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BACKGROUND The bioactive metabolite KetoC, generated by intestinal bacteria, exerts various beneficial effects. Nevertheless, its function in the pathogenesis of periodontitis remains unclear. Here, we investigated the effect of KetoC in a mouse model of periodontitis and explored the underlying mechanism. METHODS Thirty-one 8-week-old male C57BL/6N mice were randomly divided into four groups (non-ligation, non-ligation + KetoC, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KetoC) (n = 7/8 mice/group) and given a daily oral gavage of KetoC (15 mg/mL) or vehicle for 2 weeks. To induce periodontitis, a 5-0 silk ligature was placed on the maxillary left second molar on day 7, and P. gingivalis W83 (109 colony-forming unit [CFU]) was administered orally every 3 days. On day 14, all mice were euthanized. Alveolar bone destruction was determined from the level of the cemento-enamel junction to the alveolar bone crest. Moreover, bone loss level was confirmed from gingival tissue sections stained with hematoxylin and eosin. The presence of P. gingivalis was quantified using real-time polymerase chain reaction. In vitro, the bacteriostatic and bactericidal effects of KetoC were assessed by analyzing its suppressive activity on the proliferation of P. gingivalis and using a live/dead bacterial staining kit, respectively. A double-bond-deficient metabolite (KetoB) was then used to investigate the importance of double-bond structure in the antimicrobial activity of KetoC on P. gingivalis. RESULTS In vivo, KetoC attenuated alveolar bone destruction and suppressed P. gingivalis in the periodontitis group. In vitro, KetoC (but not KetoB) downregulated the proliferation and viability of P. gingivalis in a dose-dependent manner. CONCLUSIONS KetoC reduced alveolar bone destruction in a periodontitis model via its antimicrobial function. Therefore, this bioactive metabolite may be valuable in clinical applications to support periodontal therapy.

Objective To highlight the shifting paradigm of periodontitis, describe mechanism of periodontal bone destruction, and propose an updated host modulation therapy (HMT) strategy. To add further clinical relevance, related studies investigating the efficacy of several HMT agents in periodontitis will be discussed. Design Literature searches were conducted from articles published in PubMed using keywords “periodontal disease AND periodontitis AND host modulation therapy AND anti-inflammatory AND antioxidant”, and then the findings were comprehensively summarized and elaborated. Result Accumulating evidence indicates that periodontitis is no longer defined solely as a pathogen-induced disease; rather, it is now recognized as a consequence of uncontrolled immune response and oxidative stress leading to periodontal tissue damage. Although periodontopathic bacteria initiate the disease, inflammation and oxidative stress were reported to be the main causes for the severity of tissue destruction. Thus, since the concept of periodontitis has shifted, our approach to its management needs to be adjusted to accommodate the latest paradigm. Nowadays, the modulation of inflammation and oxidative stress is considered a target of HMT. HMT agents, such as probiotics, anti-inflammatory drugs, anti-chemokines, lipid mediators, and bio-active fatty acids, have been extensively investigated for their remarkable functions in modulating the immune response and providing antioxidant effects. Conclusion Findings from in vitro, in vivo, and human studies frequently demonstrate positive association by the administration of HMT in periodontitis. HMT strategy targeted on anti-inflammatory and antioxidant in periodontitis might serve as an excellent therapeutic approach to reach the level of clinical benefit.

Periodontal disease and its associated systemic diseases have gained public attention due to their increasing global prevalence. Still, the gold standard for the management of periodontitis is scaling and root planing (SRP). However, bacterial recolonization is considered a limitation of this approach. Further, the efficacy of adjunctive agents such as antibiotics, antimicrobials, and probiotics has been investigated extensively. Nowadays, drug resistance development due to antibiotics and antimicrobials abuse has become a global problem and our concern. In order to reduce the spread of drug resistance development, many investigations have been focused on the use of nutritional compounds rather than synthetic drugs for treating periodontitis, a relatively low-grade inflammatory disease. Moreover, if periodontitis is understood as a bacterial dysbiosis-induced inflammatory disease, then its treatment could be designed not only to eliminate periodontopathogens, but also to modify the host immune response. Therefore, this review will highlight the effectiveness of some pertinent nutrients towards periodontal condition. Nutrients are known to possess anti-inflammatory, antioxidant, and antimicrobial properties that maintain homeostasis. In vivo and in vitro studies have demonstrated the positive effects of nutrient intake on the maintenance and restoration of periodontal health. Vitamins, fatty acids, and probiotics are increasingly being found to have remarkable benefits and valuable properties. Further, considering the oral-systemic connection, nutritional supplementation is encouraged as a possible adjunct therapy for the improvement of both oral and systemic health.

