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Periodontal Disease, Association with Systemic Conditions and Periodontal Pathogens

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (29 November 2023) | Viewed by 24297

Special Issue Editors


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Guest Editor
Faculty of Dental Medicine, Hebrew University of Jerusalem, Big Biomedical Data Research Laboratory, Dean’s Office, Hadassah Medical Center, Jerusalem, 91120, Israel; Faculty of Dental Medicine, Hebrew University of Jerusalem, Department of Endodontics, Hadassah Medical Center, Jerusalem, 91120, Israel; Faculty of Dental Medicine, Hebrew University of Jerusalem, Department of Oral Medicine, Sedation & Maxillofacial Imaging, Hadassah Medical Center, Jerusalem, 91120, Israel.
Interests: big data analysis; associations between systemic and oral conditions
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
1. Periodontal Research Laboratory, Faculty of Dental Medicine, Hebrew University of Jerusalem 91120, Israel
2. Department of Periodontology, Hadassah Medical Center, Jerusalem 91120, Israel
Interests: periodontal disease; peri-implantitis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Periodontitis is a chronic prevalent non-communicable disease (NCDs) characterized by complex dynamic interactions among specific bacterial pathogens and inflammatory destruction of the tooth-supporting tissues. Over the last decades, a significant body of evidence supports independent associations between severe periodontitis and various systemic conditions, such as diabetes mellitus, cardiovascular disease, obesity, chronic obstructive pulmonary disease (COPD), Rheumatoid arthritis and adverse pregnancy outcomes. Consequently, the field of “Periodontal medicine” hasve evolved, to study how periodontal infection/inflammation may impact extraoral health. While the field significantly progressed, there is a need for continued extensive research on the associations between systemic conditions and the infectious, immune, inflammatory, and systemic characteristics of periodontitis. Therefore, the aim of the current Special Issue of the International Journal of Molecular Sciences is to update on the current knowledge on in the research field of “Periodontal Disease, Association with Systemic Conditions and Periodontal Pathogens” and welcomes both original research articles and review papers that encompasses molecular biology studies on the etiology, diagnosis, prognosis, treatment of periodontitis and periodontal-systemic interactions.

Prof. Dr. Galit Almoznino
Prof. Dr. Asaf Wilensky
Guest Editors

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Keywords

  • periodontal disease
  • periodontitis
  • periodontal medicine
  • periodontal–systemic interactions
  • immune response
  • periodontal pathogens

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Published Papers (10 papers)

