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Oral microbiota and systemic disease
Anaerobe 24 (2013) 90e93
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Molecular biology, genetics and biotechnology
Oral microbiota and systemic disease Purnima S. Kumar* Division of Periodontology, College of Dentistry, The Ohio State University, 4111 Postle Hall, 305 W. 12th Avenue, Columbus, OH 43210, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 October 2012 Received in revised form 17 September 2013 Accepted 19 September 2013 Available online 12 October 2013
It is well known that bacteria are the primary cause of infectious diseases, however, evidence is emerging that these organisms are also indirectly responsible for several diseases including cancer and rheumatoid arthritis. The oral cavity is home to several million bacteria that can cause two major diseases-periodontitis and caries. The relationship between periodontopathic bacteria and systemic diseases has been explored for several years. The concept of the oral cavity as a source of distant infection has been debated for at least a century. This review will discuss the historic aspects of the development of the focal infection theory, the reasons for its demise, its re-emergence and current status. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Oral bacteria Systemic disease Focal sepsis Focal infection Periodontal medicine
1. Introduction During the Anaerobe 2012 meeting, a session entitled “Oral Microbiota and Systemic Disease ” reviewed current knowledge about the inter-relationships between oral bacteria and susceptibility to systemic diseases. This article will discuss the historic aspects of the development of the focal infection theory, the reasons for its demise, its re-emergence and current status. 2. Rise, fall and rise of the focal infection theory A focus of infection is best described as a circumscribed lesion that is clinically asymptomatic and contains pathogenic bacteria. According to the theory of focal infection, bacteria and/or bacterial products are disseminated from this nidus to distant parts, leading to disease in these organ systems. Several foci of infection have been described in the literature, including tonsils, sinuses, prostate, appendix, bladder, gall bladder, and kidney. Several diseases have been attributed to focal infections, including arthritis, neuritis, myalgia, nephritis, osteomyelitis, endocarditis, pneumonia, asthma, emphysema, gastritis, pancreatitis, colitis, diabetes, goiter, thyroiditis and Hodgkin’s disease. The tooth as a focus of infection: The theory of the oral cavity as a focus of infection is not new; Hippocrates reported arthritis being cured following extraction of a tooth [1]. The term oral focal sepsis * Tel.: þ1 614 247 4532; fax: þ1 614 292 4612. E-mail address: [email protected]. 1075-9964/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.anaerobe.2013.09.010
was introduced by W.D. Miller in his 1890 article “The MicroOrganisms of the Human Mouth: The Local and General Diseases Which Are Caused by Them” and recommended removing decayed parts of a tooth and replacing them with fillings or root canal fillings [2]. However, in 1900, British physician William Hunter ascribed a plethora of systemic diseases to the preservation of a carious tooth by building ‘a veritable mausoleum of gold fillings, crowns and bridges over a mass of sepsis’ [3]. In 1940, Fish published an article on teeth as a source of systemic infections [4]. He described a state where teeth affected by periodontitis (a bacterially-induced disease that affects the structures that support the tooth and anchor it to the jawbone) “shower bacteria into the blood stream” even during the simple process of chewing or tooth brushing. He cited evidence from his own and other studies where dental bacteria could be detected in proximal and distant blood vessels (median basilic and peri-apical veins) following tooth extraction or chewing on hard candy. He proposed that the bacteria or their toxins stagnate in areas where tissues of mesenchymal origin predominate, namely joints, muscle and nerve sheaths. The purported susceptibility of these tissues was due to their ‘unique functions of repair, regeneration and scavenging of waste products’. Thus, he hypothesized that dissemination of bacteria of oral origin to tissues of mesenchymal origin led to the pathogenesis of diverse diseases like osteomyelitis, fasciitis of the sciatic nerve, fibromyalgia and endocarditis. Therapeutic impact of the oral focal sepsis theory: The focal sepsis theory gained momentum in the 19th century and the early 20th century based on the recommendations of prominent
P.S. Kumar / Anaerobe 24 (2013) 90e93
