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Molecular Links between Periodontitis and Systemic Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 42776

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Prof. Dr. Kenichi Imai

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Department of Microbiology, Nihon University School of Dentistry, 1-8-13 kanda, Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
Interests: periodontology; molecular biology; microbiology; periodontal medicine
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Dear Colleagues,

Periodontitis is one of the most prevalent diseases globally. It is a polymicrobial infection and multifactorial disease characterized by chronic inflammation in the periodontium. If left untreated, this condition leads to alveolar bone destruction and subsequently induces tooth loss, during which major periodontopathic bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, are known to be involved in the induction of proinflammatory cytokine production. Recently, periodontopathic bacteria have been involved in respiratory diseases, including aspiration pneumonia and chronic obstructive pulmonary disease (COPD), and other systemic diseases, such as diabetes and cardiovascular disease. Patients with these diseases have an increased coronavirus infectious disease 2019 (COVID-19) aggravation rate and mortality. Therefore, periodontopathic bacteria can significantly influence COVID-19 aggravation. Conversely, oral care, including periodontal treatment, prevents the onset of pneumonia and the exacerbation of COPD and diabetes. However, how periodontopathic bacteria contribute to those systemic diseases remains unclear. In an increasingly aging society, measures against systemic diseases related to periodontitis will become critical. To that end, it is crucial to explain how periodontopathic bacteria adversely affect systemic diseases at the molecular level.

In this Special Issue, we would like to provide important aspects of the molecular events by periodontopathic bacteria, focusing on periodontitis and related systemic diseases.

Prof. Dr. Kenichi Imai
Guest Editor

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Keywords

periodontitis
systemic diseases
periodontopathic bacteria
periodontal medicine

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Published Papers (11 papers)

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12 pages, 6223 KiB

Open AccessArticle

Epstein-Barr Virus Promotes the Production of Inflammatory Cytokines in Gingival Fibroblasts and RANKL-Induced Osteoclast Differentiation in RAW264.7 Cells

by Sho Yokoe, Akira Hasuike, Norihisa Watanabe, Hideki Tanaka, Hiroyuki Karahashi, Shin Wakuda, Osamu Takeichi, Takayuki Kawato, Hideki Takai, Yorimasa Ogata, Shuichi Sato and Kenichi Imai

Int. J. Mol. Sci. 2022, 23(2), 809; https://doi.org/10.3390/ijms23020809 - 12 Jan 2022

Cited by 11 | Viewed by 2388

Abstract

Periodontitis is an inflammatory condition that causes the destruction of the supporting tissues of teeth and is a major public health problem affecting more than half of the adult population worldwide. Recently, members of the herpes virus family, such as the Epstein–Barr virus (EBV), have been suggested to be involved in the etiology of periodontitis because bacterial activity alone does not adequately explain the clinical characteristics of periodontitis. However, the role of EBV in the etiology of periodontitis is unknown. This study aimed to examine the effect of inactivated EBV on the expression of inflammatory cytokines in human gingival fibroblasts (HGFs) and the induction of osteoclast differentiation. We found that extremely high levels of interleukin (IL)-6 and IL-8 were induced by inactivated EBV in a copy-dependent manner in HGFs. The levels of IL-6 and IL-8 in HGFs were higher when the cells were treated with EBV than when treated with lipopolysaccharide and lipoteichoic acid. EBV induced IκBα degradation, NF-κB transcription, and RAW264.7 cell differentiation into osteoclast-like cells. These findings suggest that even without infecting the cells, EBV contributes to inflammatory cytokine production and osteoclast differentiation by contact with oral cells or macrophage lineage, resulting in periodontitis onset and progression. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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19 pages, 3598 KiB

Open AccessArticle

Glycation of Host Proteins Increases Pathogenic Potential of Porphyromonas gingivalis

by Michał Śmiga, John W. Smalley, Paulina Ślęzak, Jason L. Brown, Klaudia Siemińska, Rosalind E. Jenkins, Edwin A. Yates and Teresa Olczak

Int. J. Mol. Sci. 2021, 22(21), 12084; https://doi.org/10.3390/ijms222112084 - 8 Nov 2021