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Research

Jump to: Review

13 pages, 3070 KiB  
Article
The Collaborative Cross-Mouse Population for Studying Genetic Determinants Underlying Alveolar Bone Loss Due to Polymicrobial Synergy and Dysbiosis
by Aysar Nashef, Rawan Qabaja, Ronen Hazan, Arne Schafer, Hatice Hasturk, Alpdogan Kantarci, Yael Houri-Haddad and Fuad A. Iraqi
Int. J. Mol. Sci. 2024, 25(1), 473; https://doi.org/10.3390/ijms25010473 - 29 Dec 2023
Cited by 1 | Viewed by 1133
Abstract
Dysbiosis of oral microbiota is associated with the initiation and progression of periodontitis. The cause-and-effect relationship between genetics, periodontitis, and oral microbiome dysbiosis is poorly understood. Here, we demonstrate the power of the collaborative cross (CC) mice model to assess the effect of [...] Read more.
Dysbiosis of oral microbiota is associated with the initiation and progression of periodontitis. The cause-and-effect relationship between genetics, periodontitis, and oral microbiome dysbiosis is poorly understood. Here, we demonstrate the power of the collaborative cross (CC) mice model to assess the effect of the genetic background on microbiome diversity shifts during periodontal infection and host suitability status. We examined the bacterial composition in plaque samples from seven different CC lines using 16s rRNA sequencing before and during periodontal infection. The susceptibility/resistance of the CC lines to alveolar bone loss was determined using the micro-CT technique. A total of 53 samples (7 lines) were collected before and after oral infection using oral swaps followed by DNA extraction and 16 s rRNA sequencing analysis. CC lines showed a significant variation in response to the co-infection (p < 0.05). Microbiome compositions were significantly different before and after infection and between resistant and susceptible lines to periodontitis (p < 0.05). Gram-positive taxa were significantly higher at the resistant lines compared to susceptible lines (p < 0.05). Gram-positive bacteria were reduced after infection, and gram-negative bacteria, specifically anaerobic groups, increased after infection. Our results demonstrate the utility of the CC mice in exploring the interrelationship between genetic background, microbiome composition, and periodontitis. Full article
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14 pages, 2648 KiB  
Article
Mutanolysin-Digested Peptidoglycan of Lactobacillus reuteri Promotes the Inhibition of Porphyromonas gingivalis Lipopolysaccharide-Induced Inflammatory Responses through the Regulation of Signaling Cascades via TLR4 Suppression
by Donghan Kim, Hanhee Choi, Hyeonjun Oh, Jiyeon Lee, Yongjin Hwang and Seok-Seong Kang
Int. J. Mol. Sci. 2024, 25(1), 42; https://doi.org/10.3390/ijms25010042 - 19 Dec 2023
Viewed by 1434
Abstract
Periodontitis is an oral infectious disease caused by various pathogenic bacteria, such as Porphyromonas gingivalis. Although probiotics and their cellular components have demonstrated positive effects on periodontitis, the beneficial impact of peptidoglycan (PGN) from probiotic Lactobacillus remains unclear. Therefore, our study sought [...] Read more.
Periodontitis is an oral infectious disease caused by various pathogenic bacteria, such as Porphyromonas gingivalis. Although probiotics and their cellular components have demonstrated positive effects on periodontitis, the beneficial impact of peptidoglycan (PGN) from probiotic Lactobacillus remains unclear. Therefore, our study sought to investigate the inhibitory effect of PGN isolated from L. reuteri (LrPGN) on P. gingivalis-induced inflammatory responses. Pretreatment with LrPGN significantly inhibited the production of interleukin (IL)-1β, IL-6, and CCL20 in RAW 264.7 cells induced by P. gingivalis lipopolysaccharide (LPS). LrPGN reduced the phosphorylation of PI3K/Akt and MAPKs, as well as NF-κB activation, which were induced by P. gingivalis LPS. Furthermore, LrPGN dose-dependently reduced the expression of Toll-like receptor 4 (TLR4), indicating that LrPGN inhibits periodontal inflammation by regulating cellular signaling cascades through TLR4 suppression. Notably, LrPGN exhibited stronger inhibition of P. gingivalis LPS-induced production of inflammatory mediators compared to insoluble LrPGN and proteinase K-treated LrPGN. Moreover, MDP, a minimal bioactive PGN motif, also dose-dependently inhibited P. gingivalis LPS-induced inflammatory mediators, suggesting that MDP-like molecules present in the LrPGN structure may play a crucial role in the inhibition of inflammatory responses. Collectively, these findings suggest that LrPGN can mitigate periodontal inflammation and could be a useful agent for the prevention and treatment of periodontitis. Full article
