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Life Extension Magazine July 2009

Oral Probiotics

The host cytokine response to Porphyromonas gingivalis is modified by gingipains.

BACKGROUND/AIMS: Clinical studies indicate that primary proinflammatory cytokines, such as interleukin-1beta (IL-1beta) are elevated in the gingival crevice around teeth with periodontitis but the secondary cytokines and chemokines, IL-6 and IL-8, are not. The human gingival epithelial cells (HGECs) lining the gingival sulcus respond to perturbation by microbes of dental plaque by releasing a wide range of cytokines. Porphyromonas gingivalis, a putative periodontal pathogen, possesses numerous virulence factors some of which directly impact on the host response. In the present study, we sought to determine how P. gingivalis influences the inflammatory cytokine responses. METHODS: HGECs were challenged with P. gingivalis and other putative periodontal pathogens, and the resultant production of IL-1beta, IL-6, and IL-8 was assayed by enzyme-linked immunosorbent assay (ELISA). Culture supernatants and recombinant human cytokines were challenged with live P. gingivalis wild-type and gingipain-deficient strains and the resultant cytokine profile was assessed by ELISA and Western blot. RESULTS: We show here that primary HGECs challenged with live P. gingivalis result in high levels of IL-1beta but not the related secondary cytokines IL-6 and IL-8. We further demonstrate that cytokine response differences are the result of the action of P. gingivalis proteases, with lysine gingipain being the most effective. CONCLUSION: We conclude that P. gingivalis, through lysine gingipain, can subvert the protective host proinflammatory response by direct cytokine degradation. Changes in the crevicular cytokine profile have consequences in periodontal disease pathogenesis that should be considered in the development of diagnostic and therapeutic modalities.

Oral Microbiol Immunol. 2009 Feb;24(1):11-7

Low-grade inflammation in chronic infectious diseases: paradigm of periodontal infections.

Increasing evidence implicates periodontitis, a chronic inflammatory disease of the tooth-supporting structures, as a potential risk factor for increased morbidity or mortality for several systemic conditions including cardiovascular disease (atherosclerosis, heart attack, and stroke), pregnancy complications (spontaneous preterm birth [SPB]), and diabetes mellitus. Cross-sectional, case-control, and cohort studies indicate that periodontitis may confer two- and up to sevenfold increase in the risk for cardiovascular disease and premature birth, respectively. Given the recently acquired knowledge that systemic inflammation may contribute in the pathogenesis of atherosclerosis and may predispose to premature birth, research in the field of periodontics has focused on the potential of this chronic low-grade inflammatory condition to contribute to the generation of a systemic inflammatory phenotype. Consistent with this hypothesis clinical studies demonstrate that periodontitis patients have elevated markers of systemic inflammation, such as C-reactive protein (CRP), interleukin 6 (IL-6), haptoglobin, and fibrinogen. These are higher in periodontal patients with acute myocardial infarction (AMI) than in patients with AMI alone, supporting the notion that periodontal disease is an independent contributor to systemic inflammation. In the case of adverse pregnancy outcomes, studies on fetal cord blood from SBP babies indicate a strong in utero IgM antibody response specific to several oral periodontal pathogens, which induces an inflammatory response at the fetal-placental unit, leading to prematurity. The importance of periodontal infections to systemic health is further strengthened by pilot intervention trials indicating that periodontal therapy may improve surrogate cardiovascular outcomes, such as endothelial function, and may reduce four- to fivefold the incidence of premature birth. Nevertheless, further research is needed to fully discern the underlying mechanisms by which local chronic infections can have an impact on systemic health, and in this endeavor periodontal disease may serve as an ideal disease model.

Ann N Y Acad Sci. 2006 Nov;1088:251-64

Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events.

OBJECTIVE: In periodontitis, overgrowth of gram-negative bacteria may cause endotoxemia and systemic inflammation leading to cardiovascular diseases (CVD). We investigated in a prospective study the associations of serum endotoxin, antibodies to periodontal pathogens, and inflammation markers with the risk of incident CVD. METHODS AND RESULTS: The FINRISK 1992 cohort of 6051 individuals was followed up for 10 years. We examined 185 incident CVD events and a control cohort of 320 individuals using a prospective case-cohort design. High antibody response to periodontal pathogens independently predicted incident CVD events with hazard ratios (HR, quartile 4 versus quartiles 1 to 3, 95% CI) of 1.87 (1.13 to 3.08). The subjects with a high antibody response and high CRP or interleukin (IL)-6 had multivariate-adjusted HRs of 3.01 (1.27 to 7.09) and 3.11 (1.42 to 6.83) compared with low-responders, respectively. The corresponding HRs for high endotoxin concentration were 1.82 (1.22 to 2.73, alone), 3.92 (1.99 to 7.74, with CRP), 3.54 (1.78 to 7.03, with IL-6), and 2.26 (1.13 to 4.52, with tumor necrosis factor (TNF)-alpha) after adjusting for age and gender. These associations were abolished after adjusting for serum lipids. High endotoxin/HDL ratio, however, had a multivariate-adjusted HR of 1.92 (1.19 to 3.08) for CVD events. CONCLUSIONS: Our results suggest that the exposure to periodontal pathogens or endotoxin induces systemic inflammation leading to increased risk for CVD.

Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1433-9

Periodontal infection: a potential risk factor for pre-term delivery of low birth weight (PLBW) babies.

Pre-term delivery of low-birth-weight (PLBW) babies is considered a major peri-natal problem in many countries and is contributing substantially to infant mortality and to childhood handicap. There is a reported incidence of pre-term delivery of low-birth-weight (PLBW) babies of 37% of all live births in Pakistan, which has a tremendous impact on health care system in this community. The prevalence of periodontal disease in Pakistan is also very high in all age groups and women of child bearing age (18-34 years) are no exception. Recent studies indicate periodontal infection as a potential independent risk factor for PLBW, and is considered to be 7 times more likely to be associated than any other risk factors. Several postulated mechanisms have been reviewed, including the virulence effects and role of asymptomatic bacteraemia, focusing on the bacterial load in periodontium facilitating its transmission from oral cavity to the uterus. The indication that periodontal disease is a potential risk factor for the delivery of PLBW; a high level of periodontal disease in women of child bearing age and similar high level of PLBW babies in country, calls for further longitudinal investigations that validate a causal relationship between periodontal infection and pre-term delivery of LBW babies in Pakistan. A review of literature and preliminary communication for a planned study is presented.

J Pak Med Assoc. 2005 Oct;55(10):448-52

The relationship between oral health and diabetes mellitus.

BACKGROUND: The term “diabetes mellitus” describes a group of disorders characterized by elevated levels of glucose in the blood and abnormalities of carbohydrate, fat and protein metabolism. A number of oral diseases and disorders have been associated with diabetes mellitus, and periodontitis has been identified as a possible risk factor for poor metabolic control in subjects with diabetes. METHODS: The authors reviewed the literature to identify oral conditions that are affected by diabetes mellitus. They also examined the literature concerning periodontitis as a modifier of glycemic control. RESULTS: Although a number of oral disorders have been associated with diabetes mellitus, the data support the fact that periodontitis is a complication of diabetes. Patients with long-standing, poorly controlled diabetes are at risk of developing oral candidiasis, and the evidence indicates that periodontitis is a risk factor for poor glycemic control and the development of other clinical complications of diabetes. Evidence suggests that periodontal changes are the first clinical manifestation of diabetes. CONCLUSIONS: Diabetes is an important health care problem. The evidence suggests that oral health care providers can have a significant, positive effect on the oral and general health of patients with diabetes mellitus.

J Am Dent Assoc. 2008 Oct;139 Suppl:19S-24S

Efficacy of periodontal treatment on glycaemic control in diabetic patients: A meta-analysis of interventional studies.

AIM: There is growing evidence that periodontal disease may favour the incidence or aggravation of diabetes and its complications. To investigate the issue, we conducted a meta-analysis of the effect of periodontal therapy on glycaemic control in diabetic patients. METHODS: A literature search was carried out using seven databases (Medline, EMBASE, LILACS, The Cochrane Library, Pascal, IADR Abstracts and Current Contents), with no language restrictions. We followed the QUOROM-recommended standards for improving the quality of reporting meta-analyses of interventional studies. RESULTS: Twenty-five studies, involving 976 subjects altogether, were included in the present systematic review. Of these, nine studies, involving a total of 485 patients, were controlled trials and were included in the meta-analysis. The standardized mean difference in HbA(1c) with the treatment of periodontal disease was 0.46 (95% CI: 0.11, 0.82). These findings suggest that periodontal treatment could lead to a significant 0.79% (95% CI: 0.19, 1.40) reduction in HbA(1c) level. CONCLUSION: The present meta-analysis represents the best information available to date that addresses this issue, and suggests that periodontal treatment could improve glycaemic control. Nevertheless, these results need to be viewed with caution because of a lack of robustness, and deficiencies in the design of some of the studies included. A randomized controlled trial with sufficient statistical power would help to confirm the results of this meta-analysis.

Diabetes Metab. 2008 Nov;34(5):497-506

Chronic periodontitis, a significant relationship with acute myocardial infarction.

BACKGROUND: Chronic periodontitis (CP) has been associated with cardiovascular diseases. The study purposes were to identify the odds of acute myocardial infarction (AMI) and CP defined at different thresholds. METHODS AND RESULTS: We studied 80 subjects with clinically confirmed AMI and 80 matched control subjects with no evidence of cardiovascular disease all receiving a comprehensive periodontal examination. Statistical analysis demonstrated a difference in the proportion of sites with a periodontal probing depth >/=6.0mm (2.7% for non-AMI and 12.1% for AMI group, 95% CI: -2.8 to 0.01, P<0.05) but no difference in the extent of gingival bleeding was found between groups. The odds ratio of having AMI and periodontitis varied between 9.2:1 to 14.1:1 with the greatest odds ratio if bone loss exceeded 4mm at >/=50% of the teeth (OR: 14.1:1, 95% CI: 5.5 to 28.2, P<0.0001). The odds ratio remained significant also when only non-smokers were considered (51 subjects) (OR: 7.0:1, 95% CI: 2.0 to 24.3, P<0.01). CONCLUSIONS: Our findings suggest that patients who at routine dental visits demonstrate evidence of bone loss around several teeth can predictably be identified as being at risk for future AMI. Such subjects should be referred for medical and periodontal examinations and treatments.