Cited by 16 | Viewed by 3682

Abstract

The non-enzymatic addition of glucose (glycation) to circulatory and tissue proteins is a ubiquitous pathophysiological consequence of hyperglycemia in diabetes. Given the high incidence of periodontitis and diabetes and the emerging link between these conditions, it is of crucial importance to define the basic virulence mechanisms employed by periodontopathogens such as Porphyromonas gingivalis in mediating the disease process. The aim of this study was to determine whether glycated proteins are more easily utilized by P. gingivalis to stimulate growth and promote the pathogenic potential of this bacterium. We analyzed the properties of three commonly encountered proteins in the periodontal environment that are known to become glycated and that may serve as either protein substrates or easily accessible heme sources. In vitro glycated proteins were characterized using colorimetric assays, mass spectrometry, far- and near-UV circular dichroism and UV–visible spectroscopic analyses and SDS-PAGE. The interaction of glycated hemoglobin, serum albumin and type one collagen with P. gingivalis cells or HmuY protein was examined using spectroscopic methods, SDS-PAGE and co-culturing P. gingivalis with human keratinocytes. We found that glycation increases the ability of P. gingivalis to acquire heme from hemoglobin, mostly due to heme sequestration by the HmuY hemophore-like protein. We also found an increase in biofilm formation on glycated collagen-coated abiotic surfaces. We conclude that glycation might promote the virulence of P. gingivalis by making heme more available from hemoglobin and facilitating bacterial biofilm formation, thus increasing P. gingivalis pathogenic potential in vivo. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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23 pages, 5149 KiB

Open AccessArticle

PPARγ-Induced Global H3K27 Acetylation Maintains Osteo/Cementogenic Abilities of Periodontal Ligament Fibroblasts

by Hang Yuan, Shigeki Suzuki, Shizu Hirata-Tsuchiya, Akiko Sato, Eiji Nemoto, Masahiro Saito, Hideki Shiba and Satoru Yamada

Int. J. Mol. Sci. 2021, 22(16), 8646; https://doi.org/10.3390/ijms22168646 - 11 Aug 2021

Cited by 14 | Viewed by 3172

Abstract

The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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11 pages, 3062 KiB

Open AccessArticle

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

by María Fernández, Alicia de Coo, Inés Quintela, Eliane García, Márcio Diniz-Freitas, Jacobo Limeres, Pedro Diz, Juan Blanco, Ángel Carracedo and Raquel Cruz

Int. J. Mol. Sci. 2021, 22(12), 6274; https://doi.org/10.3390/ijms22126274 - 10 Jun 2021

Cited by 9 | Viewed by 3712

Abstract

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10⁻⁵, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10⁻⁵, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10⁻⁵, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10⁻⁵, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10⁻⁵, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10⁻², p = 5.1 × 10⁻³, p = 1.2 × 10⁻², respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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15 pages, 1800 KiB

Open AccessArticle

Hyperlipidemic Conditions Impact Force-Induced Inflammatory Response of Human Periodontal Ligament Fibroblasts Concomitantly Challenged with P. gingivalis-LPS

by Judit Symmank, Sophie Appel, Jana Asisa Bastian, Isabel Knaup, Jana Marciniak, Christoph-Ludwig Hennig, Annika Döding, Ulrike Schulze-Späte, Collin Jacobs and Michael Wolf

Int. J. Mol. Sci. 2021, 22(11), 6069; https://doi.org/10.3390/ijms22116069 - 4 Jun 2021

Cited by 13 | Viewed by 3031

Abstract

In obese patients, enhanced serum levels of free fatty acids (FFA), such as palmitate (PA) or oleate (OA), are associated with an increase in systemic inflammatory markers. Bacterial infection during periodontal disease also promotes local and systemic low-grade inflammation. How both conditions concomitantly impact tooth movement is largely unknown. Thus, the aim of this study was to address the changes in cytokine expression and the secretion of human periodontal ligament fibroblasts (HPdLF) due to hyperlipidemic conditions, when additionally stressed by bacterial and mechanical stimuli. To investigate the impact of obesity-related hyperlipidemic FFA levels on HPdLF, cells were treated with 200 µM PA or OA prior to the application of 2 g/cm² compressive force. To further determine the additive impact of bacterial infection, HPdLF were stimulated with lipopolysaccharides (LPS) obtained from Porphyromonas gingivalis. In mechanically compressed HPdLF, PA enhanced COX2 expression and PGE2 secretion. When mechanically stressed HPdLF were additionally stimulated with LPS, the PGE2 and IL6 secretion, as well as monocyte adhesion, were further increased in PA-treated cultures. Our data emphasize that a hyperlipidemic condition enhances the susceptibility of HPdLF to an excessive inflammatory response to compressive forces, when cells are concomitantly exposed to bacterial components. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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17 pages, 1900 KiB

Open AccessArticle

Oral Microbiome in Relation to Periodontitis Severity and Systemic Inflammation

by Adelina S. Plachokova, Sergio Andreu-Sánchez, Marlies P. Noz, Jingyuan Fu and Niels P. Riksen

Int. J. Mol. Sci. 2021, 22(11), 5876; https://doi.org/10.3390/ijms22115876 - 30 May 2021

Cited by 47 | Viewed by 4906

Abstract

Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The “red complex” and “cluster B” abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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15 pages, 1948 KiB

