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Science Advances Jan 2019, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were...
, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral infection in mice resulted in brain colonization and increased production of Aβ, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established brain infection, blocked Aβ production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating brain colonization and neurodegeneration in Alzheimer's disease.
Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Bacteroidaceae Infections; Brain; Cell Line, Tumor; Disease Models, Animal; Female; Gingipain Cysteine Endopeptidases; Humans; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neuroprotective Agents; Peptide Fragments; Pilot Projects; Porphyromonas gingivalis; Prospective Studies; Saliva; Small Molecule Libraries; tau Proteins
PubMed: 30746447
DOI: 10.1126/sciadv.aau3333 -
Advances in Protein Chemistry and... 2020Periodontitis is an infection-driven inflammatory disease, which is characterized by gingival inflammation and bone loss. Periodontitis is associated with various... (Review)
Review
Periodontitis is an infection-driven inflammatory disease, which is characterized by gingival inflammation and bone loss. Periodontitis is associated with various systemic diseases, including cardiovascular, respiratory, musculoskeletal, and reproductive system related abnormalities. Recent theory attributes the pathogenesis of periodontitis to oral microbial dysbiosis, in which Porphyromonas gingivalis acts as a critical agent by disrupting host immune homeostasis. Lipopolysaccharide, proteases, fimbriae, and some other virulence factors are among the strategies exploited by P. gingivalis to promote the bacterial colonization and facilitate the outgrowth of the surrounding microbial community. Virulence factors promote the coaggregation of P. gingivalis with other bacteria and the formation of dental biofilm. These virulence factors also modulate a variety of host immune components and subvert the immune response to evade bacterial clearance or induce an inflammatory environment. In this chapter, our focus is to discuss the virulence factors of periodontal pathogens, especially P. gingivalis, and their roles in regulating immune responses during periodontitis progression.
Topics: Humans; Periodontitis; Porphyromonas gingivalis; T-Lymphocytes; Virulence Factors
PubMed: 32085888
DOI: 10.1016/bs.apcsb.2019.12.001 -
Periodontology 2000 Jun 2022In the initiation or exacerbation of Alzheimer disease, the dissemination of oral microorganisms into the brain tissue or the low-level systemic inflammation have been... (Review)
Review
In the initiation or exacerbation of Alzheimer disease, the dissemination of oral microorganisms into the brain tissue or the low-level systemic inflammation have been speculated to play a role. However, the impact of oral microorganisms, such as Porphyromonas gingivalis, on the pathogenesis of Alzheimer disease and the potential causative relationship is still unclear. The present review has critically reviewed the literature by examining the following aspects: (a) the oral microbiome and the immune response in the elderly population, (b) human studies on the association between periodontal and gut microorganisms and Alzheimer disease, (c) animal and in vitro studies on microorganisms and Alzheimer disease, and (d) preventive and therapeutic approaches. Factors contributing to microbial dysbiosis seem to be aging, local inflammation, systemic diseases, wearing of dentures, living in nursing homes and no access to adequate oral hygiene measures. Porphyromonas gingivalis was detectable in post-mortem brain samples. Microbiome analyses of saliva samples or oral biofilms showed a decreased microbial diversity and a different composition in Alzheimer disease compared to cognitively healthy subjects. Many in-vitro and animal studies underline the potential of P gingivalis to induce Alzheimer disease-related alterations. In animal models, recurring applications of P gingivalis or its components increased pro-inflammatory mediators and β-amyloid in the brain and deteriorated the animals' cognitive performance. Since periodontitis is the result of a disturbed microbial homoeostasis, an effect of periodontal therapy on the oral microbiome and host response related to cognitive parameters may be suggested and should be elucidated in further clinical trials.
Topics: Aged; Alzheimer Disease; Animals; Dysbiosis; Humans; Inflammation; Microbiota; Porphyromonas gingivalis
PubMed: 35244967
DOI: 10.1111/prd.12429 -
Frontiers in Cellular and Infection... 2020Periodontal disease is a chronic infectious disease associated with a variety of bacteria, which can cause damage to the periodontal support structure and affect a... (Review)
Review
Periodontal disease is a chronic infectious disease associated with a variety of bacteria, which can cause damage to the periodontal support structure and affect a variety of systemic system diseases such as cancer, cardiovascular disease, diabetes, rheumatoid arthritis, non-alcoholic fatty liver, and Alzheimer's disease. () is the most important pathogenic bacteria for periodontal disease. It can produce outer membrane vesicles (OMVs) and release them into the environment, playing an important role in its pathogenesis. This article focuses on OMVs, reviews its production and regulation, virulence components, mode of action and related diseases, with a view to providing new ideas for the prevention and treatment of diseases related to infections.