physicians like William Hunter, Russell Cecil and Charles Mayo [5]. Physicians recommended prophylactic or therapeutic removal of all teeth (and thus earned the moniker ‘one hundred percenters’) or just nonvital teeth, for the treatment of diverse conditions ranging from allergy to schizophrenia [6]. It was recommended as one of the most predictable treatment options for arthritis deformans, and for the treatment of blindness [7,8]. Soon, therapeutic edentulation became the norm. These treatment modalities were bolstered by Rosenow’s theory of ‘elective dissemination’, which stated that certain pathogens demonstrated affinities for colonizing specific sites [9]. However, it was soon apparent that the routine removal of teeth did not provide a cure for diverse maladies. Vaizey and Clark-Kennedy [10] in 1939 and Cecil and Angevine in 1940 [11] demonstrated a worsening of arthritic symptoms and development of digestive complications following therapeutic edentulation. Thus, focal infection was disregarded as a scientific theory for several decades. Reemergence of focal infection theory: Developments of new techniques to identify and classify microorganisms, for example polymerase chain reaction, in situ hybridization, as well as openended molecular approaches such as 16S sequencing revealed the presence of previously unknown and unsuspected organisms in the oral cavity [12,13]. The subgingival sulcus (the space between the tooth and the gingiva) was revealed as a reservoir for several systemic pathogens including Hemophilus influenzae, Pseudomonas aeruginosa and Trophyrema whipplei [14e17]. Advances in surgical techniques allowed access to deep tissues with minimal morbidity and revealed the presence of periodontal pathogens, for example, Porphyromonas gingivalis, Treponema denticola and Campylobacter rectus in atheromatous plaques, valvular vegetations, the tracheobronchial tree, joint cavities and the pancreas [18]. Thus, it soon became apparent that the oral cavity does indeed act as a reservoir of bacteria that metastasize to distant regions and cause disease in susceptible individuals. The World Workshop in Periodontics introduced the term ‘Periodontal Medicine’ in 1996 to describe the relationship between periodontitis and systemic diseases [19]. Thus, the last decade has seen a reemergence of the focal infection theory, albeit with a healthy dose of caution. 3. The periodontal pocket as a source of infection Bacteria colonize the oral cavity soon after birth and form organized, co-operating communities called biofilms within specific ecological niches, for example, the tongue, tooth, subgingival sulcus, tonsil and buccal mucosa [20]. These biofilms allow the bacteria to live in a nutrient-rich environment that is protected from environmental insults, antimicrobial agents and frictional forces. These biofilms perform two important functions e (i) they prevent pathogenic colonization and (ii) they educate the immune system to recognize ‘friend and foe’. In a state of health, equilibrium exists between biofilm antigens and toxins and the host immune response. Under certain circumstances, for example, a change in pH, oxygen tension, nutrient availability or a change in immune status, a shift occurs in the resident microflora, transforming this community from a commensal population to a pathogen enriched one [20]. The host responds to this pathogenic colonization by a florid immune response, leading to a breakdown of the attachment between the tooth, the gingiva and the alveolar socket, loss of bone that supports the tooth and a deepening of the space between the tooth and the gingiva (the sulcus) [21]. This deepened sulcus, now called a pocket, provides a protected anaerobic, reducing environment that is rich in blood and blood-derived nutrients and thus acts as a reservoir for pathogens. It has been estimated that 1 mg of dental plaque contains more than ten billion bacteria [22]. Recent molecular investigations have indicated that over 1000 bacterial species reside in the oral cavity and that each individual carries
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over 200 species in their oral microbiome [13,23]. The proximity of these bacteria to the vascular supply of the periodontium and the breakdown of epithelial integrity during disease progression predisposes to states of bacteremia when the biofilm is disrupted. Oral bacteria, bacterial products, toxins and inflammatory products can metastasize to non-oral sites both during simple oral hygiene procedures and dental procedures [24,25]. These episodes of bacteremia are higher in individuals with oral infections. The incidence of bacteremia following tooth brushing in children with extensive dental decay ranges from 17 to 40% [26]. Bacteremia has been reported in 100% of cases following dental extraction [27], 70% after routine professional dental cleaning [28], 97% following administration of dental anesthesia by needle and 20% following root canal therapy [29]. In most cases, this bacteremia is transient and the organisms are eliminated from the circulation. However, in certain cases, especially in individuals with a compromised immune system, for example diabetics and those with upper respiratory disease, the oral organisms may colonize certain non-oral sites and lead to disease. Bacterial products, for example, lipopolysaccharide (LPS) and endotoxin are also released into the systemic circulation, and may trigger inflammatory responses in the target organs. The diseased periodontium also acts as a reservoir for inflammatory molecules, especially those that mediate chronic inflammation. Tumor necrosis factor (TNFa), Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-8 (IL-8) and prostaglandins are produced in significant quantities by the diseased periodontium [30,31], and may contribute to systemic inflammation. 