Open AccessArticle

Lantibiotics Produced by Oral Inhabitants as a Trigger for Dysbiosis of Human Intestinal Microbiota

by Hideo Yonezawa, Mizuho Motegi, Atsushi Oishi, Fuhito Hojo, Seiya Higashi, Eriko Nozaki, Kentaro Oka, Motomichi Takahashi, Takako Osaki and Shigeru Kamiya

Int. J. Mol. Sci. 2021, 22(7), 3343; https://doi.org/10.3390/ijms22073343 - 25 Mar 2021

Cited by 5 | Viewed by 2791

Abstract

Lantibiotics are a type of bacteriocin produced by Gram-positive bacteria and have a wide spectrum of Gram-positive antimicrobial activity. In this study, we determined that Mutacin I/III and Smb (a dipeptide lantibiotic), which are mainly produced by the widespread cariogenic bacterium Streptococcus mutans, have strong antimicrobial activities against many of the Gram-positive bacteria which constitute the intestinal microbiota. These lantibiotics also demonstrate resistance to acid and temperature. Based on these features, we predicted that lantibiotics may be able to persist into the intestinal tract maintaining a strong antimicrobial activity, affecting the intestinal microbiota. Saliva and fecal samples from 69 subjects were collected to test this hypothesis and the presence of lantibiotics and the composition of the intestinal microbiota were examined. We demonstrate that subjects possessing lantibiotic-producing bacteria in their oral cavity exhibited a tendency of decreased species richness and have significantly reduced abundance of the phylum Firmicutes in their intestinal microbiota. Similar results were obtained in the fecal microbiota of mice fed with S. mutans culture supernatant containing the lantibiotic bacteriocin Mutacin I. These results showed that lantibiotic bacteriocins produced in the oral cavity perturb the intestinal microbiota and suggest that oral bacteria may be one of the causative factors of intestinal microbiota dysbiosis. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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13 pages, 3243 KiB

Open AccessArticle

Expression of the SARS-CoV-2 Receptor ACE2 and Proinflammatory Cytokines Induced by the Periodontopathic Bacterium Fusobacterium nucleatum in Human Respiratory Epithelial Cells

by Yuwa Takahashi, Norihisa Watanabe, Noriaki Kamio, Sho Yokoe, Ryuta Suzuki, Shuichi Sato, Toshimitsu Iinuma and Kenichi Imai

Int. J. Mol. Sci. 2021, 22(3), 1352; https://doi.org/10.3390/ijms22031352 - 29 Jan 2021

Cited by 42 | Viewed by 4167

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global public health emergency. Periodontitis, the most prevalent disease that leads to tooth loss, is caused by infection by periodontopathic bacteria. Periodontitis is also a risk factor for pneumonia and the exacerbation of chronic obstructive pulmonary disease, presumably because of the aspiration of saliva contaminated with periodontopathic bacteria into the lower respiratory tract. Patients with these diseases have increased rates of COVID-19 aggravation and mortality. Because periodontopathic bacteria have been isolated from the bronchoalveolar lavage fluid of patients with COVID-19, periodontitis may be a risk factor for COVID-19 aggravation. However, the molecular links between periodontitis and COVID-19 have not been clarified. In this study, we found that the culture supernatant of the periodontopathic bacterium Fusobacterium nucleatum (CSF) upregulated the SARS-CoV-2 receptor angiotensin-converting enzyme 2 in A549 alveolar epithelial cells. In addition, CSF induced interleukin (IL)-6 and IL-8 production by both A549 and primary alveolar epithelial cells. CSF also strongly induced IL-6 and IL-8 expression by BEAS-2B bronchial epithelial cells and Detroit 562 pharyngeal epithelial cells. These results suggest that when patients with mild COVID-19 frequently aspirate periodontopathic bacteria, SARS-CoV-2 infection is promoted, and inflammation in the lower respiratory tract may become severe in the presence of viral pneumonia. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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Review

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34 pages, 2037 KiB

Open AccessReview

Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies

by Arkadiusz Dziedzic

Int. J. Mol. Sci. 2022, 23(23), 15320; https://doi.org/10.3390/ijms232315320 - 5 Dec 2022

