Periodontal Pathogens and Their Links to Neuroinflammation and Neurodegeneration
Abstract
:1. Introduction
Gingivitis and Its Progression to Periodontitis
2. Periodontal Pathogens, Virulence Factors and Host Response
2.1. Porphyromonas gingivalis
2.2. Tannerella forsythia
2.3. Treponema denticola
2.4. Fusobacterium nucleatum
2.5. Aggregatibacter actinomycetemcomitans
2.6. Synergistic Behavior
2.7. Mechanisms of Systemic Inflammation and Its Correlation to Periodontitis
3. Neurodegenerative and Periodontal Disease
3.1. Periodontitis and Neurodegenerative Disorders
3.2. Bidirectional Interactions, Causation, and Critical Overview
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Appendix A.1. Systemic Extraction of Data
Appendix A.2. Eligibility Criteria
References
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Strain | Genome Size (bp) | Capsule | Fimbriae/Type | Mono-Species Biofilm Formation | Gingipain Activity | Virulence Potential | Citation |
---|---|---|---|---|---|---|---|
ATCC 33277 | 2,354,886 | none | Abundant/Type I | Moderate | High | Moderate | [15,32,33,34,35,36,37,38] |
FDC 381 | 2,378,872 | none | Abundant/Type I | Moderate | Medium | Moderate | [15,33,34,36,37,38,39] |
W83 | 2,343,476 | K1 encapsulated | Poor/Type IV | None | High | High | [15,32,34,35,36,37,38] |
W50 | 2,345,841 | K1 encapsulated | Poor/Type IV | None | High | High | [15,34,36,38,40] |
Bacteria | Component | Function | Citation |
---|---|---|---|
Porphyromonas gingivalis | LPS | Induces inflammation and activates the host immune system | [20,21] |
Gingipains | Accounts for 85% of the total proteolytic activity; In addition to increasing nutrient availability, it has an immunoregulatory purpose and plays a role in bacterial coaggregation | [19,20] | |
Fimbriae | Promotes adhesion, invasion of host cells, biofilm formation, and bacterial motility | [32] | |
GroEL | Induces inflammation and activates the host immune system | [97] | |
Hemagglutinins | Promotes adherence to host cells and is used for heme acquisition | [98] | |
Capsule | Polysaccharide layer that protects the bacterium from phagocytosis by host immune cells | [33] | |
Tannerella forsythia | LPS | Induces inflammation and activates the host immune system | [99] |
PrtH | Protease that plays a role in cell detachment | [41,43] | |
BspA | Necessary for attachment and invasion of epithelial cells | [41,45] | |
Karilysin | Immunoregulatory, causes bacterial serum resistance | [50] | |
Methylglyoxal | Causes inflammation and tissue damage | [47] | |
GroEL | Induces inflammation and activates the host immune system | [48] | |
S-layer | Involved in coaggregation, immunoevasion, adhesion, and invasion of cells | [52,53] | |
Treponema denticola | LOS | Impacts adherence to host cells and bacterial coaggregation | [63] |
MSP | induces inflammatory responses and forms cytotoxic pores | [60,61,62] | |
Dentilsin | Stimulates tissue destruction and activates C3 complement pathway; it also has an immunoregulatory purpose and plays a role in bacterial coaggregation | [64,65,66,71,72] | |
Leucine-rich-repeat A | Impacts adherence and invasion of host cells, while also being important for bacterial coaggregation | [100] | |
Fusobacterium nucleatum | LPS | Induces inflammation and activates the host immune system | [79,80] |
Main Adhesin (FadA) | Required for the invasion and adhesion to host cells | [80] | |
Other Adhesins (Fap2, RadD, and aid1) | Impacts binding to a variety of different bacteria and host proteins | [74,80] | |
Fusolisin | Impacts nutrient availability while also having an immunoregulatory role | [81] | |
Aggregatibacter actinomycetemcomitans | LPS | Induces inflammation and activates the host immune system | [86,87] |
Leukotoxins | Disrupts immune function | [86,91] | |
CTD | Induces DNA damage and cell cycle arrest which leads and apoptosis, with a pronounced impact on immune cells | [92,93] | |
Fimbriae | Impacts adherence and bacterial coaggregation | [101] |