4. Periodontal disease and bacterial pneumonia Pneumonia is an inflammation of the lungs caused by infection with a bacterium, virus, fungus or parasite; and the most common type is bacterial pneumonia. Typically, the lower respiratory tract is protected from microorganisms by several mechanisms, including a powerful cough reflex, ciliary movement and secretion of innate immune mediators [32]. Small amounts of bacteria normally aspirated during sleep or accidental swallowing are cleared by these mechanisms. However, these defenses can be impaired in smokers, diabetics, those with chronic obstructive pulmonary disease, and those who are intubated, immunosuppressed or have a prolonged post-operative hospital stay, resulting in community-acquired or hospital acquired (nosocomial) pneumonia [33,34]. Cross-sectional studies have demonstrated that dentate patients, those with poor oral hygiene, and those who do not regularly visit their dentist are more likely to develop pneumonia, suggesting a potential link between poor oral health and lung disease [35]. Further, treatment of periodontal disease and improving the oral hygiene decreased the incidence of pneumonia in children and hospitalized adults [36]. Dental plaque of hospitalized subjects with pneumonia has been shown to be a reservoir for P. aeruginosa [37,38], a respiratory pathogen, while periodontal pathogens, for example, P. gingivalis, Fusobacterium nucleatum, Prevotella oralis, Campylobacter gracilis, Fusobacterium necrophorum and Aggregatibacter actinomycetemcomitans have been cultured from lung fluids of subjects diagnosed with pneumonia [39e42]. Several mechanisms have been proposed to explain the role of periodontal infections in the etiopathogenesis of respiratory diseases: (i) aspiration of oral pathogens into the lungs, (ii) modification of respiratory mucosa by salivary enzymes released in the pathogenesis of periodontal disease, (iii) modification of respiratory mucosa by circulating pro-inflammatory cytokines [43]. 5. Periodontal disease and cardiovascular diseases A potential link between infections and atherosclerosis dates back to the early 19th century, when Gilbert and Lion described the
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induction of fatty sclerosis in the arterial wall of the rabbit aorta following inoculation of the bacterium Bacillus typhosus [44]. Osler, who is credited with promulgating the infection hypothesis of atherosclerosis, listed four major causes: major wear and tear, acute infections, “intoxications” (smoking, diabetes mellitus, obesity) and high blood pressure (reviewed by Nieto [44]). In 1973, the discovery that atherosclerotic plaques were monoclonal in origin, led to the implication that viral infections could be atherogenic [45]. Several studies followed in quick succession, each demonstrating that viral infection could induce endothelial cell damage, smooth muscle proliferation, acute inflammatory responses, foam cell formation, thrombotic changes and plaque instability [46e49]. It has also been demonstrated that cross reactivity between bacterial heat-shock proteins and human Hsp60 could initiate an autoimmune response that culminates in atherosclerosis [50,51]. The hypothesis that periodontitis could be part of the causal chain in the pathogenesis of atherosclerosis gained credence with studies that showed a correlation between tooth loss due to periodontal disease and cardiovascular disease [52e54]. Grau et al. found that the risk for stroke was 400 percent greater in subjects with periodontitis than those with caries [55]. The Oral Infection and Vascular Disease Epidemiology study examined the prevalence of periodontal pathogens and health-compatible bacterial species in 657 individuals and measured the incidence of carotid atherosclerosis [56]. They found a correlation between intimal thickening (which was used as a surrogate measure of atherosclerosis) and periodontal pathogens, but not health-compatible organisms. Beck et al. [57] and Pussinen et al. [58] demonstrated a correlation between systemic antibody levels to periodontal pathogens and the incidence of coronary heart disease and subclinical atherosclerosis. Thus, there appears to an association between periodontal pathogens and the incidence of cardiovascular disease.
6. Periodontal disease and pregnancy outcomes The infection hypothesis suggests that preterm birth may occur as a result of local and systemic maternal infections. This, combined with early studies that certain bacteria preferentially colonize the subgingival crevice during pregnancy [59], has led to several lines of research examining the association between disease-associated periodontal bacteria and neonatal health, however, the results have varied widely [60e67]. Pre-term birth and low birth weight has been associated with high levels of Tannerella forsythia, C. rectus, Prevotella intermedia, Prevotella nigrescens and P. gingivalis in maternal subgingival plaque [60,63,64]. P. gingivalis has been detected in both amniotic fluid and subgingival plaque of 31% of women with threatened pre-term labor [68]. Several mechanisms have been proposed and tested to explain the correlation between adverse pregnancy outcomes and periodontal infection. 1. Initiation of intrauterine inflammation from circulating proinflammatory mediators: It has been shown that periodontal bacteria elicit high levels of prostaglandin (PGE2) and cytokines in circulation and in the placenta [69,70]. Periodontal therapy was accompanied by a 3.8 fold decrease in pre-term births [63]. Together, these results suggest that periodontal bacteria may contribute to pre-term birth by indirectly inducing inflammation in the uterus. 2. Fetal immune response to maternal pathogens: pre-term infants demonstrated an increase in the levels of circulating antibodies to C. rectus (an organism that can translocate across the placental barrier) as compared to full-term neonates [70], suggesting another possible mechanism by which these organisms contribute to pre-term birth.
