Severe periodontitis is associated with systemic inflammation and a dysmetabolic status: a case-control study

BACKGROUND AND AIM: A cluster of metabolic factors defines a syndrome that predisposes to diabetes and cardiovascular disease. Chronic infections such as periodontitis might alter these individual metabolic factors and the systemic inflammatory burden. The aim of this study was to investigate the association between severe periodontitis and increase in inflammatory and metabolic risk factors for cardiovascular disease. MATERIALS AND METHODS: We examined 302 patients with severe periodontitis and 183 healthy controls, and we collected a blood sample from each subject in order to investigate differences in inflammatory (leukocyte numbers and differential counts) and metabolic markers (lipids and glucose). RESULTS: After correcting for differences in age, gender, smoking and ethnicity, periodontitis subjects exhibited a low-grade systemic inflammation (increased white cell counts, 1.10+/-1.02 x 10(9)/l, 95%CI 1.05-1.15, p=0.0001), dyslipidemia [lower high-density lipoprotein cholesterol, 1.14+/-1.03 mmol/l, 95%CI 1.08-1.20, p<0.0001 and higher low-density lipoprotein cholesterol, 1.12+/-1.03, 95%CI 1.05-1.19, p<0.0001) and increased non-fasting serum glucose levels (1.04+/-1.01 mmol/l, 95%CI 1.02-1.06, p=0.01) when compared with controls. The associations were confirmed in a subpopulation of Caucasian non-smokers. A trend for a dose dependent effect of the number of periodontal pockets on the tested inflammatory and metabolic markers was observed. Conclusions: These data suggest a possible link between severe generalized periodontitis, systemic inflammation and a dysmetabolic state in otherwise healthy individuals.     

Periodontitis is associated with preeclampsia in pregnant women

BACKGROUND: Recent investigations have demonstrated a positive association between periodontitis and pregnancy complications. The purpose of this study was to determine the effect of periodontitis and the subgingival microbial composition on preeclampsia. METHODS: A case-control study was carried out in Cali, Colombia that included 130 preeclamptic and 243 non-preeclamptic women between 26 to 36 weeks of pregnancy. Sociodemographic data, obstetric risk factors, periodontal status, and subgingival microbial composition were determined in both groups. Preeclampsia was defined as blood pressure>or=140/90 mm Hg, and >or=2+ proteinuria, confirmed by 0.3 g proteinuria/24 hours of urine specimens. Controls were healthy pregnant women. Odds ratios (ORs) for periodontitis and subgingival microbiota compositions were calculated. RESULTS: A total of 83 out of 130 preeclamptic women (63.8%) and 89 out of 243 controls (36.6%) had chronic periodontitis (OR: 3.0; 95% confidence interval (CI): 1.91 to 4.87; P<0.001). Clinical attachment loss increased in the case group (4.0+/-0.10 mm) compared to the control group (3.0+/-0.08 mm) (P<0.001). The average newborn birth weight from preeclamptic mothers was 2.453 g, whereas in controls was 2.981 g (P<0.001). Two red complex microorganisms, Porphyromonas gingivalis and Tannerella forsythensis, and the green complex microorganism Eikenella corrodens were more prevalent in the preeclamptic group than in controls (P<0.01). CONCLUSIONS: Chronic periodontal disease and the presence of P. gingivalis, T. forsythensis, and E. corrodens were significantly associated with preeclampsia in pregnant women. Further research is needed to establish pathogenic mechanisms of active periodontal disease and subgingival periodontopathogens related to preeclampsia development.     

Periodontitis in the primary dentition associated with Actinobacillus actinomycetemcomitans infection and leukocyte dysfunction

2 siblings, aged 5 years (girl) and 7 years (boy), with periodontitis in the primary dentition were studied. Actinobacillus actinomycetemcomitans was isolated from the gingival pockets of both children. The titers of IgG antibodies against A. actinomycetemcomitans were elevated, and the polymorphonuclear leukocytes had a decreased capacity to ingest IgG-coated latex particles. Other functions of the polymorphonuclear leukocytes were normal. After antibiotic therapy and for the 7-year-old boy, debridement of the gingival pockets A. actinomycetemcomitans was no longer detectable in the gingival pockets, and the phagocytic capacity of the polymorphonuclear leukocytes was normalized. After 2 1/2 years, A. actinomycetemcomitans was found again in the gingival pockets of the boy, and once more his polymorphonuclear leukocytes had a decreased capacity to ingest IgG-coated latex particles. The antibiotic therapy was repeated and 6 months later, the number of A. actinomycetemcomitans was very low and the phagocytic capacity of the polymorphonuclear leukocytes was back to normal. This case report suggests that A. actinomycetemcomitans may be involved in the etiology of periodontitis in the primary dentition, possibly by triggering a phagocytic dysfunction of polymorphonuclear leukocytes.     

