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Periodontitis: a polymicrobial disruption of host homeostasis : Article : Nature Reviews Microbiology


Nature Reviews Microbiology 8, 481-490 (July 2010) | doi:10.1038/nrmicro2337

Periodontitis: a polymicrobial disruption of host homeostasis

Richard P. Darveau1  About the author


Periodontitis, or gum disease, affects millions of people each year. Although it is associated with a defined microbial composition found on the surface of the tooth and tooth root, the contribution of bacteria to disease progression is poorly understood. Commensal bacteria probably induce a protective response that prevents the host from developing disease. However, several bacterial species found in plaque (the 'red-complex' bacteria: Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) use various mechanisms to interfere with host defence mechanisms. Furthermore, disease may result from 'community-based' attack on the host. Here, I describe the interaction of the host immune system with the oral bacteria in healthy states and in diseased states.

Periodontitis is a bacterially induced chronic inflammatory disease of the periodontium (Fig. 1). The result, the destruction of the periodontium, is the most common cause of tooth loss worldwide. The ability to non-invasively sample the microbial composition of clinically healthy and diseased sites surrounding the surface of the tooth and tooth root has resulted in a detailed and comprehensive description of dental plaque — the polymicrobial communities of these sites — associated with either healthy or diseased host tissue1, 2, 3, 4, 5, 6, 7. In addition, the ease with which gingival crevicular fluid (a serum exudate that contains systemically and locally produced cytokines) and gingival tissue can be sampled has facilitated an extensive examination of the innate host defence status of both clinically normal and diseased tissue8, 9, 10, 11, 12, 13, 14 (Box 1). These studies document strong associations between the type of polymicrobial community found in juxtaposition to gingival tissue and the corresponding innate host defence status. Nevertheless, the contributions of the different microbial communities associated with either health or disease remain unclear.

Figure 1 | The effects of periodontitis.
Figure 1 : The effects of periodontitis. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comHealthy periodontal tissue (left) contains connective tissue and alveolar bone, which support the tooth root. In addition, the oral epithelium covers this supporting tissue, and a specialized junctional epithelium connects it to the tooth surface. The space between the epithelial surface and the tooth is called the sulcus and is filled with gingival crevicular fluid. In cases of periodontitis (right), a dental-plaque biofilm accumulates on the surface of the tooth and tooth root and causes the destruction of periodontal connective tissue and alveolar bone, resulting in the most common cause of tooth loss in the world.

Several advances in the past 10 years have changed our thinking about the microbial aetiology of periodontitis. First, it is now well recognized that the host innate immune defence system is highly active in healthy tissue, and an imbalance or disruption in the expression of inflammatory mediators contributes greatly to the destruction of the tissue and bone supporting the root structures11, 15, 16. Second, the identification of the Toll-like receptor (TLR) family of receptors, which recognize microorganisms, has contributed to the realization that both commensal and periopathogenic bacteria can activate innate immune responses17, 18. Finally, the understanding that the oral microbial community is a biofilm has led to a greater emphasis on the idea that microbial community interactions may modulate the expression of host innate immune mediators4, 19. This review discusses the microbial aetiology of adult type periodontitis, the most common form of the disease, in light of these new developments.

The microbiology of periodontitis

A brief review of the relationships between oral bacteria and of their contribution to the development of periodontitis provides a perspective that is needed as we attempt to understand and treat polymicrobial communities that are associated with chronic inflammatory diseases1. Periodontitis is an ancient disease — fossil evidence demonstrates that our early ancestors experienced the localized alveolar bone loss around tooth root surfaces that is a hallmark of the disease. The loss of this bone, which supports the root structure of the tooth, leads to the eventual loss of the tooth (Fig. 1) and remains the most common cause of tooth loss in the world today. Microorganisms were first considered as possible aetiological agents of periodontitis in the late 1800s, when the germ theory of disease changed our understanding of disease aetiologies. Failure to identify a specific pathogen in the polymicrobial community dampened the enthusiasm for a microbial aetiology, and other causes for perionditis, such as trauma or disuse atrophy, were proposed. Finally, however, the resolution of gingival inflammation after the physical removal of dental plaque during routine dental cleanings led to the 'nonspecific plaque' hypothesis. The premise of this hypothesis is that the quantity of dental plaque is more important to disease pathogenesis than the identity of the individual bacterial species present.