However, other studies, including a recent, large-scale investigation on 823 pregnant women, found no association between presence or levels of subgingival periodontal pathogens and adverse pregnancy outcomes [61,62,66]. Also, these studies found little or no improvement in pregnancy outcomes following periodontal therapy. A recent systematic review concluded that poor oral hygiene might not play a causal role in the pathogenesis of preeclampsia [71]. It has been suggested that periodontal disease in women with poor pregnancy outcomes may be the result of an epiphenomenon of an exaggerated inflammatory response to pregnancy. 7. Oral bacteria and systemic diseases-future directions We have learned several important lessons from the rise and fall of the theory of focal infection: 1. Not every disease occurs due to a local or distant infection. 2. Foci of chronic infections do exist in the oral cavity and other ecological niches within the human body; however, the level of evidence has to be extremely high before these foci can be admitted into the causal chain. 3. Foci of infections may result in distant disease only in certain individuals and susceptibility plays a critical role. 4. Large numbers of prospective studies are the need of the hour. References [1] Francke OC. William Hunter’s “oral sepsis” and American odontology. Bull Hist Dent 1973;21(2):73e9. [2] Miller WD. The micro-organisms of human mouth: the local and general diseases which are caused by them. Philadelphia: S.S.White; 1880. [3] Hunter W. Oral sepsis as a cause of disease. Br Med J 1900;2(2065):215e6. [4] Fish EW. The teeth as a source of focal sepsis. Postgrad Med J 1940;16(172): 26e33. [5] Murray CA, Saunders WP. Root canal treatment and general health: a review of the literature. Int Endod J 2000;33(1):1e18. [6] Dussault G, Sheiham A. Medical theories and professional development. The theory of focal sepsis and dentistry in early twentieth century Britain. Soc Sci Med 1982;16(15):1405e12. [7] Billings F. Focal infection as the cause of general disease. Bull N Y Acad Med 1930;6(12):759e73. [8] Bocca M, Zombolo L, Coscia D, Moniaci D. The correlation between dental pathology and ophthalmic pathology. Minerva Stomatol 1989;38(10): 1117e20. [9] Rosenow EC. Elective localization of Streptococci. Br Med J 1930;1(3623): 1100e1. [10] Vaizey JM, Clark-Kennedy AE. Dental sepsis: anaemia, dyspepsia, and rheumatism. Br Med J 1939;1(4094):1269e73. [11] Cecil RL, Angevine DM. Clinical and experimental observations of focal Infection, with an analysis of 200 cases of rheumatoid arthritis. Ann Intern Med 1938;12:577e84. [12] Kumar PS, Griffen AL, Barton JA, Paster BJ, Moeschberger ML, et al. New bacterial species associated with chronic periodontitis. J Dent Res 2003;82(5): 338e44. [13] Paster BJ, Boches SK, Galvin JL, Ericson RE, Lau CN, et al. Bacterial diversity in human subgingival plaque. J Bacteriol 2001;183(12):3770e83. [14] Liljemark WF, Bloomquist CG, Uhl LA, Schaffer EM, Wolff LF, et al. Distribution of oral Haemophilus species in dental plaque from a large adult population. Infect Immun 1984;46(3):778e86. [15] Persson GR, Hitti J, Paul K, Hirschi R, Weibel M, et al. Tannerella forsythia and Pseudomonas aeruginosa in subgingival bacterial samples from parous women. J Periodontol 2008;79(3):508e16. [16] Kumar PS, Matthews CR, Joshi V, de Jager M, Aspiras M. Tobacco smoking affects bacterial acquisition and colonization in oral biofilms. Infect Immun 2011;79(11):4730e8. [17] Zinkernagel AS, Gmur R, Fenner L, Schaffner A, Schoedon G, et al. Marginal and subgingival plaqueea natural habitat of Tropheryma whipplei? Infection 2003;31(2):86e91. [18] Loesche WJ. Association of the oral flora with important medical diseases. Curr Opin Periodontol 1997;4:21e8. [19] Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol/Am Acad Periodontol 1996;1(1):821e78. [20] Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontology 2000 2005;38:135e87.
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[49] Etingin OR, Silverstein RL, Friedman HM, Hajjar DP. Viral activation of the coagulation cascade: molecular interactions at the surface of infected endothelial cells. Cell 1990;61(4):657e62. [50] Wick G, Romen M, Amberger A, Metzler B, Mayr M, et al. Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. FASEB J Off Publ Fed Am Soc Exp Biol 1997;11(13):1199e207. [51] Kol A, Sukhova GK, Lichtman AH, Libby P. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation 1998;98(4):300e7. [52] Mattila KJ, Valtonen VV, Nieminen MS, Asikainen S. Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis Off Publ Infect Dis Soc Am 1998;26(3):719e34. [53] Mattila KJ. Dental infections as a risk factor for acute myocardial infarction. Eur Heart J 1993;14(Suppl. K):51e3. [54] Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesaniemi YA, et al. Association between dental health and acute myocardial infarction. Br Med J 1989;298(6676):779e81. [55] Grau AJ, Becher H, Ziegler CM, Lichy C, Buggle F, et al. Periodontal disease as a risk factor for ischemic stroke. Stroke J Cereb Circ 2004;35(2):496e501. [56] Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs Jr DR, et al. Relationship between periodontal disease, tooth loss, and carotid artery plaque: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Stroke J Cereb Circ 2003;34(9):2120e5. [57] Beck JD, Eke P, Lin D, Madianos P, Couper D, et al. Associations between IgG antibody to oral organisms and carotid intima-medial thickness in community-dwelling adults. Atherosclerosis 2005;183(2):342e8. [58] Pussinen PJ, Alfthan G, Tuomilehto J, Asikainen S, Jousilahti P. High serum antibody levels to Porphyromonas gingivalis predict myocardial infarction. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol 2004;11(5):408e11. Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. [59] Kornman KS, Loesche WJ. The subgingival microbial flora during pregnancy. J Periodont Res 1980;15(2):111e22. [60] Mitchell-Lewis D, Engebretson SP, Chen J, Lamster IB, Papapanou PN. Periodontal infections and pre-term birth: early findings from a cohort of young minority women in New York. Eur J Oral Sci 2001;109(1):34e9. [61] Noack B, Klingenberg J, Weigelt J, Hoffmann T. Periodontal status and preterm low birth weight: a case control study. J Periodont Res 2005;40(4): 339e45. [62] Novak MJ, Novak KF, Hodges JS, Kirakodu S, Govindaswami M, et al. Periodontal bacterial profiles in pregnant women: response to treatment and associations with birth outcomes in the obstetrics and periodontal therapy (OPT) study. J Periodontol 2008;79(10):1870e9. [63] Offenbacher S, Lin D, Strauss R, McKaig R, Irving J, et al. Effects of periodontal therapy during pregnancy on periodontal status, biologic parameters, and pregnancy outcomes: a pilot study. J Periodontol 2006;77(12):2011e24. [64] Sanchez AR, Kupp LI, Sheridan PJ, Sanchez DR. Maternal chronic infection as a risk factor in preterm low birth weight infants: the link with periodontal infection. J Int Acad Periodontol 2004;6(3):89e94. [65] Dasanayake AP, Li Y, Wiener H, Ruby JD, Lee MJ. Salivary Actinomyces naeslundii genospecies 2 and Lactobacillus casei levels predict pregnancy outcomes. J Periodontol 2005;76(2):171e7. [66] Michalowicz BS, Hodges JS, DiAngelis AJ, Lupo VR, Novak MJ, et al. Treatment of periodontal disease and the risk of preterm birth. N Engl J Med 2006;355(18):1885e94. [67] Seymour GJ, Ford PJ, Cullinan MP, Leishman S, Yamazaki K. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2007;13(Suppl. 4):3e10. [68] Leon R, Silva N, Ovalle A, Chaparro A, Ahumada A, et al. Detection of Porphyromonas gingivalis in the amniotic fluid in pregnant women with a diagnosis of threatened premature labor. J Periodontol 2007;78(7): 1249e55. [69] Liu H, Redline RW, Han YW. Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response. J Immunol 2007;179(4):2501e8. [70] Madianos PN, Lieff S, Murtha AP, Boggess KA, Auten Jr RL, et al. Maternal periodontitis and prematurity. Part II: maternal infection and fetal exposure. Ann Periodontol 2001;6(1):175e82. [71] Kunnen A, Van Doormaal JJ, Abbas F, Aarnoudse JG, Van Pampus MG, et al. Review article: periodontal disease and pre-eclampsia: a systematic review. J Clin Periodontol;37(12):1075e87.
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Molecular biology, genetics and biotechnology
Oral microbiota and systemic disease Purnima S. Kumar* Division of Periodontology, College of Dentistry, The Ohio State University, 4111 Postle Hall, 305 W. 12th Avenue, Columbus, OH 43210, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 October 2012 Received in revised form 17 September 2013 Accepted 19 September 2013 Available online 12 October 2013
It is well known that bacteria are the primary cause of infectious diseases, however, evidence is emerging that these organisms are also indirectly responsible for several diseases including cancer and rheumatoid arthritis. The oral cavity is home to several million bacteria that can cause two major diseases-periodontitis and caries. The relationship between periodontopathic bacteria and systemic diseases has been explored for several years. The concept of the oral cavity as a source of distant infection has been debated for at least a century. This review will discuss the historic aspects of the development of the focal infection theory, the reasons for its demise, its re-emergence and current status. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Oral bacteria Systemic disease Focal sepsis Focal infection Periodontal medicine
1. Introduction During the Anaerobe 2012 meeting, a session entitled “Oral Microbiota and Systemic Disease ” reviewed current knowledge about the inter-relationships between oral bacteria and susceptibility to systemic diseases. This article will discuss the historic aspects of the development of the focal infection theory, the reasons for its demise, its re-emergence and current status. 2. Rise, fall and rise of the focal infection theory A focus of infection is best described as a circumscribed lesion that is clinically asymptomatic and contains pathogenic bacteria. According to the theory of focal infection, bacteria and/or bacterial products are disseminated from this nidus to distant parts, leading to disease in these organ systems. Several foci of infection have been described in the literature, including tonsils, sinuses, prostate, appendix, bladder, gall bladder, and kidney. Several diseases have been attributed to focal infections, including arthritis, neuritis, myalgia, nephritis, osteomyelitis, endocarditis, pneumonia, asthma, emphysema, gastritis, pancreatitis, colitis, diabetes, goiter, thyroiditis and Hodgkin’s disease. The tooth as a focus of infection: The theory of the oral cavity as a focus of infection is not new; Hippocrates reported arthritis being cured following extraction of a tooth [1]. The term oral focal sepsis * Tel.: þ1 614 247 4532; fax: þ1 614 292 4612. E-mail address: [email protected]. 1075-9964/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.anaerobe.2013.09.010