Disease Investigated | Study Design/Duration | Question | Adjusting for: | Number of Participants/Age [Years] | Results | Author, Date, Journal, and Citation |
---|---|---|---|---|---|---|
Mild cognitive impairment (MCI) | Prospective cohort study (8 years) | Does periodontitis correlate with cognitive decline? | Age, gender, race, education, income, smoking, alcohol consumption, and diabetes | N = 558 (total) Age group = 52–75 Age mean = 64.7 ± 4.3 | No significant correlation was found between tooth loss at baseline and cognitive capabilities. | Supawadee Naorungroj et al. (2014) Community Dentistry and Oral Epidemiology’s [145] |
Mild memory impairment (MMI) | Prospective cohort study (5 years) | Does periodontitis correlate with a decline in memory? | Age, gender, MMSE-total, education length, smoking, drinking, blood pressure, cancer, myocardial infarction, cerebrovascular disease, diabetes mellitus, hypertension, and dyslipidemia | N = 2335 (total) Age group ≥ 65 Age median = 71 | Each tooth lost at baseline slightly increased the odds of developing memory impairment: (OR = 1.02; 95% Cl 1.00–1.03; p = 0.039) | Nozomi Okamoto et al. (2015) Journal of Alzheimer’s Disease [146] |
Mild cognitive impairment (MCI) | Prospective cohort study (6 years) | Does periodontitis correlate with cognitive decline? | Age, gender, living alone, education, alcohol consumption, BMI ischemic heart disease, traumatic brain injury, and depression | N = 715 (total) N = 214 (with periodontitis) Age group = 60–96 Age mean = NA | Bone loss caused by periodontitis may be associated with faster cognitive decline: (OR = 2.2; 95% CI 1.2–3.8; NA) | Helena Nilsson et al. (2018) Journal of Clinical Periodontology [147] |
Mild cognitive impairment (MCI) | Prospective cohort study (4 years) | Does periodontitis correlate with cognitive decline? | Age, gender, hypertension, diabetes, cerebrovascular/cardiovascular disease, hypercholesterolemia, depressive symptoms, body mass index, smoking status, drinking status, duration of education, and baseline MMSE score | N = 140 (total) Age group ≥ 65 Age mean = 70.9 ± 4.3 | Tooth loss may be associated with cognitive impairment: (OR = 3.31; 95% Cl 1.07–10.2; p = 0.037) | Sho Saito et al. (2018) BMC Oral Health [148] |
Mild cognitive impairment (MCI) | Longitudinal cohort study (5 years) | Is there an association between mild cognitive impairment and periodontitis? | Age, sex, smoking status, educational level, physical activity level, obesity, depression, and diabetes | N = 179 (total) Age group ≥ 75 Age mean = 80.1 ± 4.4 | Severe periodontitis was significantly associated with MCI: (OR = 3.58; 95% Cl 1.45–8.87; p < 0.01) | Masanori Iwasaki et al. (2019) Journal of Periodontal Research [149] |
Mild cognitive impairment (MCI) | Longitudinal study (median following of 5.93 years) | Is there an association between mild cognitive impairment and severity of tooth loss? | Age, gender, ethnicity, residence, marriage status, occupation, education, smoking and drinking, activities of daily life (ADL) score, physical performance score, food diversity score, social activity score, and chronic disease score | N = 11862 (total) N = 3966 (developed MCI) Age group ≥ 65 Age mean = 81.41 | Higher tooth loss rate was associated with an increased risk of MCI in elderly subjects. 1–2 tooth loss per year [mild] (OR = 1.16; 95% Cl 1.04–1.29; NA) >2 tooth loss per year [severe] (OR = 1.28; 95% Cl 1.17–1.40; NA) | Shuyu Xu et al. (2021) Aging [150] |
Dementia | Prospective study (longitudinal checkup every 3 years for up to 32 years) | Does severity of tooth loss correlate with dementia progression? | Age, years of education, smoking, BMI, medication use, intake of substances, coronary heart disease, stroke, hypertension, cardiovascular disease, cancer, and diabetes | N = 597 (total) Age group = 28–70 Age mean = 48 ± 8 | Each tooth lost per decade since the baseline examination increased the risks of lowering the Mini-Mental State Examination score: (HR = 1.12, 95% CI 1.05–1.18; p < 0.05) | Kaye et al. (2010) Journal of the American Geriatrics Society [151] |