Our understanding of periodontitis has increased markedly with extensive analysis of the dental plaque associated with either clinically healthy or diseased sites. In the process, the microbial consortiums in plaques have become the most highly characterized microbial consortiums in humans. Similarly to other polymicrobial diseases20, 21, 22, periodontitis has been characterized as a microbial-shift disease owing to a well-characterized shift in the microorganisms that are present (from mostly Gram-positive to mostly Gram-negative species1) during the transition from periodontal health to periodontal disease23. A landmark study using whole-genome DNA probes identified several bacterial complexes associated with either periodontal health or disease2. This included three bacterial species that were designated the 'red-complex' periopathogens — Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola2 — which grouped together in diseased sites and showed a strong association with disease. Further characterization of dental plaque identified numerous uncultivable species, raising the estimate of the number of bacterial species found in periodontal tissue to greater than 500 (Ref. 24). Some of these uncultivable bacteria were found to be strongly associated with either clinically healthy25 or diseased26 sites. In addition, methanogenic archaea have been found to be associated with periodontitis27, 28. Finally, the microbial shift found in healthy versus diseased sites indicates that stability of the dental-plaque community is a good predictor of periodontal health, whereas changes in this community are associated with changes in the clinical status of the tissue29. Nevertheless, the mechanisms that maintain the stability of or induce changes in the microbial composition are not understood.

The innate host response in periodontal tissue

Owing to its juxtaposition to host periodontal tissue, dental plaque provides a constant challenge to the innate host immune system. At clinically healthy sites, this challenge may be beneficial, resulting in resistance to colonization by periopathogens and triggering other less-well-defined responses of the host innate immune system. By contrast, at diseased sites the microbial challenge clearly results in the alteration of the normal defence mechanisms in the periodontium. Periodontal tissue does not have a large mucous layer to prevent contact between the microbial community and the epithelial cell surface, unlike the intestine30. In fact, although both periodontal and intestinal tissues are in close proximity to polymicrobial communities, it seems that they use two completely different strategies to contend with the constant presence of microbial stimulation. The intestinal epithelium is a single layer of cells connected by tight junctions that channels bacteria and their components to the highly specialized Peyers patches, where a localized, fully developed lamina propria can recognize microorganisms and respond accordingly31. By contrast, the gingival epithelium (in particular, the junctional epithelium) is highly porous. Junctional epithelial cells are interconnected by a few desmosomes and the occasional gap junction, resulting in large fluid-filled, intracellular spaces30. To cope with constant microbial stimulation, the periodontium has a highly orchestrated expression of select innate host defence mediators (Fig. 2).

Figure 2 | Transit of neutrophils through periodontal tissue.
Figure 2 : Transit of neutrophils through periodontal tissue. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comThe innate host defence status of healthy periodontal tissue results in the coordinated expression of select innate defence mediators such as interleukin-8 (IL-8), facilitating neutrophil transit through the tissue. In addition, the gingival epithelium expresses several innate host defence mediators that contribute to the clearance and killing of dental-plaque bacteria, including Toll-like receptors (TLRs) (which recognize pathogens and commensal bacteria), β-defensins and lipopolysaccharide-binding protein (LBP). Further to this, the junctional epithelium produces soluble CD14 (sCD14) (another bacterial clearance mediator) and LBP. Innate host protective mechanisms are coupled with regenerative and biomechanical signalling systems, resulting in tissue homeostasis. The IL-8 gradient is depicted in blue. PMN, polymorphonuclear neutrophils.