Cited by 12 | Viewed by 3255

Abstract

It has been suggested that molecular pathological mechanisms responsible for periodontitis can be linked with biochemical alterations in neurodegenerative disorders. Hypothetically, chronic systemic inflammation as a response to periodontitis plays a role in the etiology of cognitive impairment. This study aimed to determine whether periodontitis (PDS) is a risk factor for age-related cognitive impairment (ACI) based on evidence of clinical studies. A comprehensive, structured systematic review of existing data adhering to the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) guidelines was carried out. Five electronic databases, PubMed, Embase, Scopus, Web of Science, and Cochrane, were searched for key terms published in peer-reviewed journals until January 2021. The Newcastle–Ottawa scale was used to assess the quality of studies and risk of bias. The primary and residual confounders were explored and evaluated. A meta-analysis synthesizing quantitative data was carried out using a random-effects model. Seventeen clinical studies were identified, including 14 cohort, one cross-sectional, and two case-control studies. Study samples ranged from 85 to 262,349 subjects, with follow-up between 2 and 32 years, and age above 45 years, except for two studies. The findings of studies suggesting the PDS-ACI relationship revealed substantial differences in design and methods. A noticeable variation related to the treatment of confounders was observed. Quality assessment unveiled a moderate quality of evidence and risk of bias. The subgroups meta-analysis and pooled sensitivity analysis of results from seven eligible studies demonstrated overall that the presence of PDS is associated with an increased risk of incidence of cognitive impairment (OR = 1.36, 95% CI 1.03–1.79), particularly dementia (OR = 1.39, 95% CI 1.02–1.88) and Alzheimer’s disease (OR = 1.03 95% CI 0.98–1.07)). However, a considerable heterogeneity of synthesized data (I² = 96%) and potential publication bias might affect obtained results. While there is a moderate statistical association between periodontitis and dementia, as well as Alzheimer’s disease, the risk of bias in the evidence prevents conclusions being drawn about the role of periodontitis as a risk factor for age-related cognitive impairment. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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17 pages, 2505 KiB

Open AccessReview

SARS-CoV-2 Infection and Significance of Oral Health Management in the Era of “the New Normal with COVID-19”

by Kenichi Imai and Hajime Tanaka

Int. J. Mol. Sci. 2021, 22(12), 6527; https://doi.org/10.3390/ijms22126527 - 18 Jun 2021

Cited by 17 | Viewed by 5485

Abstract

More than a year ago, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization, with the world approaching its fourth wave. During this period, vaccines were developed in a much shorter period than thought possible, with the initiation of the pertinent vaccination. However, oral cavities have come under renewed scrutiny worldwide because saliva, a mixture of salivary secretions, pharyngeal secretions, and gingival crevicular fluid, have not only been shown to contain infective viral loads, mediating the route of SARS-CoV-2 transmission via droplet, aerosol, or contagion, but also used as a sample for viral RNA testing with a usefulness comparable to the nasopharyngeal swab. The oral cavity is an important portal for ingress of SARS-CoV-2, being an entryway to the bronchi, alveoli, and rest of the lower respiratory tract, causing inflammation by viral infection. Moreover, angiotensin-converting enzyme 2, a host receptor for SARS-CoV-2, coupled with proteases responsible for viral entry have been found to be expressed on the tongue and other oral mucosae, suggesting that the oral cavity is the site of virus replication and propagation. Furthermore, there is a possibility that the aspiration of oral bacteria (such as periodontal pathogens) along with saliva into the lower respiratory tract may be a complicating factor for COVID-19 because chronic obstructive pulmonary disease and diabetes are known COVID-19 comorbidities with a greater risk of disease aggravation and higher death rate. These comorbidities have a strong connection to chronic periodontitis and periodontal pathogens, and an oral health management is an effective measure to prevent these comorbidities. In addition, oral bacteria, particularly periodontal pathogens, could be proinflammatory stimulants to respiratory epithelia upon its exposure to aspirated bacteria. Therefore, it may be expected that oral health management not only prevents comorbidities involved in aggravating COVID-19 but also has an effect against COVID-19 progression. This review discusses the significance of oral health management in SARS-CoV-2 infection in the era of “the new normal with COVID-19” and COVID-19 prevention with reference to the hypothetical mechanisms that the authors and the other researchers have proposed. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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17 pages, 801 KiB

Open AccessReview

Connection between Periodontitis-Induced Low-Grade Endotoxemia and Systemic Diseases: Neutrophils as Protagonists and Targets

by Ljubomir Vitkov, Luis E. Muñoz, Jasmin Knopf, Christine Schauer, Hannah Oberthaler, Bernd Minnich, Matthias Hannig and Martin Herrmann

Int. J. Mol. Sci. 2021, 22(9), 4647; https://doi.org/10.3390/ijms22094647 - 28 Apr 2021

Cited by 35 | Viewed by 4593

Abstract

Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways of this interconnection remain elusive. Recently, it became evident that certain microbial challenges promote a heightened response of myeloid cell populations to subsequent infections either with the same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription, and is referred to as ‘‘trained immunity’’. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness in periodontitis might be an approach to diminish or even to prevent systemic diseases. Full article

(This article belongs to the Special Issue Molecular Links between Periodontitis and Systemic Diseases)

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