Eur Heart J. 2003 Dec;24(23):2108-15

Periodontal disease is associated with renal insufficiency in the Atherosclerosis Risk In Communities (ARIC) study.

BACKGROUND: Periodontitis, a chronic bacterial infection of the oral cavity, is a novel risk factor for atherosclerotic cardiovascular disease (CVD). Given the numerous shared risk factors for CVD and chronic kidney disease (CKD), we hypothesized that periodontitis also is associated with renal insufficiency in the Dental Atherosclerosis Risk in Communities study. METHODS: We conducted a cross-sectional study of 5,537 middle-aged black and white men and women. Periodontitis was determined by using an independent clinically derived definition and categorized as healthy/gingivitis, initial, and severe. Renal

insufficiency is defined as glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 . Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals for renal insufficiency using healthy/gingivitis as the referent group. RESULTS: A total of 2,276 individuals had initial periodontitis, and 947 individuals had severe periodontal disease. One hundred ten individuals (2%) had a GFR less than 60 mL/min/1.73 m2. Compared with healthy/gingivitis, initial and severe periodontal disease were associated with a GFR less than 60 mL/min/1.73 m2 (odds ratio, 2.00; 95% confidence interval, 1.23 to 3.24) for initial periodontal disease and an odds ratio of 2.14 for severe disease (95% confidence interval, 1.19 to 3.85) after adjustment for important risk factors for CVD and CKD. Sensitivity analysis showed that initial and severe periodontitis were each associated with an elevated serum creatinine level (men, >1.4 mg/dL [>124 micromol/L]; women, >1.2 mg/dL [>106 micromol/L]; odds ratio, 3.21; 95% confidence interval, 1.32 to 7.76 and odds ratio, 5.39; 95% confidence interval, 2.08 to 13.99, respectively). CONCLUSION: This is the first study to show an association of periodontal disease with prevalent renal insufficiency. A prospective study is necessary to determine the exact nature of the observed relationship.

Am J Kidney Dis. 2005 Apr;45(4):650-7

Relationship of periodontal infection to serum antibody levels to periodontopathic bacteria and inflammatory markers in periodontitis patients with coronary heart disease.

Several reports have demonstrated a possible association of periodontal infections with coronary heart disease (CHD) by elevated antibody titre to periodontopathic bacteria in CHD patients compared with non-diseased controls. Although each periodontopathic bacterium may vary in virulence for periodontitis and atherosclerosis, antibody response to multiple bacteria in CHD patients has not been understood fully. Therefore, serum levels of antibody to 12 periodontopathic bacteria together with other atherosclerotic risk markers were compared among 51 patients with CHD, 55 patients with moderate to severe chronic periodontitis and 37 healthy individuals. The antibody response was the most prevalent for Porphyromonas gingivalis, a major causative organism, in CHD as well as periodontitis patients. However, antibody positivity was different between CHD and periodontitis if the response was analysed for two different strains of P. gingivalis, namely FDC381 and Su63. While periodontitis patients were positive for both P. gingivalis FDC381 and Su63, a high frequency of antibody positivity for P. gingivalis Su63 but not for FDC381 was observed in CHD patients. The results indicate that the presence of particular periodontopathic bacteria with high virulence may affect atherogenesis. Identifying the virulence factors of P. gingivalis Su63 may gain insight into the new therapeutic modality for infection-induced deterioration of atherosclerosis.

Clin Exp Immunol. 2007 Sep;149(3):445-52

Adherence to a daily flossing regimen in university students: effects of planning when, where, how and what to do in the face of barriers.

OBJECTIVES: Regular (daily) dental flossing is recommended for preventing oral diseases, but adherence is unsatisfactory. Social cognitive theory (SCT) specifies determinants of dental flossing: cognitions about risk, positive and negative outcome expectations and the perceived ability to perform behaviour predict motivation, which in turn predicts behaviour. Recent research suggests that motivation alone may not suffice to predict behaviour, and proposes if-then-planning. This study aims to predict flossing adherence from social cognitive variables and planning. MATERIAL AND METHODS: Questionnaire data from 157 non-dental university students on flossing, SCT variables and planning were gathered at three measurement points over 6 weeks. Residual floss was used to validate behaviour self-reports. RESULTS: Social cognitive variables and planning correlated significantly with flossing at all times. Discriminant function analysis suggests that after controlling for Time 1 flossing, planning Time 2 (Wilk’s lambda=0.77; p<0.01) is more important in discriminating between adherent and non-adherent participants at Time 3 than Time 1 social cognitive measures. Regression analyses confirmed this result with planning as only predictor of flossing change (p<0.05). CONCLUSIONS: These results suggest targeting planning in interventions to increase compliance with flossing recommendations. Implications for such interventions are discussed.

J Clin Periodontol. 2006 Sep;33(9):612-9

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