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17 pages, 3057 KiB  
Article
Genetic Control of GCF Exudation: Innate Immunity Genes and Periodontitis Susceptibility
by Zsolt M. Lohinai, Kasidid Ruksakiet, Anna Földes, Elek Dinya and Martin Levine
Int. J. Mol. Sci. 2023, 24(18), 14249; https://doi.org/10.3390/ijms241814249 - 18 Sep 2023
Cited by 1 | Viewed by 1426
Abstract
Chronic periodontitis is a bacterial infection associated with dentally adherent biofilm (plaque) accumulation and age-related comorbidities. The disease begins as an inflammatory exudate from gingival margins, gingival crevicular fluid (GCF) in response to biofilm lysine. After a week of experimental gingivitis (no oral [...] Read more.
Chronic periodontitis is a bacterial infection associated with dentally adherent biofilm (plaque) accumulation and age-related comorbidities. The disease begins as an inflammatory exudate from gingival margins, gingival crevicular fluid (GCF) in response to biofilm lysine. After a week of experimental gingivitis (no oral hygiene), biofilm lysine concentration was linearly related to biofilm accumulation (plaque index) but to GCF as an arch-shaped double curve which separated 9 strong from 6 weak GCF responders (hosts). Host DNA was examined for single nucleotide polymorphisms (SNPs) of alleles reported in 7 periodontitis-associated genes. Across all 15 hosts, an adenine SNP (A) at IL1B-511 (rs16944), was significant for strong GCF (Fisher’s exact test, p < 0.05), and a thymidine SNP (T) at IL1B+3954 (rs1143634) for weak GCF provided 2 hosts possessing IL6-1363(T), rs2069827, were included. The phenotype of IL1B+3954(T) was converted from weak to strong in one host, and of the non-T allele from strong to weak in the other (specific epistasis, Fisher’s exact test, p < 0.01). Together with homozygous alternate or reference SNPs at IL10-1082 or CD14-260 in 4 hosts, all hosts were identified as strong or weak GCF responders. The GCF response is therefore a strong or weak genetic trait that indicates strong or weak innate immunity in EG and controllable or uncontrollable periodontal disease, dental implant survival and late-life comorbidities. Full article
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17 pages, 7442 KiB  
Article
GV1001 Inhibits the Severity of the Ligature-Induced Periodontitis and the Vascular Lipid Deposition Associated with the Periodontitis in Mice
by Sharon Y. Kim, Yun-Jeong Kim, Suyang Kim, Mersedeh Momeni, Alicia Lee, Alexandra Treanor, Sangjae Kim, Reuben H. Kim and No-Hee Park
Int. J. Mol. Sci. 2023, 24(16), 12566; https://doi.org/10.3390/ijms241612566 - 8 Aug 2023
Cited by 3 | Viewed by 2323
Abstract
GV1001, a 16 amino acid peptide derived from the catalytic segment of human telomerase reverse transcriptase, was developed as an anti-cancer vaccine. Subsequently, it was found to exhibit anti-inflammatory and anti-Alzheimer’s disease properties. Periodontitis is a risk factor for a variety of systemic [...] Read more.
GV1001, a 16 amino acid peptide derived from the catalytic segment of human telomerase reverse transcriptase, was developed as an anti-cancer vaccine. Subsequently, it was found to exhibit anti-inflammatory and anti-Alzheimer’s disease properties. Periodontitis is a risk factor for a variety of systemic diseases, including atherosclerosis, a process in which chronic systemic and vascular inflammation results in the formation of plaques containing lipids, macrophages, foam cells, and tissue debris on the vascular intima. Thus, we investigated the effect of GV1001 on the severity of ligature-induced periodontitis, vascular inflammation, and arterial lipid deposition in mice. GV1001 notably reduced the severity of ligature-induced periodontitis by inhibiting gingival and systemic inflammation, alveolar bone loss, and vascular inflammation in wild-type mice. It also significantly lowered the amount of lipid deposition in the arterial wall in ApoE-deficient mice receiving ligature placement without changing the serum lipid profile. In vitro, we found that GV1001 inhibited the Receptor Activator of NF-κB ligand (RANKL)-induced osteoclast formation and tumor necrosis factor-α (TNF-α)-induced phenotypic changes in endothelial cells. In conclusion, our study suggests that GV1001 prevents the exacerbation of periodontitis and atherosclerosis associated with periodontitis partly by inhibiting local, systemic, and vascular inflammation and phenotypic changes of vascular endothelial cells. Full article