The unique coordinated expression of E-selectin, intercellular adhesion molecules (ICAMs) and interleukin-8 (IL-8) facilitates the transit of neutrophils from the highly vascularized gingival tissue to the gingival crevice32, 33, 34, 35, 36, 37, where they form a wall between the host tissue and the dental-plaque biofilm37. The tissue architecture of the junctional epithelium assists the transit of these and other immune cells30. It has been calculated that approximately 30,000 polymorphonuclear neutrophils (PMNs) transit through periodontal tissue every minute37, 38. Normally, the presence of neutrophils in host tissue is a sign of bacterial infection; however, it is important to note that the neutrophils transiting though periodontal tissue do not reside in it. Individuals with congenital deficiencies in either neutrophil number39, 40, 41, 42 or transit (called leukocyte adhesion deficiency type 1 (LAD 1) and LAD 2) or who have neutropenia due to chemical induction with antimitotic agents such as cyclophosphamide43, 44, 45, 46 invariably develop periodontitis. These observations show that this component of the innate defence response in clinically healthy tissue is very important for periodontal health.

Periodontal tissue also expresses numerous other innate host mediators, such as human β-defensin 1 (BD1), BD2 and BD3 (Refs 47, 48) as well as soluble49 and membrane-bound50 CD14 and lipopolysaccharide-binding protein (LBP)51 (Fig. 2). Furthermore, higher levels of soluble CD14 in gingival crevicular fluid were associated with fewer and shallower periodontal pockets49. In addition, LBP mRNA and LBP are more highly expressed in healthy tissues than in diseased tissues51. It is interesting to note that gingival epithelial cells are a source of LBP, which is also produced in the liver as part of the acute-phase response. These studies strongly implicate soluble CD14 and LBP in the clearance of bacteria and bacterial components and suggest that they act in a manner similar to the mucous layer of the intestine, by reducing bacterial interactions with the epithelium. Like the intestinal epithelium, clinically healthy human gingival tissue expresses a wide range of TLRs, including TLR1–TLR952, 53, 54. However, it is not known if gingival epithelial cells regulate expression of these receptors to reduce microbial interactions in a manner similar to that observed in intestinal epithelium55. One mechanism by which the inflammatory response may be dampened is the absence of membrane-bound CD14 in epithelial cells56, which effectively reduces the potency of microbial-ligand stimulation. Nevertheless, these data are all consistent with the notion that the expression of innate host defence mediators is key to the maintenance of periodontal health.

Cytokines in clinically healthy tissue

The innate host response to commensal oral bacteria may contribute to the highly protective defensive status of periodontal tissue57. In response to oral bacteria, the outermost layers of the gingival epithelium, which are in close contact with the commensal oral bacteria, produce IL-8 and β-defensins36, 48, 58, 59, 60, 61, 62. However, little information concerning the effect of commensal colonization is available. Although germ-free mice have been used as experimental models to examine the microbial aetiology of periodontitis63, this model system has not yet been used to study the contribution of commensal bacteria to the innate host defence status of the periodontium. The finding that levels of IL-1β in mouse periodontal tissue are higher in conventionally reared mice than in age-matched germ-free animals64 indicates that periodontal tissue can respond to commensal colonization and is not merely a passive protection barrier. By contrast, studies using germ-free65, 66, 67, 68, 69, 70, 71, 72, 73, 74 and knockout75 mice have established that intestinal commensal bacteria play an active part in establishing both immune and innate protective mechanisms and also participate in tissue development. These studies showed that commensal bacteria contribute to a 'controlled inflammatory state' in the intestine72, 73 that is very similar to the state observed in clinically healthy periodontal tissue.

