Cited by 420Oral microbiology and periodontitis researchPeriodontal Regeneration and TreatmentsDental Research and COVID-19

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The Pathobiology of Periodontal Diseases May Affect Systemic Diseases: Inversion of a Paradigm

Page, Roy C.·1998·Annals of Periodontology

DOI 10.1902/annals.1998.3.1.108

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Abstract

A new paradigm for the pathobiology of periodontitis is presented, and the manner in which periodontitis may relate to susceptibility for certain systemic diseases such as cardiovascular disease and preterm labor is described. Periodontitis is caused by a small group of Gram‐negative bacteria present on the tooth root surfaces as biofilms. Lipopolysaccharide (LPS) and other substances gain access to the gingival tissues, initiate and perpetuate immunoinflammation, resulting in production of high levels of proinflammatory cytokines. These induce production of matrix metalloproteinases which destroy the connective tissues of the gingiva and periodontal ligament, and prostaglandins which mediate alveolar bone destruction. Periodontitis may enhance susceptibility to systemic diseases in several ways. LPS and viable Gram‐negative bacteria from the biofilms and proinflammatory cytokines from the inflamed periodontal tissues may enter the circulation in pathogenic quantities. In addition, periodontitis and certain systemic diseases, such as cardiovascular disease, share risk factors including tobacco smoking, male gender, race/ethnicity, stress, and aging. Ann Periodontol 1998;3:108–120.