was introduced by W.D. Miller in his 1890 article “The MicroOrganisms of the Human Mouth: The Local and General Diseases Which Are Caused by Them” and recommended removing decayed parts of a tooth and replacing them with fillings or root canal fillings [2]. However, in 1900, British physician William Hunter ascribed a plethora of systemic diseases to the preservation of a carious tooth by building ‘a veritable mausoleum of gold fillings, crowns and bridges over a mass of sepsis’ [3]. In 1940, Fish published an article on teeth as a source of systemic infections [4]. He described a state where teeth affected by periodontitis (a bacterially-induced disease that affects the structures that support the tooth and anchor it to the jawbone) “shower bacteria into the blood stream” even during the simple process of chewing or tooth brushing. He cited evidence from his own and other studies where dental bacteria could be detected in proximal and distant blood vessels (median basilic and peri-apical veins) following tooth extraction or chewing on hard candy. He proposed that the bacteria or their toxins stagnate in areas where tissues of mesenchymal origin predominate, namely joints, muscle and nerve sheaths. The purported susceptibility of these tissues was due to their ‘unique functions of repair, regeneration and scavenging of waste products’. Thus, he hypothesized that dissemination of bacteria of oral origin to tissues of mesenchymal origin led to the pathogenesis of diverse diseases like osteomyelitis, fasciitis of the sciatic nerve, fibromyalgia and endocarditis. Therapeutic impact of the oral focal sepsis theory: The focal sepsis theory gained momentum in the 19th century and the early 20th century based on the recommendations of prominent
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physicians like William Hunter, Russell Cecil and Charles Mayo [5]. Physicians recommended prophylactic or therapeutic removal of all teeth (and thus earned the moniker ‘one hundred percenters’) or just nonvital teeth, for the treatment of diverse conditions ranging from allergy to schizophrenia [6]. It was recommended as one of the most predictable treatment options for arthritis deformans, and for the treatment of blindness [7,8]. Soon, therapeutic edentulation became the norm. These treatment modalities were bolstered by Rosenow’s theory of ‘elective dissemination’, which stated that certain pathogens demonstrated affinities for colonizing specific sites [9]. However, it was soon apparent that the routine removal of teeth did not provide a cure for diverse maladies. Vaizey and Clark-Kennedy [10] in 1939 and Cecil and Angevine in 1940 [11] demonstrated a worsening of arthritic symptoms and development of digestive complications following therapeutic edentulation. Thus, focal infection was disregarded as a scientific theory for several decades. Reemergence of focal infection theory: Developments of new techniques to identify and classify microorganisms, for example polymerase chain reaction, in situ hybridization, as well as openended molecular approaches such as 16S sequencing revealed the presence of previously unknown and unsuspected organisms in the oral cavity [12,13]. The subgingival sulcus (the space between the tooth and the gingiva) was revealed as a reservoir for several systemic pathogens including Hemophilus influenzae, Pseudomonas aeruginosa and Trophyrema whipplei [14e17]. Advances in surgical techniques allowed access to deep tissues with minimal morbidity and revealed the presence of periodontal pathogens, for example, Porphyromonas gingivalis, Treponema denticola and Campylobacter rectus in atheromatous plaques, valvular vegetations, the tracheobronchial tree, joint cavities and the pancreas [18]. Thus, it soon became apparent that the oral cavity does indeed act as a reservoir of bacteria that metastasize to distant regions and cause disease in susceptible individuals. The World Workshop in Periodontics introduced the term ‘Periodontal Medicine’ in 1996 to describe the relationship between periodontitis and systemic diseases [19]. Thus, the last decade has seen a reemergence of the focal infection theory, albeit with a healthy dose of caution. 3. The periodontal pocket as a source of infection Bacteria colonize the oral cavity soon after birth and form organized, co-operating communities called biofilms within specific ecological niches, for example, the tongue, tooth, subgingival sulcus, tonsil and buccal mucosa [20]. These biofilms allow the bacteria to live in a nutrient-rich environment that is protected from environmental insults, antimicrobial agents and frictional forces. These biofilms perform two important functions e (i) they prevent pathogenic colonization and (ii) they educate the immune system to recognize ‘friend and foe’. In a state of health, equilibrium exists between biofilm antigens and toxins and the host immune response. Under certain circumstances, for example, a change in pH, oxygen tension, nutrient availability or a change in immune status, a shift occurs in the resident microflora, transforming this community from a commensal population to a pathogen enriched one [20]. The host responds to this pathogenic colonization by a florid immune response, leading to a breakdown of the attachment between the tooth, the gingiva and the alveolar socket, loss of bone that supports the tooth and a deepening of the space between the tooth and the gingiva (the sulcus) [21]. This deepened sulcus, now called a pocket, provides a protected anaerobic, reducing environment that is rich in blood and blood-derived nutrients and thus acts as a reservoir for pathogens. It has been estimated that 1 mg of dental plaque contains more than ten billion bacteria [22]. Recent molecular investigations have indicated that over 1000 bacterial species reside in the oral cavity and that each individual carries