The presence of IL-1β in the periodontal tissue of germ-free mice, albeit at low levels, is consistent with the theory that cytokines contribute to host homeostatic processes independently of bacterial colonization. The periodontium contains self-renewing tissues, including the periodontal ligament and the gingival epithelium30, 76. In addition, the extracellular matrix and collagen type I of the connective tissue help stabilize periodontal tissues, and fibronectins affect cell morphology, migration and differentiation77. The coordinated regulation of these cell proliferation and differentiation events is controlled by host signalling mechanisms and is referred to as tissue homeostasis. These signalling mechanisms maintain homeostasis of the periodontal tissue by regulating epithelial cell functions as well as connective-tissue resident cells and haematopoietic cells. Gingival crevicular fluid is a serum and local-tissue exudate that collects locally around each tooth surface and provides an accurate representation of tissue and serum concentrations of inflammatory mediators11, 12. Many cytokines that are normally associated with inflammation, such as the potentially damaging cytokines IL-1β, tumour necrosis factor (TNF) and prostaglandin E2 (PGE2), are found at lower levels in gingival crevicular fluid from clinically healthy sites13 than in fluid from diseased sites78.Therefore, alongside the expression of protective innate defence components, the periodontium continuously expresses host cytokines, chemokines and cell adhesion molecules that are involved in maintaining periodontal tissue homeostasis. Currently, the relative contributions of commensal bacteria and host developmental programmes to the expression of the cytokine, chemokine and cell adhesion repertoire in clinically healthy tissue are not known.

The host response contributes to periodontitis

The recognition that the host contributes to the tissue destruction and alveolar bone resorption that are characteristic of periodontitis was a major conceptual advance79; one consequence of an increase in the concentrations of inflammatory mediators is the resorption of alveolar bone, which is the hallmark of periodontitis (Fig. 3). The main mechanism that regulates the normal bone resorption and deposition activities that occur during bone remodelling is the ratio of RANKL (receptor–activator of nuclear factor-κB ligand; also known as TNFSF11) to OPG (osteoprotegrin; also known as TNFRSF11B)80, 81, 82, and this mechanism probably also contributes to the bone loss observed in periodontitis. RANKL is present on several cell types and binds to RANK (also known as TNFRSF11A) on osteoclast precursors, causing them to differentiate into active macrophage-like cells that secrete enzymes which degrade bone. OPG is a soluble receptor of RANKL that prevents the RANK–RANKL interaction. At high OPG concentrations, RANKL does not bind to osteoclast precursors and bone loss is averted. OPG levels are regulated by transforming growth factor-β-related bone morphogenic proteins, whereas the synthesis of RANKL is induced by pro-inflammatory cytokines such as IL-1β and TNF. Therefore, increases in the concentration of pro-inflammatory cytokines in healthy periodontal tissue can directly affect bone loss by increasing the RANKL/OPG ratio.

Figure 3 | Microbial alteration of bone homeostasis leads to localized bone loss.
Figure 3 : Microbial alteration of bone homeostasis leads to localized bone loss. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | Alveolar bone is constantly being remodelled, but the amount of bone formation — triggered by an excess of OPG (osteoprotegrin; also known as TNFRSF11B) — is normally equal to the amount of bone loss — triggered by an excess of RANKL (receptor–activator of nuclear factor-κB ligand; also known as TNFSF11) — resulting in bone homeostasis. b | Localized microbial communities such as those forming dental plaque can alter the RANKL/OPG ratio, resulting in a net increase in bone loss.

Studies in animal models of disease have shown that other host inflammatory mediators also contribute to bone loss83, 84, 85, 86. In a mouse model of periodontitis, bone loss was decreased after administration of soluble decoy receptors for IL-1α and IL-1β or TNF83, 85, 86 (thereby inhibiting these proteins from binding to their receptors) and also in mice deficient in interferon-γ (IFNγ), IL-6 or TNF receptor 1 (TNFR1)84, 87, demonstrating a link between the host inflammatory response and the clinical manifestation of periodontitis. In addition, mice that are deficient in both E-selectin and P-selectin88 or in IL-1089 spontaneously develop periodontitis. Low levels of E-selectin are found in healthy human periodontal tissue32, 33, 34, 35, 36 and are thought to contribute to neutrophil transit though the periodontium35. Periodontitis did not develop in mice that were deficient in both E-selectin and P-selectin and that were given continuous antibiotic administration88, confirming the contribution of oral bacteria to disease. Likewise, the spontaneous disease observed in IL-10-knockout mice points to a role for IL-10 in preventing overexpression of the innate host components that are expressed in response to commensal oral bacteria. The development of disease in the absence of IL-10 shows that a balance between pro- and anti-inflammatory mediators is needed to maintain periodontal health, although systemic antibiotic administration is required to test this hypothesis. Therefore, spontaneous disease in these knockout mouse models is due to a disruption in the normal balance between the oral commensal flora and the innate immune status of periodontal tissue.