Periodontal disease early in pregnancy is associated with maternal systemic inflammation among African American women

BACKGROUND: Maternal periodontal disease is a chronic oral infection with local and systemic inflammatory responses and may be associated with adverse pregnancy outcomes. This study determined whether maternal periodontal disease in early pregnancy is associated with elevated serum C-reactive protein (CRP) levels and whether maternal race influences the relationship between maternal periodontal disease and systemic inflammatory responses. METHODS: A secondary analysis of prospectively collected data from the Oral Conditions and Pregnancy study was conducted. Healthy women at <26 weeks of gestation underwent an oral health examination and had blood collected. Periodontal disease was categorized by clinical criteria, and maternal serum was analyzed for CRP levels using highly sensitive enzyme-linked immunosorbent assay kits. An elevated CRP level was defined as >75th percentile. Demographic and medical data were obtained from the women's charts. Chi-square and multivariable logistic regression models were used to determine maternal factors associated with an elevated CRP. An adjusted odds ratio (OR) for elevated CRP levels was calculated and stratified by race and periodontal disease category. RESULTS: The median (interquartile) CRP level was 4.8 (0.6 to 15.7) microg/ml, and an elevated CRP level (>75th percentile) was 15.7 microg/ml. African American race and moderate/severe periodontal disease were significantly associated with elevated CRP levels. When stratified by race, moderate/severe periodontal disease remained associated with an elevated CRP level among African American women (adjusted OR: 4.0; 95% confidence interval [CI]: 1.2 to 8.5) but not among white women (adjusted OR: 0.9; 95% CI: 0.2 to 3.6) after adjusting for age, smoking, parity, marital status, insurance status, and weight. CONCLUSION: Among African American women, moderate/severe periodontal disease is associated with elevated CRP levels early in pregnancy.     

Local inflammatory markers and systemic endotoxin in aggressive periodontitis

While much research has focused on local and systemic factors contributing to periodontal disease, little is known regarding mechanisms linking these factors. We have previously reported a systemic hyper-inflammatory response to bacterial endotoxin in localized aggressive periodontitis (LAP). The objectives of this study were to delineate cyto/chemokines in gingival crevicular fluid (GCF) and evaluate systemic levels of endotoxin associated with LAP. Clinical parameters, GCF, and peripheral blood were collected from: 34 LAP, 10 healthy siblings, and nine healthy unrelated control individuals. Cyto/chemokines were quantified in GCF, systemic endotoxin levels were quantified in plasma, and correlation analysis was performed among all parameters. Nine mediators were elevated in LAP diseased sites as compared with healthy sites (TNFα, INFγ, IL1β, IL2, IL6, IL10, Il12p40, GMCSF, and MIP1α, p < 0.001), while MCP1, IL4, and IL8 were elevated in healthy sites (p < 0.01). Four- to five-fold-higher endotoxin levels were detected in LAP plasma compared with that from healthy participants (p < 0.0001), which correlated with all clinical parameters and most cyto/chemokines analyzed. In conclusion, higher systemic levels of endotoxin were found in LAP, which correlates with an exacerbated local inflammatory response and clinical signs of disease. (Clinicaltrials.gov number, NCT01330719).     

Periodontitis is associated with aggravation of prediabetes in Zucker fatty rats

BACKGROUND: Prediabetes is part of the natural history of type 2 diabetes. Few human studies have addressed the relationship between periodontitis and prediabetes. The Zucker fatty rat (ZFR) is a known model of prediabetes, characterized by hyperinsulinemia, dyslipidemia, and moderate hypertension. The aim of the present study was to investigate whether periodontitis affects the prediabetic state of ZFRs. METHODS: Male adult ZFRs (fa/fa; N = 24) and their lean littermates (+/fa; N = 24) were studied. Periodontitis was induced with ligatures in half of the ZFRs and lean rats, whereas the other half served as controls. After 4 weeks, body weight, food intake, glucose tolerance, insulin resistance, free fatty acids, cytokines, and alveolar bone loss were recorded. RESULTS: ZFRs with periodontitis presented increased glucose intolerance (P = 0.03) and a slight increase in fasting glucose from initial to final evaluation, as detected through paired analysis (P = 0.03). Among lean rats, those with periodontitis presented higher final glucose intolerance than those without periodontitis (P = 0.01). Furthermore, periodontitis in lean rats was associated with increased fasting glucose, insulin, and insulin resistance, as evaluated through paired analysis (P = 0.003, P = 0.008, and P = 0.001, respectively). Regarding alveolar bone analysis, ZFRs with periodontitis demonstrated significantly more bone loss compared to lean rats with periodontitis (P <0.001). CONCLUSIONS: Prediabetes worsened periodontitis, and periodontitis, in turn, was associated with deterioration of glucose metabolism in ZFRs, suggesting a progress toward diabetes. Furthermore, periodontitis also affected glucose regulation in lean rats.     

