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Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

Nature Reviews Immunology volume 21, pages 426–440 (2021)Cite this article

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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.

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Fig. 1: Periodontal disease and associated inflammatory comorbidities.
Fig. 2: Periodontal bacterial translocation leading to bacteraemia and alterations in the bone marrow that promote osteoclastogenesis in different sites.
Fig. 3: Trained myelopoiesis in the bone marrow as a mechanistic basis of inflammatory comorbidities.
Fig. 4: Oral–gut axis mechanisms that promote colitis.
Fig. 5: Mechanisms of periodontal bacterial action in extra-oral pathologies.

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Acknowledgements

The authors’ research is supported by grants from the US National Institutes of Health (DE024153, DE024716, DE029436 to G.H.; DE026152 and DE028561 to G.H. and T.C.) and the German Research Foundation (CRC-TR127 and CRC1181 to T.C.). The authors regret that several important studies could only be cited indirectly through comprehensive reviews, owing to space and reference number limitations.

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  1. Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    George Hajishengallis

  2. Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

    Triantafyllos Chavakis

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  1. George Hajishengallis
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  2. Triantafyllos Chavakis
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Correspondence to George Hajishengallis.

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Glossary

Inflammatory bowel disease

(IBD). A chronic inflammatory disorder of the gastrointestinal tract with a complex aetiology, including genetic, environmental, microbial and host immune factors. Two major IBD conditions are Crohn’s disease (which may affect anywhere in the digestive tract) and ulcerative colitis (which affects only the colon).

Microbiome/microbiota

Microbiota is a diverse microbial community that exists within a defined anatomical niche (for example, an environmentally exposed surface of a mammalian organism). The term microbiome represents the microbial community, its combined genetic material and its collective functions.

Dysbiosis

An imbalanced interaction, between bacteria in a community and/or between the microbial community and the host immune system, which has detrimental effects on the host (as in periodontitis or inflammatory bowel disease). The microbial imbalance derives from changes in the abundance and/or influence of individual species relative to their abundance or influence in health.

Periodontal treatment

A procedure that involves mechanical debridement (scaling and root planing) to remove the microbial biofilm (dental plaque) and calculus (tartar) from the tooth surfaces and beneath the gingiva to enable inflammation resolution, and to smooth the root surfaces to deter further biofilm/calculus build-up. Advanced periodontitis may additionally require periodontal surgery, such as pocket reduction surgery, to reduce the depth of the pockets between the teeth and the surrounding gingiva.

Inflammophilic

From inflammation and the Greek suffix philic indicating fondness. A property of bacteria that thrive under inflammatory conditions by utilizing products derived from the inflammatory breakdown of tissues as nutritional substrates.

Periodontal pockets

The physiological narrow space between the tooth root and the free gingiva is known as subgingival crevice; during periodontitis progression, however, this crevice deepens into a periodontal pocket, which is a pathognomonic feature of the disease.

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

(NAFLD/NASH). NAFLD is a condition associated with obesity and metabolic syndrome and involves excessive fat accumulation (steatosis) in the liver in the absence of significant alcohol consumption. NAFLD may progress to NASH, where fat accumulation in the liver is accompanied by inflammation, leading to fibrosis and ultimately cirrhosis (advanced scarring/fibrosis) and end-stage liver failure.

HbA1c

HbA1c, or glycated haemoglobin, represents a form of haemoglobin that has glucose attached to it via a non-enzymatic reaction called glycation. The concentration of HbA1c in blood reflects the average levels of blood glucose of the previous 3–4 months. Therefore, HbA1c is used not only in the diagnosis of diabetes but, importantly, as a measure for monitoring glycaemic control in patients with diabetes.

Atheromatous plaque

Fat accumulation in the intima (inner lining) of arteries that results in fibrous thickening or calcification of the arteries, restriction of blood flow and an enhanced risk of thrombotic occlusion.

Emergency myelopoiesis

A tightly regulated process initiated in response to systemic infection for de novo generation of mature myeloid cells, resulting from accelerated proliferation and enhanced myeloid differentiation of progenitors in the bone marrow. The goal is to meet the increased demand for neutrophils and other phagocytes that are consumed in large quantities during systemic infections.

Rheumatoid arthritis

A chronic inflammatory autoimmune disease typified by production of autoantibodies to various targets (for example, citrullinated matrix proteins) and induction of inflammation that causes progressive erosion of cartilage and bone in the joints. Its aetiology is complex and includes both genetic and environmental factors.

Keystone pathogen

A pathogen that exerts a disproportionately large effect on its community relative to its abundance, forming the ‘keystone’ of the community’s structure; for instance, in experimental periodontitis, low-abundance Porphyromonas gingivalis modulates the size and composition of the local microbial community in a manner that promotes dysbiosis.

Gingipains

A family of Porphyromonas gingivalis-derived trypsin-like cysteine proteases that make a major contribution to its virulence. High-molecular mass arginine-specific gingipain A (HRgpA), arginine-specific gingipain B (RgpB) and lysine-specific gingipain (Kgp) are the members of the gingipain family.

Alzheimer disease

Progressive neuroinflammatory and neurodegenerative brain disease, characterized by extraneuronal deposition of amyloid-β peptides (neuritic plaques) and intraneuronal accumulation of hyperphosphorylated and fragmented tau, a microtubule-associated protein (neurofibrillary tangles).

Pathobionts

Organisms that are generally benign or commensal but that have the capacity to promote pathology under specific conditions of disrupted host–microbiota homeostasis (for example, resulting from immune deficiencies, antibiotic treatment, tissue damage or dietary shifts).

Non-canonical inflammasome

Inflammasome is a cytosolic, multiprotein complex that activates caspases (predominantly caspase 1) in response to infection or injury. This in turn results in cleavage and secretion of inflammatory cytokines, such as IL-1β and IL-18. Non-canonical is a caspase 1-independent but caspase 11-mediated pathway of inflammasome activation, which is crucial for controlling Gram-negative bacterial infections and can also trigger caspase 1 activation and subsequent maturation and secretion of IL-1β and IL-18. Both pathways may induce a specific form of cell death, called pyroptosis.

Citrullination

Post-translational modification of a protein involving deimination of arginine by peptidylarginine deiminase to generate citrulline. Uncontrolled citrullination may result in neoepitopes that induce autoantibody generation.

Clonal haematopoiesis of indeterminate potential

(CHIP). Age-related acquisition of somatic mutations, which confer haematopoietic stem cell clonal expansion advantage and are associated with increased risk of myeloid malignancies, cardiovascular disease and all-cause mortality. The generated mutant myeloid cells comprise a disproportionately large fraction of leukocytes (in peripheral blood and tissues) and display a hyper-inflammatory phenotype, suggesting that CHIP may also be related to chronic inflammatory diseases in general.

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Hajishengallis, G., Chavakis, T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 21, 426–440 (2021). https://doi.org/10.1038/s41577-020-00488-6

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