Quantitative proteomic workflow based on mass spectrometry (MS) is recently developed by the researchers to screen for biomarkers in periodontal diseases comprising periodontitis. Periodontitis is known for chronic inflammatory disease characterized by progressive destruction of the tooth-supporting apparatus, yet has a lack of clear pathobiology based on a discrepancy between specified categories and diagnostic vagueness. The objective of this review was to outlined the accessible information related to proteomics studies on periodontitis. The Preferred Reporting Items for Systematical Reviews and Meta-Analysis (PRISMA) statement guides to acquaint proteomic analysis on periodontal diseases was applied. Three databases were used in this study, such as Pubmed, ScienceDirect and Biomed Central from 2009 up to November 2019. Proteomics analysis platforms that used in the studies were outlined. Upregulated and downregulated proteins findings data were found, in which could be suitable as candidate biomarkers for this disease., Cell biology; Proteins; Biochemistry; Molecular Biology; Dentistry; proteomics; Periodontitis; Periodontal disease; Biomarker

Background: Gut microbiota plays a pivotal role in regulating host metabolism that affects the systemic health. To date, several studies have confirmed the fact that microbiota interacts with host, modulating immunity, controlling the homeostasis environment, and maintaining systemic condition. Recent studies have focused on the protective function of poly unsaturated fatty acids, 10-oxo-trans-11-oxadecenoic acid (KetoC) and 10-hydroxy-cis-12-octadecenoic acid (HYA), generated by gut microbiota on periodontal disease. Nevertheless, the mechanism remains unclear as investigations are limited to in vivo and in vitro studies. In this present review, we found that the administration of metabolites, KetoC and HYA, by a probiotic gut microbiota Lactobacillus plantarum from linoleic acid is found to inhibit the oxidation process, possess an antimicrobial function, and prevent the inflammation. These findings suggest the promising use of functional lipids for human health. Conclusion: Protective modalities of bioactive metabolites may support periodontal therapy by suppressing bacterial dysbiosis and regulating periodontal homeostasis in the clinical setting.

Background There is rapidly developing interest into the role of several anti-inflammatory agents to resolve inflammation in periodontal disease. A bioactive polyunsaturated fatty acid, 10-oxo-trans-11-octadecenoic acid (KetoC), is known to have various beneficial physiological effects; however, the effect of KetoC on inflammation remains unclear. Here, we investigated the effect of KetoC on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide, and explored the intracellular mechanism responsible for its anti-inflammatory effects. Methods RAW 264.7 cells were pre-treated with or without KetoC, and then stimulated with or without P. gingivalis lipopolysaccharide. Levels of tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-1β were determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Specific antagonists for G protein-coupled receptor (GPR)40 and GPR120 were used to clarify the receptor for KetoC. The intracellular mechanism was investigated using western blotting analysis to separate nuclear and cytosolic NF-κB p65 protein. Result KetoC (5 μmol/L) was not toxic to RAW 264.7 cells, and significantly reduced the expression of TNFα and IL-6 mRNA and protein, and IL-1β mRNA. No protein production of IL-1β was observed. Additionally, when bound to GPR120, KetoC trended to downregulate nuclear NF-κB p65 protein levels. However, the antagonist for GPR40 failed to diminish the action of KetoC. Conclusion KetoC suppressed the proinflammatory cytokines TNFα, IL-6 and IL-1β via NF-κB p65, by binding to its receptor GPR120. KetoC is a promising candidate in future studies as a bioactive anti-inflammatory agent in treating periodontal disease.