Topics: Humans; Periodontal Diseases; Porphyromonas gingivalis; Virulence; Virulence Factors
PubMed: 33585266
DOI: 10.3389/fcimb.2020.585917 -
Periodontology 2000 Jun 2022Oral and esophageal squamous cell carcinomas harbor a diverse microbiome that differs compositionally from precancerous and healthy tissues. Though causality is yet to... (Review)
Review
Oral and esophageal squamous cell carcinomas harbor a diverse microbiome that differs compositionally from precancerous and healthy tissues. Though causality is yet to be definitively established, emerging trends implicate periodontal pathogens such as Porphyromonas gingivalis as associated with the cancerous state. Moreover, infection with P. gingivalis correlates with a poor prognosis, and P. gingivalis is oncopathogenic in animal models. Mechanistically, properties of P. gingivalis that have been established in vitro and could promote tumor development include induction of a dysbiotic inflammatory microenvironment, inhibition of apoptosis, increased cell proliferation, enhanced angiogenesis, activation of epithelial-to-mesenchymal transition, and production of carcinogenic metabolites. The microbial community context is also relevant to oncopathogenicity, and consortia of P. gingivalis and Fusobacterium nucleatum are synergistically pathogenic in oral cancer models in vivo. In contrast, oral streptococci, such as Streptococcus gordonii, can antagonize protumorigenic epithelial cell phenotypes induced by P. gingivalis, indicating functionally specialized roles for bacteria in oncogenic communities. Consistent with the notion of the bacterial community constituting the etiologic unit, metatranscriptomic data indicate that functional, rather than compositional, properties of the tumor-associated communities have more relevance to cancer development. A consistent association of P. gingivalis with oral and orodigestive carcinoma could have diagnostic potential for early detection of these conditions that have a high incidence and low survival rates.
Topics: Animals; Carcinoma, Squamous Cell; Fusobacterium nucleatum; Humans; Microbiota; Mouth Neoplasms; Porphyromonas gingivalis; Tumor Microenvironment
PubMed: 35244980
DOI: 10.1111/prd.12425 -
Archives of Razi Institute Oct 2022Chronic periodontitis is an inflammatory disease of the dental plaque and affects the soft tissues supporting the tooth. It is one of the most practical oral health... (Review)
Review
Chronic periodontitis is an inflammatory disease of the dental plaque and affects the soft tissues supporting the tooth. It is one of the most practical oral health issues across the globe and adversely affects the quality of life. In a neutrophil-mediated action, the inflammatory response to periodontitis destroys the periodontal ligaments, gums, the alveolar bone, and the cementum. Some of the most associated invasive pathogens with periodontitis are , , and . Google Scholar and PubMed were used to search the evidence using key terms like 'periodontitis,' ',' 'Oral Dysbiosis and Periodontitis,' ' and Periodontitis,' etc. Only studies were included reviewing the and its role in periodontitis. It has been observed from several oral pathogens that has received immense attention due to a strong association between and periodontal disease. also disrupts the delicate balance between various members of the oral microbial communities and promotes oral dysbiosis. The dysbiotic state of the oral microbiome is distinct in functional capabilities and shows a higher expression of genes involved in lipopolysaccharide synthesis, energy regulation, and bacterial motility. Certain virulence factors such as gingipains, LPS, and fimbriae also increase the invasion and pathogenicity of . Its presence in the periodontal tissues increases the secretion of numerous pro-inflammatory mediators such as TNF-α, IL-8, and IL-1β, leading to the destruction of soft gingival tissues and ligaments. Early detection of periodontitis and immediate treatment can prevent soft tissue destruction and dentition loss. In conclusion, details about the oral microbiome, oral dysbiosis, and inflammation may offer new therapeutic options in the future, including a personalized approach and the use of combination therapy.
Topics: Dysbiosis; Inflammation; Periodontitis; Porphyromonas gingivalis; Quality of Life; Humans
PubMed: 37123122
DOI: 10.22092/ARI.2021.356596.1875 -
International Journal of Oral Science Sep 2021Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a...
Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0-40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31-40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.
Topics: Animals; Colitis, Ulcerative; Mice; Mice, Inbred C57BL; Porphyromonas gingivalis; Protein-Arginine Deiminases; Virulence Factors
PubMed: 34593756
DOI: 10.1038/s41368-021-00136-2 -
International Journal of Oral Science Sep 2021Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite...
Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite mechanisms remain elusive. Emerging evidence supports an association between mitochondrial dysfunction and AS. In our study, the impact of P. gingivalis on mitochondrial dysfunction and the potential mechanism were investigated. The mitochondrial morphology of EA.hy926 cells infected with P. gingivalis was assessed by transmission electron microscopy, mitochondrial staining, and quantitative analysis of the mitochondrial network. Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP) levels. Cellular ATP production was examined by a luminescence assay kit. The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence. Mdivi-1, a specific Drp1 inhibitor, was used to elucidate the role of Drp1 in mitochondrial dysfunction. Our findings showed that P. gingivalis infection induced mitochondrial fragmentation, increased the mtROS levels, and decreased the MMP and ATP concentration in vascular endothelial cells. We observed upregulation of Drp1 (Ser616) phosphorylation and translocation of Drp1 to mitochondria. Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P. gingivalis. Collectively, these results revealed that P. gingivalis infection promoted mitochondrial fragmentation and dysfunction, which was dependent on Drp1. Mitochondrial dysfunction may represent the mechanism by which P. gingivalis exacerbates atherosclerotic lesions.