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16 pages, 3994 KiB  
Article
A Sequential Micro-Immunotherapy Medicine Increases Collagen Deposition in Human Gingival Fibroblasts and in an Engineered 3D Gingival Model under Inflammatory Conditions
by Maria del Mar Ferrà-Cañellas, Marta Munar-Bestard, Ilaria Floris, Joana Maria Ramis, Marta Monjo and Laura Garcia-Sureda
Int. J. Mol. Sci. 2023, 24(13), 10484; https://doi.org/10.3390/ijms241310484 - 22 Jun 2023
Cited by 5 | Viewed by 1689
Abstract
Periodontal therapies use immune mediators, but their side effects can increase with dosage. Micro-immunotherapy (MI) is a promising alternative that employs immune regulators at low and ultralow doses to minimize adverse effects. In this study, the effects of 5 capsules and the entire [...] Read more.
Periodontal therapies use immune mediators, but their side effects can increase with dosage. Micro-immunotherapy (MI) is a promising alternative that employs immune regulators at low and ultralow doses to minimize adverse effects. In this study, the effects of 5 capsules and the entire 10-capsule sequence of the sequential MI medicine (MIM-seq) were tested in two in vitro models of periodontitis. Firstly, human gingival fibroblasts (hGFs) exposed to interleukin (IL)-1β to induce inflammation were treated with five different capsules of MIM-seq for 3 days or with MIM-seq for 24 days. Subsequently, MIM-seq was analyzed in a 3D model of human tissue equivalent of gingiva (GTE) under the same inflammatory stimulus. Simultaneously, a non-IL-1β-treated control and a vehicle were included. The effects of the treatments on cytotoxicity, collagen deposition, and the secreted levels of IL-1α, IL-6, prostaglandin E2 (PGE2), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were evaluated. None of the tested items were cytotoxic. The complete sequence of MIM-seq decreased PGE2 release and restored collagen deposition levels induced by IL-1β treatment in hGFs exposed to IL-1β. MIM-seq treatment restored collagen production levels in both models. These promising preclinical findings suggest that MIM-seq should be further investigated for periodontitis treatment. Full article
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11 pages, 299 KiB  
Communication
Retrospective Case-Control Study Genes Related to Bone Metabolism That Justify the Condition of Periodontal Disease and Failure of Dental Implants in Patients with down Syndrome
by María Baus-Domínguez, Raquel Gómez-Díaz, Daniel Torres-Lagares, Jose-Luis Gutiérrez-Pérez, Guillermo Machuca-Portillo and María-Ángeles Serrera-Figallo
Int. J. Mol. Sci. 2023, 24(9), 7723; https://doi.org/10.3390/ijms24097723 - 23 Apr 2023
Cited by 2 | Viewed by 1713
Abstract
Down syndrome patients show success rates in dental implants much lower than those observed in the general population. This retrospective case-control study aimed to identify possible genes that are related to the regulation of inflammatory responses and bone metabolism related to periimplantitis and [...] Read more.
Down syndrome patients show success rates in dental implants much lower than those observed in the general population. This retrospective case-control study aimed to identify possible genes that are related to the regulation of inflammatory responses and bone metabolism related to periimplantitis and implant loss, as well as genes related to bone quality. This process involved using the functional analysis of the gene expression software Transcriptome Analysis Console (TAC version 4.0 Applied BiosystemsTM, Thermo Fisher Scientific, Waltham, MA, USA) and a search for possible candidate genes involved. The focus was placed on the 93 genes related to periodontitis, periimplantitis, bone loss, implant loss, and genes related to bone quality and regulators underlying the establishment and maintenance of osseointegration. Five genes showed statistically significant results (p < 0.05) in our comparison. Four of them, IL1B (p = 0.023), IL1RN (p = 0.048), BGLAP (p = 0.0372) and PTK2 (p = 0.0075) were down-regulated in the periodontal disease and implant rejection group, and only one was overexpressed: FOXO1A (p = 0.0552). The genes with statistically significant alterations described in this article determine that the group of Down syndrome patients with periodontal disease and implant failure is a group of patients genetically susceptible to suffering from both conditions together. Full article