Dementia | Longitudinal cohort study (5 years) | Are periodontal conditions associated with dementia onset? | Age, gender, educational level, living condition, tobacco intake, alcohol consumption, BMI, stroke, angina pectoris, diabetes, hypertension, depression, and myocardial infarction | N = 348 (total) N = 246(with some form of periodontal condition) Age group = 66–80 Age median = 70 | Periodontal condition was not associated with an increased risk of dementia: (HR = 1.13; 95% CI 0.60–2.12; NA) | E. Arrivé et al. (2011) Community Dentistry and Oral Epidemiology’s [152] |
Dementia | Retrospective matched-cohort study (10 years) | Is there an Association between Chronic Periodontitis and Gingivitis with Dementia? | Age, sex, monthly income, urbanization level, geographic region, hypertension, diabetes, hyperlipidemia, obesity, depression, chronic kidney disease, and stroke | N = 8828 (total) N = 2207 (with periodontitis or gingivitis) Age group ≥ 20 Age mean = NA | Patients with chronic periodontitis and gingivitis have a higher risk of developing dementia: (HR = 2.54; 95% CI 1.297–3.352; p = 0.002). | Nian-Sheng Tzeng et al. (2016) Journal of Neuroepidemiology [153] |
Dementia | Prospective matched-cohort study (13 years) | Is there an association of chronic periodontitis with dementia onset? | Age, gender, geographic region, urbanization level, hypertension, diabetes mellitus, cardiovascular disease, congestive heart failure, atrial fibrillation, stroke, and chronic renal disease | N = 6056 (total) N = 3028 (with periodontitis) Age group ≥ 65 Age mean = 72.4 ± NA | Patients with periodontitis were at higher risk of developing dementia: (HR = 1.16; 95% Cl 1.01–1.32; p = 0.03) | Yao-Tung Lee et. al (2016) Journal of the American Geriatrics Society [154] |
Dementia | Retrospective cohort study (10 years) | Does treatment of periodontitis affect dementia onset and progression? | Age, gender, socioeconomic status, residential urbanicity, hypertension, diabetes, and hyperlipidemia | N = 182,747 (total—all with periodontitis) N = 19,674 (did not receive treatment for periodontitis) N = 6133 (developed dementia) Age group ≥ 45 Age mean = NA | Subjects who had not received Periodontitis treatment were at greater risk of developing dementia: (HR = 1.14; 95% CI 1.04–1.24; p ≤ 0.001) | Ya-Ling Lee et al. (2017) Journal of the American Geriatrics Society [155] |
Dementia | Prospective cohort study (5 years) | Does severity of tooth loss correlate with dementia onset? | Age, gender, occupation, educational level, tobacco intake, alcohol consumption, BMI, stroke, angina pectoris, diabetes, hypertension, and tooth brushing frequency | N = 1566 (total) N = 180 (developed dementia) Age group ≥ 60 Age mean = NA | Tooth loss may be associated with a higher risk of dementia: 10–19 teeth: (HR = 1.62, 95% CI = 1.06–2.46), 1–9 teeth (HR = 1.81, 95% CI = 1.11–2.94), 0 teeth (HR = 1.63, 95% CI = 0.95–2.80) | Kenji Takeuchi et al. (2017) Journal of the American Geriatrics Society [156] |
Dementia | Retrospective matched-cohort study (10 years) | Is there an association of chronic periodontitis with dementia onset? | Age, sex, household income, smoking status, alcohol consumption, physical activity, BMI, blood pressure, fasting serum glucose, total cholesterol, and Charlson Comorbidity Index | N = 262,349 (total) N = 46,344 (with periodontitis) Age group ≥ 50 Age mean = 60.2 ± 7.3 | Chronic periodontitis may be associated with a higher risk of developing dementia: Overall dementia (HR = 1.06; 95% CI 1.01–1.11; p = 0.015) Alzheimer’s (HR = 1.05; 95% CI 1.00–1.11; p = 0.042). The risk-increasing effect of chronic periodontitis on dementia tended to be stronger among participants with healthy lifestyle behaviors. | Seulggie Choi et al. (2019) Journal of the American Geriatrics Society [157] |