In a transgenic mouse strain that overproduces IL-1α, periodontitis develops even with the continuous administration of systemic antibiotics90, demonstrating that it is possible to develop periodontitis owing to the excessive production of host inflammatory mediators in the absence of a bacterial component. Therefore, bone loss may result from disruption of these host mediators, consistent with the hypothesis that different disruptions in tissue homeostasis can lead to excessive inflammation and result in disease.

The finding that members of the TLR family of microbial-recognition receptors are present in the periodontium has opened the possibility that many bacterial species, including commensal and periopathogenic bacteria, have the ability to change tissue homeostasis. These pattern recognition receptors91 recognize microbial components (such as DNA, flagella and fimbriae) that are shared by oral commensal and periopathogenic species and recognize peptidoglycan and lipoteichoic acids in Gram-positive bacteria as well as lipopolysaccharide in Gram-negative bacteria, and they then activate various innate host responses92. Therefore, once the dental-plaque composition changes, various bacteria found in the subgingival plaque may contribute to a destructive inflammatory response. Dental-plaque samples containing various microorganisms can activate either TLR2 or TLR4 (Ref. 93). Although dental plaque obtained from individuals with more plaque elicited significantly more TLR4 activation than plaque from individuals with less plaque, samples from both groups induced activation of TLR2 and TLR4 (Ref. 93). Furthermore, there is no strong association between specific bacterial species in the dental plaque and the ability to activate TLR2 or TLR4. Surprisingly, TLR2 mediates bone loss in response to P. gingivalis in a mouse model (Box 2), even though TLR4 ligation is thought to be a more potent inflammatory stimulator94, 95. These data support the theory that TLR2, a host receptor that can interact with Gram-positive oral commensal bacteria, can initiate a destructive inflammatory response.

A disruption of tissue homeostasis that leads to the production of destructive host inflammatory cytokines thus clearly contributes to the damage associated with periodontitis. However, the plethora of different bacterial species present and the ability of TLR family members to recognize both pathogenic and commensal bacteria precludes the identification of the specific bacterial species that contribute to the dysfunctional modulation of the innate immune response.

Red complex periopathogens

Although we do not know the specific microbial functions involved in the destructive response, red-complex periopathogens P. gingivalis, T. forsythia and T. denticola2, which are often associated with each other and with diseased sites, may inhibit innate host defence functions.

Inhibition of IL-8. P. gingivalis, the best characterized periopathogen, can inhibit host defence functions — including the gingival epithelial secretion of IL-8 that is induced by other oral bacteria — by several mechanisms58, 60, 96, 97, 98. This phenomenon, termed 'local chemokine paralysis' (Ref. 58), was proposed to be a virulence mechanism, as it can impair the IL-8 gradient in clinically healthy tissue (Fig. 4a) that provides directionality to the transit of neutrophils from the vasculature through the periodontal tissue and into the gingival crevice. Commensal bacteria are thought to contribute to this gradient, as the concentration of IL-8 is highest in gingival tissue closest to dental plaque36 and gingival epithelial cells secrete IL-8 in response to several oral bacterial species58, 59, 60. The contribution of commensal bacteria to IL-8 levels has not been formally examined in germ-free mice, but studies have shown that P. gingivalis can inhibit constitutive IL-8 secretion96, 97 without the activation of commensal bacteria. Additional studies have shown that the P. gingivalis phosphoserine phosphatase SerB contributes to the inhibition of IL-8 (Ref. 99). Synthesis of SerB is induced on contact with gingival epithelial cells100 and may modify normal host cell functions to create a suitable intracellular environment for the bacteria.