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Molloy, J., Wolff, L. F., Lopez‐Guzman, A., & Hodges, J. S. (2004) · Journal Of Clinical Periodontology · doi:10.1111/j.1600-051x.2004.00539.x · Cited by 69
Periodontal disease and diabetes mellitus
Pucher, J. J., & Stewart, J. E. (2004) · Current Diabetes Reports · doi:10.1007/s11892-004-0011-y · Cited by 69
Informational Paper: Modulation of the Host Response in Periodontal Therapy
Research, S. (2002) · Journal of Periodontology · doi:10.1902/jop.2002.73.4.460 · Cited by 68
Non‐Surgical Periodontal Therapy Lowers Serum Inflammatory Markers: A Pilot Study
Bokhari, S. A. H., Khan, A. A., Tatakis, D. N., Azhar, M., Hanif, M., & Izhar, M. (2009) · Journal of Periodontology · doi:10.1902/jop.2009.090001 · Cited by 67
Herpesviruses in HIV-periodontitis
Contreras, A., Mardirossian, A., & Slots, J. (2001) · Journal Of Clinical Periodontology · doi:10.1034/j.1600-051x.2001.280115.x · Cited by 67
Full‐mouth profile of active MMP‐8 in periodontitis patients
Kraft‐Neumärker, M., Lorenz, K., Koch, R., Hoffmann, T. K., Mäntylä, P., Sorsa, T. A., & Netuschil, L. (2011) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.2011.01416.x · Cited by 66
Effects of Tumor Necrosis Factor‐α Inhibitors Pentoxifylline and Thalidomide on Alveolar Bone Loss in Short‐Term Experimental Periodontal Disease in Rats
Lima, V., Vidal, F. D. P., Rocha, F. A. C., Brito, G. A. D. C., & Ribeiro, R. A. (2004) · Journal of Periodontology · doi:10.1902/jop.2004.75.1.162 · Cited by 64
A Role for Non-Antimicrobial Actions of Tetracyclines in Combating Oxidative Stress in Periodontal and Metabolic Diseases: A Literature Review
Soory, M. (2008) · The Open Dentistry Journal · doi:10.2174/1874210600802010005 · Cited by 63
“Specific periodontal pathogens and their products associated with host virulence can contribute to a significant systemic inflammatory burden [6-8].”
Background
Analysis of host responses and risk for disease progression
Sahingur, S. E., & Cohen, R. E. (2004) · Periodontology 2000 · doi:10.1046/j.0906-6713.2002.003425.x · Cited by 62
Essentials of periodontal medicine in preventive medicine.
Gulati, M., Anand, V., Jain, N. K., Anand, B., Bahuguna, R., Govila, V., & Rastogi, P. K. (2013) · Europe PMC (PubMed Central) · Cited by 61
Periodontal, metabolic, and cardiovascular disease: Exploring the role of inflammation and mental health
Makkar, H., Reynolds, M. A., Wadhawan, A., Dagdag, A., Merchant, A. T., & Postolache, T. T. (2018) · Pteridines · doi:10.1515/pteridines-2018-0013 · Cited by 66
Stress and periodontal disease
Reners, M., & Brecx, M. C. (2007) · International Journal of Dental Hygiene · doi:10.1111/j.1601-5037.2007.00267.x · Cited by 60
Periodontitis: a potential risk factor for Alzheimer's disease
Cerajewska, T. L., Davies, M., & West, N. X. (2015) · BDJ · doi:10.1038/sj.bdj.2014.1137 · Cited by 63
Using 8-Hydroxy-2′-Deoxiguanosine (8-OHdG) as a Reliable Biomarker for Assessing Periodontal Disease Associated with Diabetes
Goriuc, A., Cojocaru, K.-A., Luchian, I. A., Ursu, R. G., Butnaru, O., & Foia, L. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031425 · Cited by 59
“The well-vascularized nature of the inflamed periodontium in individuals with periodontal disease results in a sustained release of various substances, including cytokines, potentially modifying diverse physiological states and pathological processes [16].”
Background
Resistin: A Potential Biomarker for Periodontitis Influenced Diabetes Mellitus and Diabetes Induced Periodontitis
Devanoorkar, A., Kathariya, R., Guttiganur, N., Gopalakrishnan, D., & Bagchi, P. (2014) · Disease Markers · doi:10.1155/2014/930206 · Cited by 59
“These cells and the cytokines produced such as TNF-α, CRP, interleukins, prostaglandins, and resistin not only result in the local tissue destruction characterized by periodontal attachment loss and alveolar bone loss but also exert certain distant systemic effects such as increased risk for atherosclerosis, PTLBW, an…”
Background
Capnocytophaga spp. in Periodontitis Patients Manifesting Diabetes Mellitus
Ciantar, M., Gilthorpe, M. S., Hurel, S. J., Newman, H. N., Wilson, M., & Spratt, D. A. (2005) · Journal of Periodontology · doi:10.1902/jop.2005.76.2.194 · Cited by 59
The effects of periodontal therapy on gingival crevicular fluid matrix metalloproteinase‐8, interleukin‐6 and prostaglandin E2 levels in patients with rheumatoid arthritis
Kurgan, Ş., Fentoğlu, Ö., Önder, C., Serdar, M. A., Eser, F., Tatakis, D. N., & Günhan, M. (2015) · Journal of Periodontal Research · doi:10.1111/jre.12337 · Cited by 57
A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor κB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis
Elburki, M. S., Rossa, C., Guimarães, M. R., Lee, H., Curylofo‐Zotti, F. A., Johnson, F., & Golub, L. M. (2017) · Inflammation · doi:10.1007/s10753-017-0587-4 · Cited by 58
“IL-1β and TNF-α also activate other mediators of inflammation such as cycloxygenase-2 and 5lipoxygenase, leading to the production of lipid mediators of inflammation, such as prostaglandins and leukotrienes [73].”
Background
Periodontitis Is an Important and Occult Source of Inflammation in Hemodialysis Patients
Kadiroğlu, A. K., Kadiroğlu, E. T., Şit, D., Dağ, A., & Yılmaz, M. E. (2006) · Blood Purification · doi:10.1159/000093683 · Cited by 56
Pathogenic Mechanisms Linking Periodontal Diseases With Adverse Pregnancy Outcomes
Cetin, I., Pileri, P., Villa, A., Calabrese, S., Ottolenghi, L., & Abati, S. (2012) · Reproductive Sciences · doi:10.1177/1933719111432871 · Cited by 53
“39 Furthermore, these mediators can cross fetal membranes; so, it is possible that high levels of these cytokines synthesized at the level of periodontal infection could interfere with fetoplacental functions and contribute to the onset of preterm labor.(40,41) Increased levels of intraamniotic cytokines have indeed b…”
Background
Periodontal infections and community-acquired pneumonia: a case–control study
Neto, J. P. M., Melo, M. S. A. E., Pereira, S. A. D. S., Martinez, E. F., Okajima, L. S., & Saba‐Chujfi, E. (2012) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-012-1710-y · Cited by 54
Apical periodontitis and related factors in an adult Lithuanian population
Aleksejūnienė, J., ERIKSEN, H. M., Sidaravičius, B., & Haapasalo, M. (2000) · Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology · doi:10.1067/moe.2000.107059 · Cited by 54
Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response
Hatasa, M., Yoshida, S., Takahashi, H., Tanaka, K., Kubotsu, Y., Ohsugi, Y., Katagiri, T., Iwata, T., & Katagiri, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073728 · Cited by 57
“Secondly, in patients with periodontitis, bacteremia may originate from periodontal pockets, as patients with generalized chronic periodontitis showed ulcers in inflamed periodontal pockets, and the total area of the ulcers was estimated to be as large as the size of the palm [15].”
Background
Porphyromonas gingivalis impairs glucose uptake in skeletal muscle associated with altering gut microbiota
Watanabe, K., Katagiri, S., Takahashi, H., Sasaki, N., Maekawa, S., Komazaki, R., Hatasa, M., Kitajima, Y., Maruyama, Y., Shiba, T., et al. (2020) · The FASEB Journal · doi:10.1096/fj.202001158r · Cited by 52
Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis
Kuraji, R., Shiba, T., Dong, T. S., Numabe, Y., & Kapila, Y. L. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i6.967 · Cited by 53
Effect of nonsurgical periodontal therapy (with or without oral doxycycline delivery) on glycemic status and clinical periodontal parameters in patients with prediabetes: a short-term longitudinal randomized case–control study
Javed, F., Ahmed, H., Mehmood, A., Bain, C., & Romanos, G. (2014) · Clinical Oral Investigations · doi:10.1007/s00784-014-1185-6 · Cited by 46
“Studies [34-36] have anticipated that bacteria and their products (such as lipopolysaccharides) enter systemic circulation from infected periodontal pockets, which may worsen insulin resistance by potentially increasing low-grade inflammation.”
Background
Melatonin as a Topical/Systemic Formulation for the Management of Periodontitis: A Systematic Review
Balaji, T. M., Varadarajan, S., Jagannathan, R., Mahendra, J., Fageeh, H. I., Fageeh, H. N., Mushtaq, S., Baeshen, H. A., Bhandi, S., Gupta, A. A., et al. (2021) · Materials · doi:10.3390/ma14092417 · Cited by 49
“of pro-inflammatory cytokines and mediators such as prostaglandins, leukotrienes, and acute phase reactants such as C-reactive protein [45].”
Background
Treatment of Periodontal Diseases Reduces Chronic Systemic Inflammation in Maintenance Hemodialysis Patients
Siribamrungwong, M., & Puangpanngam, K. (2012) · Renal Failure · doi:10.3109/0886022x.2011.643351 · Cited by 49
Periodontal Disease: A Covert Source of Inflammation in Chronic Kidney Disease Patients
Ismail, G., Dumitriu, H. T., Dumitriu, A. S., & Ismail, F. B. (2013) · International Journal of Nephrology · doi:10.1155/2013/515796 · Cited by 48
DOES THE MOUTH PUT THE HEART AT RISK?
SLAVKIN, H. C. (1999) · The Journal of the American Dental Association · doi:10.14219/jada.archive.1999.0038 · Cited by 46
Prevalência e características associadas à síndrome metabólica em nipo-brasileiros com e sem doença periodontal
Borges, P. K. D. O., Gimeno, S. G. A., Tomita, N. E., & Ferreira, S. R. G. (2007) · Cadernos de Saúde Pública · doi:10.1590/s0102-311x2007000300024 · Cited by 46
Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies
Dziedzic, A. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315320 · Cited by 49
Accuracy of Self‐Reported Periodontal Disease in the Women's Health Initiative Observational Study
LaMonte, M. J., Hovey, K. M. O., Millen, A. E., Genco, R. J., & Wactawski‐Wende, J. (2013) · Journal of Periodontology · doi:10.1902/jop.2013.130488 · Cited by 45
“…study group; 2) the several objective periodontal measures with demonstrated reliability obtained from standardized oral examinations; and 3) the relative consistency of findings according to cohort subgroups in which opportunity for, or recall of, periodontal disease diagnosis could…”