Dementia | Retrospective matched-cohort study (14 years) | Is severe periodontitis with tooth loss a risk factor for the onset of dementia? | Age, sex, household income, insurance status, BMI, total cholesterol level, smoking status, drinking status, physical activity, hypertension, and diabetes mellitus | N = 20,230 (total) N = 10,115 (with periodontitis) Age group = 40–80 Age mean = NA | Patients with severe periodontitis with 1–9 remaining teeth were at higher risk for developing dementia: Alzheimer’s (HR = 1.08; 95% CI 1.01–1.14; p = 0.022) Vascular dementia (HR = 1.24; 95% CI 1.16–1.32; p < 0.001) Mixed dementia (HR = 1.16; 95% CI 1.09–1.24; p < 0.001) | Do-Hyung Kim et al. (2020) Journal of periodontal and implant science [158] |
Dementia | Retrospective matched-cohort study (14 years) | Is there an association of chronic periodontitis with dementia onset? | Age, gender, influenza vaccination, income, hypertension, mental disorders, diabetes, ischemic heart disease, stroke, hyperlipidemia, chronic obstructive pulmonary disease, heart failure, liver cirrhosis, and traumatic brain injury | N = 102,036 (total) N = 56,018 (with periodontitis) Age group ≥ 50 Age mean = NA | Patients with periodontitis were at higher risk of developing dementia: (HR = 1.73; 95% CI 1.61–1.86; p < 0.0001) Periodontitis was associated with a higher risk of developing dementia in people with no underlying medical conditions: =0 (HR 6.16; 95% CI 5.13–7.40; p < 0.05) =1 (HR 1.27; 95% CI 1.10–1.46; p < 0.05) ≥2 (HR 1.20; 95% CI 1.09–1.31; p < 0.05) | Chia-Yen Lee et al. (2020) Journal of Clinical Periodontology [159] |
Dementia | Retrospective longitudinal matched-cohort study (13 years with median following of 6.6 years) | Is there a difference in dementia onset between groups of people severe or mild chronic periodontitis? | Age, gender, income level, smoking status, alcohol consumption, regular exercise, BMI, systolic blood pressure, diastolic blood pressure, fasting blood glucose levels, total cholesterol levels, hypertension, diabetes, dyslipidemia, heart disease, cerebrovascular disease, depression, and Charlson Comorbidity Index | N = 8624 (with mild chronic periodontitis) N = 8624 (with severe chronic periodontitis) Age group ≥ 60 Age mean = 70.9 ± 4.8 | Dementia onset was significantly associated with the severity of periodontitis. (HR = 1.15; 95% CI; 1.04–1.27; p = 0.01) | Seon-Rye Kim et al. (2022) Epidemiology and health [160] |
Dementia | Cohort study (Follow up 7.6 ± 1.1 years) | Is there an association of deep probing pocket depths and tooth count with dementia onset? | Age, gender, civil status, disposable income, education, geographical area, and Charlson Comorbidity Index | N = 37,174 (total) N = 7992 (with ≥4 teeth and/or dental implants with probing pocket depth ≥6 mm) Age group = 40–80 Age mean = 61 | Tooth loss and deep probing pocket depth does not increase the risk of developing dementia: (HR = 1.13; 95% CI 0.39–3.24; p > 0.05) | Jacob Holmer et al. (2022) Journal of Clinical Periodontology [161] |
Dementia | Prospective cohort study (6 years) | Does tooth loss increase the risk of dementia onset? | Age, gender, marital status, denture use, education level, income level, social network, smoking status, alcohol consumption, diabetes treatment, and hypertension | N = 35,744 (total) N = 22,164 (<20 teeth) Age group ≥ 65 Age mean = 73.2 ± 5.5 | Number of teeth may increase the risk of dementia onset: (HR = 1.14; 95% CI 1.01–1.28 p = 0.041) When the nutritional and social mediators (weight loss, vegetable and fruit intake, and regular exercise) were included, the effect was reduced to: HR = 1.10 95% CI; 0.98–1.25; p = 0.113) | S Kiuchi et al. (2022) Journal of Dental Research [162] |