Figure 4 | Porphyromonas gingivalis, a member of the red-complex bacteria, inhibits innate host defence functions in gingival epithelium.
Figure 4 : Porphyromonas gingivalis, a member of the red-complex bacteria, inhibits innate host defence functions in gingival epithelium. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comThe ability to impair the innate host response to bacteria is a phenotype of red-complex bacteria that makes them key species for disease development. It facilitates the exposure of host connective tissues to other species in the biofilm community, which in turn, may modulate other host tissue homeostasis programmes. a | SerB, a phosphoserine phosphatase, inhibits interleukin-8 (IL-8) and may disrupt other epithelial-cell homeostasis programmes (see Refs 99, 100). b | Specific lipid A structures in the Porphyromonas gingivalis lipopolysaccharide (LPS) inhibit the response of Toll-like receptor 4 (TLR4) to other bacteria.

T. denticola can also inhibit IL-8 function96, but the mechanism of inhibition is not understood. The major outer-membrane protease of T. denticola, dentilisin, can degrade IL-8 in vitro101, but a protease mutant that does not degrade IL-8 does not induce higher levels of IL-8 (Ref. 101). Similarly, P. gingivalis contains proteins with strong proteolytic activity that can degrade IL-8, but decreased IL-8 levels are still observed with low numbers of bacteria that do not have sufficient protease activity to degrade the existing IL-8 (Ref. 58). In addition, T. forsythia does not elicit IL-8 secretion from gingival epithelial cells, but the mechanism of this evasion is not known96.

Modulation of signalling in lipid rafts. P. gingivalis interferes with an innate host defence protection mechanism by inducing crosstalk between TLR2 and CXC-chemokine receptor 4 (CXCR4) after they are recruited to a lipid raft in response to P. gingivalis fimbriae102. This crosstalk attenuates the protective and bactericidal response to P. gingivalis. These findings provide another example of how bacteria manipulate the intricate regulatory mechanisms of host cells to survive in the host.

Lipid A as a regulator of TLR4 signalling. The red-complex bacteria can inhibit innate host defence functions by producing a lipid A structure that acts as a TLR4 antagonist103, 104 (Fig. 4b). The structure of lipid A (which is part of the lipopolysaccharide on the outer membrane of Gram-negative bacteria) in P. gingivalis is heterogeneous, similar to lipid A in other bacteria105, 106, 107, 108, 109, 110, 111, 112, 113, 114. A 5-acyl monophosphate structure is a weak TLR4 agonist, whereas a 4-acyl monophosphate structure is a TLR4 antagonist113; these properties have been confirmed by lipid A analogues that have been chemically synthesized115, 116, 117. The expression of both the TLR4 agonist and TLR4 antagonist lipid A structures in P. gingivalis is regulated by the hemin concentration in the growth medium, most likely through lipid A phosphatases118, 119. The TLR4 antagonist decreased β-defensin expression in a reconstituted human gingival epithelium system120 and interrupted the epidermal growth factor (EGF)-dependent signalling pathways (which involve mitogen-activated protein kinase (MAPK) signalling cascades) that are involved in remodelling of the periodontal tissue matrix121, 122. The lipid A antagonist of TLR4 from P. gingivalis inhibits EGF-mediated signalling at the level of extracellular signal-regulated kinase 1 (ERK1; also known as MAPK3), ERK2 (also known as MAPK1), p38 MAPKs and CREB proteins, which are components of the MAPK signalling cascade121. Thus, independently of the innate host response, P. gingivalis can disrupt tissue homeostasis through the host cell signalling pathways that are shared by the innate host response and the tissue remodelling pathway.

Multispecies pathogenesis

The recognition that dental plaque is a biofilm has important implications for the understanding of microbial interactions with the host. Dental plaque displays community characteristics such as tertiary structures with aqueous or exopolysaccharide-filled channels, and microbial members of dental plaque demonstrate physiological co-dependence and quorum sensing4, 19, 123, 124. In this respect, biofilms mimic tissues, as individual microorganisms contribute to the structure and function of the biofilm community125. Therefore, efforts are now underway to understand oral microbial interactions that may lead to either the maintenance of health or the development of disease, focusing on the interplay that occurs between the numerous oral bacteria in the biofilm community. For example, viewing resistance to host defences or pathogenic assaults as community events in which multiple members of the oral consortium participate opens new possibilities for understanding microbial-shift diseases such as periodontitis.