Review

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25 pages, 724 KiB  
Review
Investigating the Interplay: Periodontal Disease and Type 1 Diabetes Mellitus—A Comprehensive Review of Clinical Studies
by Stefania Vlachou, Alexandre Loumé, Catherine Giannopoulou, Evangelos Papathanasiou and Alkisti Zekeridou
Int. J. Mol. Sci. 2024, 25(13), 7299; https://doi.org/10.3390/ijms25137299 - 2 Jul 2024
Cited by 3 | Viewed by 1743
Abstract
Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from [...] Read more.
Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from the interplay between oral microbiota and the host immune response. A comprehensive search of studies published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population. Full article
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31 pages, 2213 KiB  
Review
Periodontal Disease and Its Association with Metabolic Syndrome—A Comprehensive Review
by Itay Aizenbud, Asaf Wilensky and Galit Almoznino
Int. J. Mol. Sci. 2023, 24(16), 13011; https://doi.org/10.3390/ijms241613011 - 21 Aug 2023
Cited by 16 | Viewed by 4167
Abstract
Periodontal disease is a complex and progressive chronic inflammatory condition that leads to the loss of alveolar bone and teeth. It has been associated with various systemic diseases, including diabetes mellitus and obesity, among others. Some of these conditions are part of the [...] Read more.
Periodontal disease is a complex and progressive chronic inflammatory condition that leads to the loss of alveolar bone and teeth. It has been associated with various systemic diseases, including diabetes mellitus and obesity, among others. Some of these conditions are part of the metabolic syndrome cluster, a group of interconnected systemic diseases that significantly raise the risk of cardiovascular diseases, diabetes mellitus, and stroke. The metabolic syndrome cluster encompasses central obesity, dyslipidemia, insulin resistance, and hypertension. In this review, our objective is to investigate the correlation between periodontal disease and the components and outcomes of the metabolic syndrome cluster. By doing so, we aim to gain insights into the fundamental mechanisms that link each systemic condition with the metabolic syndrome. This deeper understanding of the interplay between these conditions and periodontal disease can pave the way for more effective treatments that take into account the broader impact of managing periodontal disease on the comprehensive treatment of systemic diseases, and vice versa. Full article
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28 pages, 2280 KiB  
Review
The Roles of Periodontal Bacteria in Atherosclerosis
by Xiaofei Huang, Mengru Xie, Xiaofeng Lu, Feng Mei, Wencheng Song, Yang Liu and Lili Chen
Int. J. Mol. Sci. 2023, 24(16), 12861; https://doi.org/10.3390/ijms241612861 - 16 Aug 2023
Cited by 3 | Viewed by 2983
Abstract
Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. [...] Read more.
Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. This review concisely outlines several prevalent periodontal pathogens identified within atherosclerotic plaques, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum. We review the existing epidemiological evidence elucidating the association between these pathogens and AS-related diseases, and the diverse mechanisms for which these pathogens may engage in AS, such as endothelial barrier disruption, immune system activation, facilitation of monocyte adhesion and aggregation, and promotion of foam cell formation, all of which contribute to the progression and destabilization of atherosclerotic plaques. Notably, the intricate interplay among bacteria underscores the complex impact of periodontitis on AS. In conclusion, advancing our understanding of the relationship between periodontal pathogens and AS will undoubtedly offer invaluable insights and potential therapeutic avenues for the prevention and management of AS. Full article
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18 pages, 2233 KiB  
Review
Periodontitis and COVID-19: Immunological Characteristics, Related Pathways, and Association
by Manlin Qi, Wenyue Sun, Kun Wang, Wen Li, Jinying Lin, Jing Gong and Lin Wang
Int. J. Mol. Sci. 2023, 24(3), 3012; https://doi.org/10.3390/ijms24033012 - 3 Feb 2023
Cited by 11 | Viewed by 4352
Abstract
Both periodontitis and Coronavirus disease 2019 (COVID-19) pose grave threats to public health and social order, endanger human life, and place a significant financial strain on the global healthcare system. Since the COVID-19 pandemic, mounting research has revealed a link between COVID-19 and [...] Read more.
Both periodontitis and Coronavirus disease 2019 (COVID-19) pose grave threats to public health and social order, endanger human life, and place a significant financial strain on the global healthcare system. Since the COVID-19 pandemic, mounting research has revealed a link between COVID-19 and periodontitis. It is critical to comprehend the immunological mechanisms of the two illnesses as well as their immunological interaction. Much evidence showed that there are many similar inflammatory pathways between periodontitis and COVID-19, such as NF-κB pathway, NLRP3/IL-1β pathway, and IL-6 signaling pathway. Common risk factors such as gender, lifestyle, and comorbidities contribute to the severity of both diseases. Revealing the internal relationship between the two diseases is conducive to the treatment of the two diseases in an emergency period. It is also critical to maintain good oral hygiene and a positive attitude during treatment. This review covers four main areas: immunological mechanisms, common risk factors, evidence of the association between the two diseases, and possible interventions and potential targets. These will provide potential ideas for drug development and clinical treatment of the two diseases. Full article
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