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over 200 species in their oral microbiome [13,23]. The proximity of these bacteria to the vascular supply of the periodontium and the breakdown of epithelial integrity during disease progression predisposes to states of bacteremia when the biofilm is disrupted. Oral bacteria, bacterial products, toxins and inflammatory products can metastasize to non-oral sites both during simple oral hygiene procedures and dental procedures [24,25]. These episodes of bacteremia are higher in individuals with oral infections. The incidence of bacteremia following tooth brushing in children with extensive dental decay ranges from 17 to 40% [26]. Bacteremia has been reported in 100% of cases following dental extraction [27], 70% after routine professional dental cleaning [28], 97% following administration of dental anesthesia by needle and 20% following root canal therapy [29]. In most cases, this bacteremia is transient and the organisms are eliminated from the circulation. However, in certain cases, especially in individuals with a compromised immune system, for example diabetics and those with upper respiratory disease, the oral organisms may colonize certain non-oral sites and lead to disease. Bacterial products, for example, lipopolysaccharide (LPS) and endotoxin are also released into the systemic circulation, and may trigger inflammatory responses in the target organs. The diseased periodontium also acts as a reservoir for inflammatory molecules, especially those that mediate chronic inflammation. Tumor necrosis factor (TNFa), Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-8 (IL-8) and prostaglandins are produced in significant quantities by the diseased periodontium [30,31], and may contribute to systemic inflammation. 4. Periodontal disease and bacterial pneumonia Pneumonia is an inflammation of the lungs caused by infection with a bacterium, virus, fungus or parasite; and the most common type is bacterial pneumonia. Typically, the lower respiratory tract is protected from microorganisms by several mechanisms, including a powerful cough reflex, ciliary movement and secretion of innate immune mediators [32]. Small amounts of bacteria normally aspirated during sleep or accidental swallowing are cleared by these mechanisms. However, these defenses can be impaired in smokers, diabetics, those with chronic obstructive pulmonary disease, and those who are intubated, immunosuppressed or have a prolonged post-operative hospital stay, resulting in community-acquired or hospital acquired (nosocomial) pneumonia [33,34]. Cross-sectional studies have demonstrated that dentate patients, those with poor oral hygiene, and those who do not regularly visit their dentist are more likely to develop pneumonia, suggesting a potential link between poor oral health and lung disease [35]. Further, treatment of periodontal disease and improving the oral hygiene decreased the incidence of pneumonia in children and hospitalized adults [36]. Dental plaque of hospitalized subjects with pneumonia has been shown to be a reservoir for P. aeruginosa [37,38], a respiratory pathogen, while periodontal pathogens, for example, P. gingivalis, Fusobacterium nucleatum, Prevotella oralis, Campylobacter gracilis, Fusobacterium necrophorum and Aggregatibacter actinomycetemcomitans have been cultured from lung fluids of subjects diagnosed with pneumonia [39e42]. Several mechanisms have been proposed to explain the role of periodontal infections in the etiopathogenesis of respiratory diseases: (i) aspiration of oral pathogens into the lungs, (ii) modification of respiratory mucosa by salivary enzymes released in the pathogenesis of periodontal disease, (iii) modification of respiratory mucosa by circulating pro-inflammatory cytokines [43]. 5. Periodontal disease and cardiovascular diseases A potential link between infections and atherosclerosis dates back to the early 19th century, when Gilbert and Lion described the
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induction of fatty sclerosis in the arterial wall of the rabbit aorta following inoculation of the bacterium Bacillus typhosus [44]. Osler, who is credited with promulgating the infection hypothesis of atherosclerosis, listed four major causes: major wear and tear, acute infections, “intoxications” (smoking, diabetes mellitus, obesity) and high blood pressure (reviewed by Nieto [44]). In 1973, the discovery that atherosclerotic plaques were monoclonal in origin, led to the implication that viral infections could be atherogenic [45]. Several studies followed in quick succession, each demonstrating that viral infection could induce endothelial cell damage, smooth muscle proliferation, acute inflammatory responses, foam cell formation, thrombotic changes and plaque instability [46e49]. It has also been demonstrated that cross reactivity between bacterial heat-shock proteins and human Hsp60 could initiate an autoimmune response that culminates in atherosclerosis [50,51]. The hypothesis that periodontitis could be part of the causal chain in the pathogenesis of atherosclerosis gained credence with studies that showed a correlation between tooth loss due to periodontal disease and cardiovascular disease [52e54]. Grau et al. found that the risk for stroke was 400 percent greater in subjects with periodontitis than those with caries [55]. The Oral Infection and Vascular Disease Epidemiology study examined the prevalence of periodontal pathogens and health-compatible bacterial species in 657 individuals and measured the incidence of carotid atherosclerosis [56]. They found a correlation between intimal thickening (which was used as a surrogate measure of atherosclerosis) and periodontal pathogens, but not health-compatible organisms. Beck et al. [57] and Pussinen et al. [58] demonstrated a correlation between systemic antibody levels to periodontal pathogens and the incidence of coronary heart disease and subclinical atherosclerosis. Thus, there appears to an association between periodontal pathogens and the incidence of cardiovascular disease.