Serum antibodies to periodontal pathogens and markers of systemic inflammation

AIM: We examined the relationship between serum antibodies against Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, and plasma fibrinogen and serum C-reactive protein (CRP) in a nationally representative sample. METHODS: Data on 2,973 participants aged 40 years and older from the third National Health and Nutrition Examination Survey, second phase (1991-1994) were used. Three logistic regression models adjusted for gender, race, educational attainment, diabetes, cigarette smoking, body mass index (BMI), and other inflammatory conditions were constructed, based on three different assumptions: (A) no access to dental/periodontal data; (B) knowledge of number of teeth present but not of clinical periodontal status; and (C) knowledge of both dental and clinical periodontal status. RESULTS: High fibrinogen (>400 mg/dl) was unrelated to P. gingivalis and A. actinomycetemcomitans antibodies in all models. High CRP (>0.4 mg/dl) was related to high antibody levels to P. gingivalis in models A [odds ratios (OR) 1.63, 95% confidence intervals (CI) 1.15-2.32], B (OR 1.69, 95% CI 1.18-2.41), and C (OR 1.58, 95% CI 1.12-2.23). In model C, high CRP was related to >30% extent of attachment loss of >or=3 mm (OR 1.58, 95% CI 1.19-2.08). Antibodies to A. actinomycetemcomitans were not associated with high CRP levels in any model. CONCLUSIONS: High serum titre to P. gingivalis and the presence of periodontal disease are independently related to high CRP levels.     

Periodontitis and diabetes interrelationships: role of inflammation

Diabetes mellitus is a systemic disease with several major complications affecting both the quality and length of life. One of these complications is periodontal disease (periodontitis). Periodontitis is much more than a localized oral infection. Recent data indicate that periodontitis may cause changes in systemic physiology. The interrelationships between periodontitis and diabetes provide an example of systemic disease predisposing to oral infection, and once that infection is established, the oral infection exacerbates systemic disease. In this case, it may also be possible for the oral infection to predispose to systemic disease. In order to understand the cellular/molecular mechanisms responsible for such a cyclical association, one must identify common physiological changes associated with diabetes and periodontitis that produce a synergy when the conditions coexist. A potential mechanistic link involves the broad axis of inflammation, specifically immune cell phenotype, serum lipid levels, and tissue homeostasis. Diabetes-induced changes in immune cell function produce an inflammatory immune cell phenotype (upregulation of proinflammatory cytokines from monocytes/polymorphonuclear leukocytes and downregulation of growth factors from macrophages). This predisposes to chronic inflammation, progressive tissue breakdown, and diminished tissue repair capacity. Periodontal tissues frequently manifest these changes because they are constantly wounded by substances emanating from bacterial biofilms. Diabetic patients are prone to elevated low density lipoprotein cholesterol and triglycerides (LDL/TRG) even when blood glucose levels are well controlled. This is significant, as recent studies demonstrate that hyperlipidemia may be one of the factors associated with diabetes-induced immune cell alterations. Recent human studies have established a relationship between high serum lipid levels and periodontitis. Some evidence now suggests that periodontitis itself may lead to elevated LDL/TRG. Periodontitis-induced bacteremia/endotoxemia has been shown to cause elevations of serum proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), which have been demonstrated to produce alterations in lipid metabolism leading to hyperlipidemia. Within this context, periodontitis may contribute to elevated proinflammatory cytokines/serum lipids and potentially to systemic disease arising from chronic hyperlipidemia and/or increased inflammatory mediators. These cytokines can produce an insulin resistance syndrome similar to that observed in diabetes and initiate destruction of pancreatic beta cells leading to development of diabetes. Thus, there is potential for periodontitis to exacerbate diabetes-induced hyperlipidemia, immune cell alterations, and diminished tissue repair capacity. It may also be possible for chronic periodontitis to induce diabetes.     