Alzheimer’s disease (AD) | Case-control study with a follow-up over a six-month period | Does periodontitis affect the speed of cognitive decline? | Age, gender, and baseline cognitive status | N = 52 (total) N = 20 (with periodontitis) Age group = NA Age mean = 77.7 ± 8.6 | The presence of periodontitis at baseline was not related to baseline cognitive state: (MD = 1.1; 95% Cl -5.6–7.7; p = 0.8) Rate of cognitive decline: (MD = 4.9; 95% Cl 1.2–8.6; p = 0.01) | Mark Ide et al. (2016) PlOS One [163] |
Alzheimer’s disease (AD) | Retrospective matched-cohort study (8 years) | Is there an association between chronic periodontitis and the risk of Alzheimer’s disease? | Age, gender, index year, urbanization level, hypertension, hyperlipidemia, chronic kidney disease, depression, stroke, diabetes mellitus, and traumatic brain injury | N = 27,963 (total) N = 9291 (with periodontitis) Age group ≥ 50 Age mean = 54.1 ± 10.5 | The association between chronic periodontitis and AD was significant in patients that have had over 10 years of exposure to chronic periodontitis: (HR = 1.707; 95% CI 1.152–2.528; p = 0.0077). | Chang-Kai Chen et al. (2017) Alzheimer’s Research and Therapy [164] |
Parkinson’s disease (PD) | Retrospective matched-cohort study (5 years) | Does chronic periodontitis increase the risk of PD incidence? | Age, gender, urbanization level of residence, index year, stroke, and depression | N = 320,106 (total N = 53,351 (with periodontitis) Age group ≥ 40 Age mean = NA | Chronic periodontitis may increase the risk of Parkinson’s disease: (HR = 1.43; 95% 1.32–1.55; NA) | Tsai-Ching Liu et al. (2013) Movement Disorders [165] |
Parkinson’s disease (PD) | Retrospective matched-cohort study (8 years) | Does periodontitis and its severity correlate with PD incidence? | Age, gender, CCI score, urbanization level, stroke, depression, hyperlipidemia, cancer, chronic kidney disease, and traumatic brain injury | N = 16,188 (total) N = 5396 (with periodontitis) Age group ≥ 40 Age mean = 54.1 ± 10.5 | Periodontitis correlates with the incidence rate of PD: (HR = 1.431; 95% CI 1.141–1.794; p = 0.002) | Chang-Kai Chen et al. (2017) Peer.J [166] |
Parkinson’s disease (PD) | Longitudinal cohort study (10.4 years) | Does chronic periodontitis increase the risk of PD incidence? | Age, gender, income level, body mass index, lifestyle habits, such as alcohol intake, smoking status, physical activity, blood pressure, renal disease, hypertension, diabetes mellitus, and dyslipidemia | N = 153,165 N ≈ 30,480 (with periodontitis) Age group ≥ 40 Age mean = 52.8 | Chronic periodontitis did not significantly increase the risk of PD incidence: (HR = 0.91; 95% Cl 0.78–1.06; p = 0.232) Tooth loss (≥15) correlated to higher PD incidence: (HR = 1.38; 1.03–1.85; p = 0.029) | Ho Geol Woo et al. (2020) Parkinson’s Disease [167] |
Parkinson’s disease (PD) | Retrospective cohort study in South Korea (8 years) | Do periodontitis and its severity correlate with PD incidence? | Age, sex, smoking status, drinking habits, exercise habits, income level, BMI, diabetes mellitus, hypertension, dyslipidemia, stroke, and depression | N = 6,856,180(total) N = 903,063 (with periodontitis) Age group ≥ 40 Age mean = 55.47 ± 9.97 | The severity of periodontitis correlates with the incidence rate of PD: (HR = 1.114; 95% CI 1.062–1.146; p < 0.001) | Eunkyung Jeong et al. (2021) Scientific report—Nature [168] |
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Visentin, D.; Gobin, I.; Maglica, Ž. Periodontal Pathogens and Their Links to Neuroinflammation and Neurodegeneration. Microorganisms 2023, 11, 1832. https://doi.org/10.3390/microorganisms11071832
Visentin D, Gobin I, Maglica Ž. Periodontal Pathogens and Their Links to Neuroinflammation and Neurodegeneration. Microorganisms. 2023; 11(7):1832. https://doi.org/10.3390/microorganisms11071832
Chicago/Turabian StyleVisentin, David, Ivana Gobin, and Željka Maglica. 2023. "Periodontal Pathogens and Their Links to Neuroinflammation and Neurodegeneration" Microorganisms 11, no. 7: 1832. https://doi.org/10.3390/microorganisms11071832