Topics: Endothelial Cells; Mitochondria; Mitochondrial Dynamics; Porphyromonas gingivalis
PubMed: 34475379
DOI: 10.1038/s41368-021-00134-4 -
Microbiology Spectrum Feb 2023The outer membrane vesicles (OMVs) produced by Porphyromonas gingivalis contain a variety of bioactive molecules that may be involved in the progression of...
The outer membrane vesicles (OMVs) produced by Porphyromonas gingivalis contain a variety of bioactive molecules that may be involved in the progression of periodontitis. However, the participation of P. gingivalis OMVs in the development of periodontitis has not been elucidated. Here, we isolated P. gingivalis OMVs and confirmed their participation in periodontitis both and . Microcomputed tomography (micro-CT) and histological analysis showed that under stimulation with P. gingivalis OMVs, the alveolar bone of rats was significantly resorbed in vivo. We found that P. gingivalis OMVs were taken up by human periodontal ligament cells ([hPDLCs]) , which subsequently resulted in apoptosis and inflammatory cytokine release, which was accomplished by the microRNA-size small RNA (msRNA) sRNA45033 in the P. gingivalis OMVs. Through bioinformatics analysis and screening of target genes, chromobox 5 (CBX5) was identified as the downstream target of screened-out sRNA45033. Using a dual-luciferase reporter assay, overexpression, and knockdown methods, sRNA45033 was confirmed to target CBX5 to regulate hPDLC apoptosis. In addition, CUT&Tag (cleavage under targets and tagmentation) analysis confirmed the mechanism that CBX5 regulates apoptosis through the methylation of p53 DNA. Collectively, these findings indicate that the role of P. gingivalis OMVs is immunologically relevant and related to bacterial virulence during the development of periodontitis. P. gingivalis is a bacterium often associated with periodontitis. This study demonstrates that (i) sRNA45033 in P. gingivalis OMVs targets CBX5, (ii) CBX5 regulates the methylation of p53 DNA and its expression, which is associated with apoptosis, and (iii) a novel mechanism of interaction between hosts and pathogens is mediated by OMVs in the occurrence of periodontitis.
Topics: Humans; Rats; Animals; Porphyromonas gingivalis; DNA Methylation; Tumor Suppressor Protein p53; X-Ray Microtomography; Periodontitis; Apoptosis
PubMed: 36629433
DOI: 10.1128/spectrum.03288-22 -
Journal of Advanced Research Dec 2023Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs)...
INTRODUCTION
Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs) contain inflammation-inducing virulence factors, including gingipains (GPs) and lipopolysaccharide (LPS).
OBJECTIVES
To understand how PG could cause cognitive decline, we investigated the effects of PG and pEVs on the etiology of periodontitis and cognitive impairment in mice.
METHODS
Cognitive behaviors were measured in the Y-maze and novel object recognition tasks. Biomarkers were measured using ELISA, qPCR, immunofluorescence assay, and pyrosequencing.
RESULTS
pEVs contained neurotoxic GPs and inflammation-inducible fimbria protein and LPS. Gingivally exposed, but not orally gavaged, PG or pEVs caused periodontitis and induced memory impairment-like behaviors. Gingival exposure to PG or pEVs increased TNF-α expression in the periodontal and hippocampus tissues. They also increased hippocampal GPIba1, LPSIba1, and NF-κBIba1 cell numbers. Gingivally exposed PG or pEVs decreased BDNF, claudin-5, and N-methyl-D-aspartate receptor expression and BDNFNeuN cell number. Gingivally exposed fluorescein-5-isothiocyanate-labeled pEVs (F-pEVs) were detected in the trigeminal ganglia and hippocampus. However, right trigeminal neurectomy inhibited the translocation of gingivally injected F-EVs into the right trigeminal ganglia. Gingivally exposed PG or pEVs increased blood LPS and TNF-α levels. Furthermore, they caused colitis and gut dysbiosis.
CONCLUSION
Gingivally infected PG, particularly pEVs, may cause cognitive decline with periodontitis. PG products pEVs and LPS may be translocated into the brain through the trigeminal nerve and periodontal blood pathways, respectively, resulting in the cognitive decline, which may cause colitis and gut dysbiosis. Therefore, pEVs may be a remarkable risk factor for dementia.
Topics: Mice; Animals; Porphyromonas gingivalis; Lipopolysaccharides; Dysbiosis; Tumor Necrosis Factor-alpha; Brain-Derived Neurotrophic Factor; Periodontitis; Inflammation; Trigeminal Nerve; Colitis; Cognitive Dysfunction
PubMed: 36796586
DOI: 10.1016/j.jare.2023.02.006