One mechanism by which the oral microbial community may disrupt periodontal tissue homeostasis is by capitalizing on the inhibitory phenotype of the red-complex organisms against the host innate response. The inhibition of epithelial cell IL-8 responses by P. gingivalis and the presence of a TLR4 antagonist may affect the interaction of the entire microbial community with the host. Once the innate immune status of the periodontal pocket is compromised by the reduction in IL-8 secretion, neutrophil transit may be disrupted, resulting in an increase in the number and types of bacteria in the dental plaque. Likewise, the TLR4 antagonist form of P. gingivalis lipid A can block the TLR4 activation that occurs in response to several oral bacteria126 by competitive binding to the lipid A binding site on MD2 (also known as LY96), which is an essential lipid recognition protein that forms the functional TLR–MD2 receptor complex103, 104. P. gingivalis releases lipopolysaccharide in the form of vesicles that can penetrate gingival tissue127, 128, thus the TLR4 antagonist form of P. gingivalis lipid A has the potential to dampen TLR4 responses for the entire oral microbial community. As bacterial numbers increase, the proteases found in all three red-complex organisms129, 130 may further compromise innate defence functions by inactivating potentially protective host responses. Although this specific theory awaits validation, it underscores the fact that virulence on the community level may be multifactorial131.

In P. gingivalis, quorum sensing through LuxS contributes to biofilm formation and regulates the expression of stress response genes such as htrA, which contributes to bacterial invasion of epithelial cells and bacterial survival in mouse models of infection132, 133, 134. Furthermore, direct contact between microorganisms regulates the expression of the fimbrilin gene (fimA) in P. gingivalis, and, as discussed above, this bacterium subverts innate host responses by capitalizing on the lipid raft-based host response to fimbriae102, 135. Metabolic cooperation, either through co-aggregation or close association of genetically distinct bacteria136, not only increases species diversity but also facilitates beneficial relationships. For example, serum resistance in Aggregatibacter actinomycetemcomitans is the result of H2O2 production by streptococcal species137. Incorporating the principles of biofilm community growth, including ecological considerations as described by the 'ecological plaque hypothesis', into the disease model for periodontitis will lead to a better understanding of the interactions between polymicrobial communities and the host immune system. The identification of key species that perform essential functions for the entire community and an understanding of the essential mechanisms for either maintenance or destruction of the innate defence system in the periodontium will facilitate metagenomic analyses that could identify novel prognostic or therapeutic avenues.

Therapeutic interventions

The goal of periodontal treatment is to restore the homeostatic relationship between periodontal tissue and its polymicrobial dental-plaque community. The oldest, most effective and most widely used treatment is physical removal of the pathogenic dental-plaque biofilm by scaling and root planing. The homeostatic relationship is restored through microbial recolonization with oral commensals and through the ensuing tissue healing process, as determined by clinical attachment levels, bleeding on probing and pocket depth138. Adjunctive therapies that include the local administration of antibiotics139 or anti-inflammatory agents140, 141 along with plaque removal have shown a statistically significant improvement in clinical parameters. However, the clinical benefit of either antibiotic or anti-inflammatory adjunctive therapies has been marginal. This may be due to the fact that multiple species with differing antimicrobial susceptibilities, as well as multiple disruptions in host tissue homeostatic mechanisms, can result in the initiation of destructive inflammation.

