Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

Abstract

Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer. Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions. The potential causal link between periodontitis and its comorbidities is further strengthened by recent experimental animal studies establishing biologically plausible and clinically consistent mechanisms whereby periodontitis could initiate or aggravate a comorbid condition. This multi-faceted 'mechanistic causality' aspect of the link between periodontitis and comorbidities is the focus of this Review. Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities.

Fig. 1. Periodontal disease and associated inflammatory comorbidities.

On the basis of epidemiological, clinical intervention and animal model-based studies, periodontitis has been linked with a number of comorbid conditions, such as those indicated. Mechanistically, periodontitis is associated with bacteraemias and systemic inflammation, which can induce acute-phase responses as well as metabolic and inflammatory alterations in the liver and bone marrow, activities that can influence comorbid conditions. Moreover, periodontal bacteria can disseminate by different routes — haematogenous, oro-pharyngeal and oro-digestive — to reach extra-oral sites where they can cause or exacerbate inflammatory pathologies.

Fig. 2. Periodontal bacterial translocation leading to bacteraemia and alterations in the bone marrow that promote osteoclastogenesis in different sites.

Periodontal bacteria may translocate through the ulcerated epithelium of the periodontal pockets into the circulation, causing bacteraemia and systemic inflammation. Blood-borne Porphyromonas gingivalis causes an increase in the serum levels of IL-6, which in turn induces the expansion of an osteoclast precursor population (defined as CD11b⁺CSF1R⁺Ly6C^hi) in the bone marrow. This osteoclast precursor population displays enhanced osteoclastogenic lineage bias and populates various bone resorption sites, where it can differentiate into mature osteoclasts, in response to locally produced receptor activator of NF-κB ligand (RANKL) (for example, produced by osteoblasts stimulated by T helper 17 (T_H17) cell-derived IL-17). This concept may be a mechanism whereby the bone marrow might link periodontitis to other bone loss disorders, such as rheumatoid arthritis.

Fig. 3. Trained myelopoiesis in the bone marrow as a mechanistic basis of inflammatory comorbidities.

Periodontitis-associated bacteraemias and systemic inflammation, for example, inflammatory cytokines, such as IL-1β, can be sensed in the bone marrow, leading to induction of long-term metabolic and epigenetic rewiring in haematopoietic stem cells (HSCs). These inflammation-adapted HSCs proliferate and preferentially undergo myeloid-biased differentiation, leading to expansion of multipotent progenitors (MPPs) with myeloid potential and granulocyte–macrophage progenitors (GMPs) and ultimately production of ‘trained’ myeloid cell populations. These hyper-reactive neutrophils or monocytes/macrophages can be recruited to the periodontium and other sites of infection, inflammation or injury, thereby potentially exacerbating periodontitis and promoting inflammatory pathology of comorbid conditions such as cardiovascular disease.

Fig. 4. Oral–gut axis mechanisms that promote colitis.

Periodontitis-associated pathobionts can reach the gut through the oro-digestive route (owing to constant saliva swallowing) and can promote colitis in susceptible hosts, in part through induction of IL-1β by inflammatory macrophages. Oral pathobiont-reactive T cells (enriched in T helper 17 (T_H17) cells), which expand during periodontitis, migrate through the lymphatics to the gut, where they are activated by the ectopically colonized oral pathobionts upon their processing by antigen-presenting cells (APCs). The oral pathobiont-induced elevation of IL-1β contributes to the activation and proliferation of the transmigrated T_H17 cells, which become colitogenic and exacerbate intestinal inflammation. Thus, ectopically colonized oral pathobionts may exacerbate colitis by activating both innate immunity (local inflammatory macrophages) and adaptive immunity (transmigrated T_H17 cells of oral origin).

Fig. 5. Mechanisms of periodontal bacterial action in extra-oral pathologies.

a | Porphyromonas gingivalis causes vascular endothelial barrier disruption and increased permeability by disrupting intercellular junctions. This action is mediated by its gingipain proteases, which degrade platelet endothelial cell adhesion molecule (PECAM1) and vascular endothelial cadherin (VE-cadherin), which are crucial for junctional integrity. Endothelial damage and elevated permeability may instigate several processes that potentially induce or exacerbate atherogenesis, including induction of pro-inflammatory cytokines, platelet aggregation and increased leukocyte extravasation to subendothelial areas. b | P. gingivalis-induced pathology in Alzheimer disease. P. gingivalis DNA and gingipains have been detected in brain autopsies of patients with Alzheimer disease as well as in the brain of mice orally infected with this pathogen. The presence of P. gingivalis in the mouse brain is associated with increased levels of amyloid-β, complement activation and neuroinflammation. The gingipains of the pathogen cleave the microtubule-associated protein tau, an activity that promotes aberrant phosphorylation of tau and accumulation of misfolded insoluble tau in Alzheimer disease. c | Role of periodontal bacteria in the generation of anti-citrullinated protein antibodies (ACPAs). P. gingivalis expresses a unique (among prokaryotic organisms) peptidyl-arginine deiminase (PPAD), which can citrullinate proteins including host proteins. The PPAD activity is facilitated by the pathogen’s arginine-specific gingipains, which cleave proteins and expose C-terminal arginine residues for citrullination by PPAD. Alternatively, Aggregatibacter actinomycetemcomitans indirectly causes host protein citrullination by secreting leukotoxin A (LtxA), a pore-forming toxin that induces calcium influx and hyperactivation of PAD enzymes in neutrophils, as well as cytolysis (by NETosis, a form of cell death typified by the release of decondensed chromatin and granular contents to the extracellular milieu), thereby releasing the generated citrullinated autoantigens. Thus, through distinct mechanisms, both pathogens can contribute to the generation of the rheumatoid arthritis-specific ACPAs that promote disease in individuals with HLA-DRB1 shared epitope (SE) alleles. APC, antigen-presenting cell.