6. Periodontal disease and pregnancy outcomes The infection hypothesis suggests that preterm birth may occur as a result of local and systemic maternal infections. This, combined with early studies that certain bacteria preferentially colonize the subgingival crevice during pregnancy [59], has led to several lines of research examining the association between disease-associated periodontal bacteria and neonatal health, however, the results have varied widely [60e67]. Pre-term birth and low birth weight has been associated with high levels of Tannerella forsythia, C. rectus, Prevotella intermedia, Prevotella nigrescens and P. gingivalis in maternal subgingival plaque [60,63,64]. P. gingivalis has been detected in both amniotic fluid and subgingival plaque of 31% of women with threatened pre-term labor [68]. Several mechanisms have been proposed and tested to explain the correlation between adverse pregnancy outcomes and periodontal infection. 1. Initiation of intrauterine inflammation from circulating proinflammatory mediators: It has been shown that periodontal bacteria elicit high levels of prostaglandin (PGE2) and cytokines in circulation and in the placenta [69,70]. Periodontal therapy was accompanied by a 3.8 fold decrease in pre-term births [63]. Together, these results suggest that periodontal bacteria may contribute to pre-term birth by indirectly inducing inflammation in the uterus. 2. Fetal immune response to maternal pathogens: pre-term infants demonstrated an increase in the levels of circulating antibodies to C. rectus (an organism that can translocate across the placental barrier) as compared to full-term neonates [70], suggesting another possible mechanism by which these organisms contribute to pre-term birth.
However, other studies, including a recent, large-scale investigation on 823 pregnant women, found no association between presence or levels of subgingival periodontal pathogens and adverse pregnancy outcomes [61,62,66]. Also, these studies found little or no improvement in pregnancy outcomes following periodontal therapy. A recent systematic review concluded that poor oral hygiene might not play a causal role in the pathogenesis of preeclampsia [71]. It has been suggested that periodontal disease in women with poor pregnancy outcomes may be the result of an epiphenomenon of an exaggerated inflammatory response to pregnancy. 7. Oral bacteria and systemic diseases-future directions We have learned several important lessons from the rise and fall of the theory of focal infection: 1. Not every disease occurs due to a local or distant infection. 2. Foci of chronic infections do exist in the oral cavity and other ecological niches within the human body; however, the level of evidence has to be extremely high before these foci can be admitted into the causal chain. 3. Foci of infections may result in distant disease only in certain individuals and susceptibility plays a critical role. 4. Large numbers of prospective studies are the need of the hour. References [1] Francke OC. William Hunter’s “oral sepsis” and American odontology. Bull Hist Dent 1973;21(2):73e9. [2] Miller WD. The micro-organisms of human mouth: the local and general diseases which are caused by them. Philadelphia: S.S.White; 1880. [3] Hunter W. Oral sepsis as a cause of disease. Br Med J 1900;2(2065):215e6. [4] Fish EW. The teeth as a source of focal sepsis. Postgrad Med J 1940;16(172): 26e33. [5] Murray CA, Saunders WP. Root canal treatment and general health: a review of the literature. Int Endod J 2000;33(1):1e18. [6] Dussault G, Sheiham A. Medical theories and professional development. The theory of focal sepsis and dentistry in early twentieth century Britain. Soc Sci Med 1982;16(15):1405e12. [7] Billings F. Focal infection as the cause of general disease. Bull N Y Acad Med 1930;6(12):759e73. [8] Bocca M, Zombolo L, Coscia D, Moniaci D. The correlation between dental pathology and ophthalmic pathology. Minerva Stomatol 1989;38(10): 1117e20. [9] Rosenow EC. Elective localization of Streptococci. Br Med J 1930;1(3623): 1100e1. [10] Vaizey JM, Clark-Kennedy AE. Dental sepsis: anaemia, dyspepsia, and rheumatism. Br Med J 1939;1(4094):1269e73. [11] Cecil RL, Angevine DM. Clinical and experimental observations of focal Infection, with an analysis of 200 cases of rheumatoid arthritis. Ann Intern Med 1938;12:577e84. [12] Kumar PS, Griffen AL, Barton JA, Paster BJ, Moeschberger ML, et al. New bacterial species associated with chronic periodontitis. J Dent Res 2003;82(5): 338e44. [13] Paster BJ, Boches SK, Galvin JL, Ericson RE, Lau CN, et al. Bacterial diversity in human subgingival plaque. J Bacteriol 2001;183(12):3770e83. [14] Liljemark WF, Bloomquist CG, Uhl LA, Schaffer EM, Wolff LF, et al. Distribution of oral Haemophilus species in dental plaque from a large adult population. Infect Immun 1984;46(3):778e86. [15] Persson GR, Hitti J, Paul K, Hirschi R, Weibel M, et al. Tannerella forsythia and Pseudomonas aeruginosa in subgingival bacterial samples from parous women. J Periodontol 2008;79(3):508e16. [16] Kumar PS, Matthews CR, Joshi V, de Jager M, Aspiras M. Tobacco smoking affects bacterial acquisition and colonization in oral biofilms. Infect Immun 2011;79(11):4730e8. [17] Zinkernagel AS, Gmur R, Fenner L, Schaffner A, Schoedon G, et al. Marginal and subgingival plaqueea natural habitat of Tropheryma whipplei? Infection 2003;31(2):86e91. [18] Loesche WJ. Association of the oral flora with important medical diseases. Curr Opin Periodontol 1997;4:21e8. [19] Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol/Am Acad Periodontol 1996;1(1):821e78. [20] Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontology 2000 2005;38:135e87.
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