Periodontitis: from microbial immune subversion to systemic inflammation

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Abstract

Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.

Key Points

  • Periodontitis is a dysbiotic oral disease that increases the patients' risk of developing systemic inflammatory disorders. The dysbiosis of the periodontal microbiota is characterized by an imbalance in the relative abundance or influence of microbial species with distinct roles that converge to shape a pathogenic microbial community.

  • Within the community, periodontal bacteria use sophisticated strategies to evade immune-mediated killing while promoting a nutritionally favourable inflammatory response. The host response is initially subverted by keystone pathogens with the aid of accessory pathogens and is subsequently overactivated by the emerging pathobionts, which leads to destructive inflammation.

  • Periodontal bacteria (including Porphyromonas gingivalis) have been detected in circulating leukocytes and in aortic tissues, where clinical and mechanistic animal-model studies indicate that they act as pro-atherogenic stimuli.

  • P. gingivalis expresses a unique citrullinating enzyme that is involved in the generation of autoantibodies that contribute to the pathogenesis of rheumatoid arthritis.

  • Bacteria that originate from the periodontal tissue (such as Fusobacterium nucleatum) have been detected in the placenta, where they can cause adverse pregnancy outcomes, as suggested by clinical and mechanistic evidence. The periodontal biofilm also acts as a reservoir for respiratory infections and for exacerbations of chronic obstructive pulmonary disease in synergy with local opportunistic pathogens.

  • Understanding how oral pathogens subvert the host response at the molecular level will not only provide insights into the pathogenesis of periodontitis and associated systemic conditions, but could also reveal new therapeutic targets.

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Figure 1: Polymicrobial synergy and dysbiosis in periodontitis.
Figure 2: Porphyromonas gingivalis subversion of neutrophils leads to dysbiotic inflammation.
Figure 3: Biologically plausible mechanisms linking periodontitis to systemic inflammation and disease.
Figure 4: Microbial immune subversion in atherogenesis.
Figure 5: Porphyromonas gingivalis-mediated citrullination and induction of anti-citrullinated protein antibodies in rheumatoid arthritis.

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Acknowledgements

The author's research is supported by grants from the US National Institutes of Health (DE015254, DE017138, DE021685 and AI068730). The author regrets that several studies could only be cited indirectly through comprehensive reviews, owing to space and reference number limitations.

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Correspondence to George Hajishengallis.

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Glossary

Microbiota

A complex and diverse community of microorganisms that live within a given anatomical niche (such as an environmentally exposed surface of a multicellular eukaryotic organism).

Dysbiosis

A condition that is characterized by an imbalance in the relative abundance or influence of species within a microbial community that is associated with a disease; for instance, periodontitis or inflammatory bowel disease.

Homeostasis

A condition of equilibrium or stability in a system that is maintained by adjusting physiological processes to counteract external changes. An example of homeostasis is the balanced relationship between host tissues and the resident microbiota that prevents destructive inflammation or disease.

Subgingival crevice

Narrow space between the tooth surface and the free gingiva.

Gingival crevicular fluid

Serum exudate that originates in the gingival capillaries and flows into the gingival crevice carrying locally produced immune and inflammatory mediators such as complement, cytokines and antimicrobial peptides.

Keystone pathogen

A pathogen with a disproportionately large effect on its environment relative to its abundance; for example, low-abundance P. gingivalis remodels a commensal microbial community into a dysbiotic and disease-provoking microbiota.

Pathobionts

Commensal microorganisms with the potential to induce pathology under conditions of disrupted homeostasis.

Accessory pathogens

Commensal bacteria that are not pathogenic by themselves in a given niche, but that can enhance the virulence of keystone pathogens by, for example, facilitating their colonization or providing metabolic support.

Gingipains

A family of trypsin-like cysteine proteinases that are secreted by P. gingivalis and contribute to its virulence, as well as to the pathogenesis of periodontitis. Members of this family include the high molecular mass arginine-specific gingipain A (HRgpA), the arginine-specific gingipain B (RgpB) and the lysine-specific gingipain (Kgp).

Inflammophilic

This term refers to bacteria that thrive on inflammation as they feed off inflammatory tissue breakdown products. The literal meaning is 'attracted to inflammation', which is derived from the combined meaning of inflammation and the Greek suffix philic denoting fondness.

Periodontal pockets

The pathologically deepened subgingival crevices in periodontitis, which are characteristic of the disease.

Inflammasome

A cytosolic, multiprotein complex that responds to infection or tissue injury by activating pro-inflammatory caspases (mainly caspase 1), leading to the cleavage and release of pro-inflammatory cytokines (such as interleukin-1β (IL-1β) and IL-18) and under certain conditions, such as when myeloid cells are infected with pathogenic bacteria, leads to pyroptosis, a form of necrotic cell death.

Non-canonical inflammasome

A caspase-11-dependent pathway of inflammasome activation that is crucial for the control of infections caused by Gram-negative bacteria and can induce cell death (pyroptosis) independently of caspase 1.

Atheromas

Accumulated fatty deposits in the inner lining (intima) of an artery that lead to the restriction of blood flow and an increased risk of thrombosis.

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Hajishengallis, G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 15, 30–44 (2015) doi:10.1038/nri3785

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