Effects of periodontal therapy on systemic markers of inflammation in patients with metabolic syndrome: a controlled clinical trial

Background: The systemic inflammation in both metabolic syndrome (MetS) and periodontitis is a common denominator of the association of these conditions with higher risk of atherosclerosis. The current study investigates whether periodontal therapy may reduce systemic inflammation in patients with MetS and reduce cardiovascular risk. Methods: A parallel‐arm, double‐blind, randomized clinical trial of 1‐year duration in patients with MetS and periodontitis was conducted. Participants were randomized to an experimental treatment group (ETG) (n = 82) that received plaque control and root planing plus amoxicillin and metronidazole or to a control treatment group (CTG) (n = 83) that received plaque control instructions, supragingival scaling, and two placebos. Risk factors for cardiovascular disease were recorded; serum lipoprotein cholesterol, glucose, body mass index (BMI), C‐reactive protein (CRP) and fibrinogen concentrations, and clinical periodontal parameters were assessed at baseline and every 3 months until 12 months after therapy. The primary and secondary outcomes were changes in CRP and fibrinogen levels, respectively. Results: The baseline patients’ characteristics of both groups were similar. No significant changes in lifestyle factors, frequency of hypertension, BMI, serum lipoprotein cholesterol, and glucose levels were observed during the study period. The periodontal parameters significantly improved in both groups 3 months after therapy (P = 0.0001) and remained lower than baseline up to 12 months. The improvement of periodontal status was significantly greater in the ETG (P = 0.0001). A multiple linear regression analysis, controlled for sex, smoking, hypertension, and extent of periodontitis, demonstrated that CRP levels decreased with time and that this reduction was significant at 9 (P = 0.024) and 12 (P = 0.001) months in both groups, without difference between the groups. Fibrinogen levels significantly decreased in the ETG at 6 and 12 months but not in the CTG. Conclusion: Reduction of periodontal inflammation either with root planing and systemic antibiotics or with plaque control and subgingival scaling significantly reduces CRP levels after 9 months in patients with MetS.     

P. gingivalis and E. coli lipopolysaccharides exhibit different systemic but similar local induction of inflammatory markers

BACKGROUND: Porphyromonas gingivalis is a Gram-negative bacterium that is an important etiologic agent of human adult periodontitis. The goal of the study was to test the hypothesis that two isoforms of P. gingivalis lipopolysaccharide (PgLPS), PgLPS(1435)(/1449) and PgLPS(1690), exhibit differences in their capacity to stimulate systemic versus local responses compared to Escherichia coli lipopolysaccharide (LPS). METHODS: LPS was inoculated into the scalp of mice, and the response was measured locally at the site of inoculation and systemically in the heart/aorta. Vascular cell adhesion molecule (VCAM)-1 was assessed at the protein level by enzyme-linked immunosorbent assay, and VCAM-1, E-selectin, and intercellular adhesion molecule (ICAM)-1 were assessed at the RNA level of the RNase protection assay. Serum tumor necrosis factor-alpha (TNF-alpha) levels were also measured. RESULTS: E. coli LPS and both isoforms of P. gingivalis LPS were relatively potent in stimulating the expression of inflammatory markers, with E. coli LPS being more potent. In contrast, when the systemic response was measured in the heart/aorta, E. coli LPS, but not P. gingivalis LPS, significantly induced inflammatory markers. At moderate to low doses (1 and 10 microg per injection), serum TNF-alpha levels were minimally induced by P. gingivalis LPS compared to E. coli LPS. CONCLUSIONS: Both forms of P. gingivalis LPS stimulated an inflammatory response when injected into connective tissue but were minimally stimulatory when a systemic response was measured. In contrast, E. coli LPS was a potent stimulus at the systemic and local levels.     

Host modulation: controlling the inflammation to control the infection

Historically, periodontal disease (gingivitis and periodontitis) has been recognized as being primarily of bacterial origin. However, recent evidence indicates that while bacteria are necessary for disease development they are not sufficient for the clinical manifestation of the many and varied forms of periodontal disease. It is becoming increasingly apparent that it is the host inflammatory response to the subgingival bacteria that is responsible for the tissue damage and, most likely, progression of the disease. We explore the concept that it is the subgingival microenvironment modified by the inflammatory response that leads to a change from a commensal to pathogenic microbiota. In this review, we examine the evidence for the emerging paradigm supporting the central role of inflammation rather than specific microbiota in the pathogenesis of periodontitis, and that by controlling the inflammation, it is possible to control the infection. As an extension of this, we propose a working model for the ongoing monitoring of periodontal patients using the medical model of ‘treat to target’.