Authors: Page, R. C.
Affiliations: University of Washington (US)
Corresponding author: Page, Roy C.
Venue: Annals of Periodontology
Publisher: Wiley
Published: 1998-07
Volume: 3
Issue: 1
Pages: 108-120
ISSN: 1553-0841 (ISSN-L)
2162-5131
DOI: 10.1902/annals.1998.3.1.108
OpenAlex: W1967814211
Cited by: 420
References: 45
Citations by year: 2026: 4 · 2025: 8 · 2024: 16 · 2023: 8 · 2022: 17 · 2021: 20 · 2020: 14 · 2019: 16 · 2018: 12 · 2017: 18 · 2016: 12 · 2015: 18 · 2014: 18 · 2013: 26 · 2012: 34
FWCI: 19.34
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of Periodontology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p01de008555-10)
National Institute of Dental and Craniofacial Research (T32 DE 07063, P30 DE09743, P01DE08555, T32DE007063, P30DE009743)
Topics: Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Health Sciences › Dentistry › Periodontics › Periodontal Regeneration and Treatments
Health Sciences › Dentistry › General Dentistry › Dental Research and COVID-19
Keywords: periodontitis, cardiovascular disease, preterm labor, Gram-negative bacteria, biofilm, lipopolysaccharide, immune inflammation, inflammatory cytokines, matrix metalloproteinases, prostaglandins, alveolar bone loss, periodontal ligament, risk factors, smoking
MeSH terms: Animals, Cardiovascular Diseases, Disease Susceptibility, Focal Infection, Dental, Gram-Negative Anaerobic Bacteria, Health Status, Humans, Periodontitis, Risk Factors, Cytokines, Biofilms, Inflammation Mediators

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The Pathobiology of Periodontal Diseases May Affect Systemic Diseases: Inversion of a Paradigm

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