainly affected by the antibiotics were Bacteroidetes and Spirochaetes. Their levels were inversely associated with the number of prescriptions (p = 0.010 and p < 0.001) and directly associated with the time since the last prescription (p = 0.019 and p < 0.001). Significant inverse associations were observed between the number of prescriptions and saliva concentrations of Prevotella intermedia, Tannerella forsythia, and Treponema denticola and subgingival bacterial amounts of Porphyromonas gingivalis, P. intermedia, T. forsythia, and T. denticola. Saliva or serum antibody levels did not present an association with the use of antibiotics. Both serum (p = 0.031) and saliva (p = 0.032) LPS activity was lower in patients having any antibiotic course less than 1 month before sampling. Systemic antibiotics have effects on periodontal inflammation and oral microbiota composition, whereas the effects on host immune responses against the periodontal biomarker species seem unchanged.

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Headlines Chronic oral infections are associated with cardiovascular diseases via direct and indirect mechanisms Inflammation is an important link between oral infections and CVD Oral infections and CVD share many common risk factors Periodontal treatment has been proven to be beneficial for general health in addition to oral health