Other therapeutic interventions such as active or passive immunization directed against P. gingivalis have shown promise in preclinical studies142, 143, 144. A study performed in rats found that immunization with the adhesin motif of the P. gingivalis haemagglutinin (HagB) was able to reduce bone loss145. Vaccination of mice with a 40 kDa outer-membrane protein146 or the P. gingivalis gingipain R1 (RgpA)–lysine gingipain (Kgp) protease complex144 (a known virulence factor147) as immunogens resulted in reduced alveolar bone loss in vaccinated animals. Another vaccine using the P. gingivalis protease complex reduced bone loss, decreased P. gingivalis numbers in dental plaque and reduced the gingival crevicular levels of PGE2 in Macaca fascicularis monkeys143. A DNA-based vaccine targeting the protease also protected against bone loss148. Furthermore, synthetic adhesion-binding-motif peptides or active-site peptides of the RgpA–Kgp protease complex protected against bone loss in the mouse model of disease when bound to the diphtheria vaccine144. Lastly, in a human clinical study a monoclonal antibody directed against the P. gingivalis protease complex prevented recolonization of periodontal lesions for up to 9 months after repeated passive local administrations of the antibody to diseased sites142. The ability to treat a polymicrobial disease by targeting P. gingivalis proteins strengthens the theory that select bacteria of the polymicrobial community are key members that provide an essential function for the entire consortium.

A recent study examined the efficacy of a pro-resolving mediator designated RvE1 (Ref. 149). RvE1 is representative of a new class of eicosanoid compounds that contain both anti-inflammatory and pro-resolving characteristics150. These compounds arise late in the inflammatory response and actively contribute to restoring host homeostasis150. The identification and characterization of pro-resolving compounds, such as lipoxins, resolvins (including RvE1) and protectins, has found that the resolution of inflammation is not a passive process in which host inflammatory mediators gradually fall below their effective concentrations owing to the loss of the inflammatory stimuli150. Rather, the host actively induces resolution of the inflammatory lesion by secreting mediators that impede neutrophil infiltration, induce neutrophil apoptosis and attenuate inflammatory-cytokine secretion150. For example, two known receptors for RvE1, CHEMR23 (also known as CMKLR1) and BLT1 (also known as LTB4R), attenuate inflammation by inhibiting TNF-stimulated nuclear factor-κB (NF-κB) activation or by acting as a stereospecific inhibitor of the inflammatory mediator leukotriene B4, respectively. The active resolution of inflammation is particularly useful in chronic inflammatory diseases, in which the host has difficulty clearing the inflammatory stimuli. Accordingly, RvE1 was examined in a rabbit model of P. gingivalis-induced periodontitis in which ligatures were tied around select teeth and P. gingivalis was then applied149. The compound was efficacious as a prophylactic, preventing periodontitis when added simultaneously with P. gingivalis, and as a therapeutic, when it was added after P. gingivalis-induced periodontitis had occurred. Consistent with the inflammation-resolving characteristics of RvE1, new bone was formed in the rabbit model, indicative of a restored RANKL/OPG ratio. When combined with scaling and root planing, which remove dental plaque, RvE1 offers the promise of aiding the host in the resolution of inflammation initiated by multiple mechanisms.


Periodontitis may involve multiple disruptions to host homeostasis in periodontal tissue. However, surprising little is known about how bacterial modulation of host cytokine expression repertoires may lead to destructive inflammation. Research in this area will improve our understanding of periodontitis and, potentially, other chronic inflammatory diseases. Although many different bacteria in the oral microbial consortium may participate in the disruption of host homeostasis, the identification of red-complex bacteria facilitated investigations that revealed the ability of these bacteria to impair innate defence systems. Additional cataloguing of microbial inhabitants associated with polymicrobial diseases and of their interactions with other members of the biofilm as well as with the host will increase our understanding of how these bacteria may act together as a community and result in either improved host health or host disease.



The author thanks M. Curtis for critical review of the manuscript, M. Thomashow and F. Roberts for fruitful discussions and C. Zenobia for help with the figures. He also thanks the past and present members of his lab and department for continued inspiring conversations. The editorial assistance of N. Balch is greatly appreciated. Work in the author's laboratory is supported by the National Institute of Dental and Craniofacial Research.

Competing interests statement

The author declares no competing financial interests.



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Author affiliations

  1. University of Washington, 1959 NE Pacific St., Room D-570 Health Sciences Building, Seattle, Washington 98195, USA.

Published online 1 June 2010


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