Current concepts in the pathogenesis of periodontitis: from symbiosis to dysbiosis

Abstract

The primary etiological agent for the initiation and progression of periodontal disease is the dental plaque biofilm which is an organized aggregation of microorganisms residing within a complex intercellular matrix. The non-specific plaque hypothesis was the first attempt to explain the role of the dental biofilm in the pathogenesis of periodontal diseases. However, the introduction of sophisticated diagnostic and laboratory assays has led to the realisation that the development of periodontitis requires more than a mere increase in the biomass of dental plaque. Indeed, multispecies biofilms exhibit complex interactions between the bacteria and the host. In addition, not all resident microorganisms within the biofilm are pathogenic, since beneficial bacteria exist that serve to maintain a symbiotic relationship between the plaque microbiome and the host's immune-inflammatory response, preventing the emergence of pathogenic microorganisms and the development of dysbiosis. This review aims to highlight the development and structure of the dental plaque biofilm and to explore current literature on the transition from a healthy (symbiotic) to a diseased (dysbiotic) biofilm in periodontitis and the associated immune-inflammatory responses that drive periodontal tissue destruction and form mechanistic pathways that impact other systemic non-communicable diseases.

Keywords: Dental biofilm; dysbiosis; inflammation; periodontal disease; symbiosis.

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Figures

Figure 1.

Biofilm formation and development in the oral cavity. a. acquired pellicle formation; b. initial attachment of early colonizers; c. maturation of biofilm and coaggregation of bacteria; D. dispersion of bacteria.

Figure 2.

The association among subgingival species (adapted from Socransky et al. [13,27]). Presence of 40 subgingival species and the association among them in subgingival dental biofilm samples (n = 13,321) were analysed using checkerboard DNA-DNA hybridization and cluster analysis and community ordination techniques, respectively. The base of the pyramid represents the early colonizers, followed by the orange complex, which bridges the early colonizers with the red complex that dominates the biofilm at the advanced stages of periodontitis.

Figure 3.

Components of dental biofilm with their functions and relation of chemical gradients to the depth of dental biofilm. DB: dental biofilm, G+ve: Gram-positive, G-ve; Gram-negative.

Figure 4.

Bacterial virulence factors and metabolism.

Figure 5.

Inflammation-Mediated Polymicrobial Emergence and Dysbiotic Exacerbation (IMPEDE) model. According to this proposed model, plaque-induced periodontitis is mainly derived from inflammation. This model consists of 5 stages: stage 1: gingivitis, stage 2: emergence of polymicrobial diversity in early periodontitis, stage 3: inflammation mediated dysbiosis and opportunistic infection, and stage 4: late stage of periodontitis. Adapted from Van Dyke et al., 2020 [147].

Figure 6.

Neutrophils-induced inflammatory mechanisms involved in tissue destruction and bone loss. Neutrophils are recruited in a developmental endothelial locus (Del)-1-induced pathway into the gingival epithelium that fail to encounter the dysbiotic bacteria which invade the gingival connective tissue and interact with different host cells such as dendritic cells and γδ T cells. Host-bacterial interaction results in production of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, IL-23, and IL-17. IL-17 has an activating influence on T helper (Th)-17 and B cells, which upon activation increase receptor activator of nuclear factor kappa-B ligand (RANKL) expression, which is also directly activated via the recruited extravasated neutrophils. RANKL drives the activation and maturation of osteoclast precursor to be an active osteoclast that predisposes to bone resorption. The recruited neutrophils have a tissue degradation effect through inducing the expression of matrix metalloproteinases (MMP) and cytotoxic substances such as reactive oxygen species (ROS). The microbial-innate-adaptive cell interactions demonstrate some of the main mechanisms involved in the continuity of inflammation if not resolved, leading to tissue destruction.

Figure 7.

Porphyromonas gingivalis enhancing dysbiosis through uncoupling of inflammation from bactericidal activity of the phagocytic cells. P. gingivalis interacts with Toll-like receptor (TLR2), and acts on complement component 5 (C5) through P. gingivalis-associated arginine gingipains (HRgpA and RgpB) to produce C5a and C5b. C5a ligand then interacts with its specific complement C5a receptor (C5ar1) that together are co-activated with TLR2 on the surface of phagocytic cells. The cross-reactivity of both receptors could induce myeloid differentiation primary response 88 (MYD88)-induced inflammation or be blocked if MyD88 is inactivated. However, the same cross-reactivity of TLR2-C5aR1 complex could bypass MyD88 and induce the phosphoinositide 3-kinases (PI3K) pathway that may induce inflammation in phagocytic cells. In a similar manner, the activated PI3K could inhibit bacterial phagocytosis/apoptosis and supress phagolysosomal maturation, enhancing bacterial persistence. The latter mechanism is dependent on increased concentration of C5a beyond a threshold level (100 nM). The insurance of bacterial survival while inducing inflammation results in increased inflammophilic pathobionts and enhances dysbiosis.

Figure 8.

Porphyromonas gingivalis-induced chemokine paralysis. The activated Toll-like receptors (TLR), following interaction with oral pathobionts such as Fusobacterium nucleatum, induce proinflammatory signaling mechanisms. The invading keystone pathogen (P. gingivalis) can suppress interleukin (IL)-8 production through dephosphorylation of S536 residue of p65 subunit of nuclear factor kappa B (NF-kB) by the activity of serine phosphatase B (SerB), disrupting neutrophil recruitment. Similarly, the expression of chemokine CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (ITAC) could be inhibited through blocking the signal transducer and activator of transcription 1 (STAT1)-interferon regulatory factor 1 (IRF1) pathway by P. gingivalis, leading to T cell imbalance, including TH17 activation (IL-6, IL-23) and TH1 suppression (IL-12). These immune subversion mechanisms lead to enhanced inflammatory responses and dysbiosis.