The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

Background and objectives Recent evidence suggests that oral bacteria can affect extra-oral diseases by modulating aspects of the gut environment such as the microbiome, metabolome, and immune profiles. However, differences in the effects of different types of oral bacteria, particularly periodontopathic and health-associated bacteria, remain elusive. Materials and methods Five-week-old germ-free mice were orally administered with either periodontopathic bacteria as oral pathobionts (Porphyromonas gingivalis, Filifactor alocis, and Fusobacterium nucleatum) or bacteria associated with periodontal health (Actinomyces naeslundii, Streptococcus mitis, and Veillonella rogosae) twice a week for five weeks. The presence of all bacterial species in the feces and the livers of the mice was analyzed via polymerase chain reaction (PCR), using specific primers for 16S rRNA genes. Alveolar bone resorption was evaluated histologically. The expression profiles of various genes in the liver and small intestine were analyzed using real-time PCR. Sera were analyzed to determine the levels of antibodies and endotoxin. The proportions of T helper 17 (Th17) and regulatory T (Treg) cells in mesenteric lymph nodes and Peyer's patches were analyzed using flow cytometry. Results Neither of the types of bacteria administered in this experiment induced alveolar bone resorption. All bacteria elicited some degree of systemic antibody response in the mice, although the response to S. mitis was not obvious. The response to P. gingivalis and V. rogosae was strongest. Generally, the health-associated bacteria but not the periodontitis-associated bacteria were detected in fecal samples. Interestingly, only Fusobacterium nucleatum DNA was detected in the liver, despite that live Fusobacterium nucleatum were not detected in the liver. The levels of interleukin-17 in the intestine and genes related to lipid accumulation in the liver were significantly higher in the mice that received periodontitis-associated bacteria. In addition, expression of the gene associated with endoplasmic reticulum stress was higher and that of the gene controlling circadian rhythm was lower in the periodontitis group. There was no difference in serum endotoxin, T-cell phenotypes in the lymphatic tissues, or genes related to the gut barrier. Conclusion Oral administration of periodontitis-associated bacteria can induce pathological changes in the liver and intestine that are implicated in the process of periodontitis. These findings further support the importance of the oral–gut connection.

Objective Oxidative stress, which is defined as an imbalance between pro-oxidant and antioxidant systems, has been implicated in the development and/or progression of several inflammatory diseases, including periodontal disease. The reactive oxygen species (ROS) are the primary inducers of oxidative stress. In the induction of cytoprotective enzymes, the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling in antioxidant systems takes a main role. Notably, 10-oxo-trans-11-octadecenoic acid (KetoC), known as a bioactive metabolite generated by intestinal microorganisms, has been reported to have beneficial effects on several biological responses. Therefore, we investigated the antioxidant effect of KetoC on gingival epithelial cells (GECs) in this present study. Methods An SV40-T antigen-transformed human gingival epithelial cell line (Epi4) was used for experiments. The alteration of anti-oxidative stress related genes was analyzed by qPCR. The cellular ROS levels were evaluated by flow cytometry. To explore its molecular mechanisms, ARE promotor activity was analyzed by luciferase assay; the involvement of mitogen-activated protein kinase (MAPK) and G protein-coupled receptor 120 (GPR120) were evaluated by Western blotting and luciferase assay, respectively. Results KetoC significantly increased the expression of antioxidant-related genes in GECs. The level of ROS was significantly inhibited by the pretreatment of KetoC. Extracellular signal-regulated kinase (ERK) phosphorylation by KetoC promoted both the nuclear translocation of Nrf2 and its binding to the ARE in GECs. Further, GPR120 regulated the activation of KetoC induced-Nrf2-ARE signaling. Conclusion KetoC exerts a protective function against the oxidative stress in GECs through GPR120-dependent ERK-Nrf2-ARE signaling.

Background Periodontitis is an inflammatory disease that results in alveolar bone resorption due to inflammatory cytokine production induced by bacterial antigens such as lipopolysaccharides (LPS). Here, the preventive effect of the Amyl-1-18 peptide derived from rice in an experimental model of periodontitis and the effect on the anti-inflammatory response were assessed. Methods Alveolar bone resorption, gene transcription of proinflammatory cytokines in the gingiva, and the endotoxin level in the oral cavity were evaluated after oral administration of the Amyl-1-18 peptide for 14 days using a ligature-induced periodontitis model in mice. Additionally, murine macrophages were incubated with LPS of Escherichia coli or Porphyromonas gingivalis in the presence of Amyl-1-18 to analyze the suppressive effects of Amyl-1-18 on the cell signaling pathways associated with proinflammatory cytokine production, including inflammasome activities. Results Oral administration of Amyl-1-18 suppressed alveolar bone resorption and gene transcription of interleukin (il)6 in the gingiva of the periodontitis model, and decreased endotoxin levels in the oral cavity, suggesting modulation of periodontal inflammation by inhibition of endotoxin activities in vivo. Also, Amyl-1-18 suppressed IL-6 production induced by LPS and recombinant IL-1β in macrophages in vitro but had no effect on inflammasome activity. Conclusions The Amyl-1-18 peptide from rice inhibited alveolar bone destruction in mouse periodontitis model via suppressing inflammatory cytokine production induced by LPS. It was suggested that Amyl-1-18 peptide has anti-inflammatory property against LPS, not only by neutralization of LPS and subsequent inhibition of nuclear factor-κB signaling but also by inhibition of the IL-1R-related signaling cascade.

Several studies have demonstrated the remarkable properties of microbiota and their metabolites in the pathogenesis of several inflammatory diseases. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive metabolite generated by probiotic microorganisms during the process of fatty acid metabolism, has been studied for its protective effects against epithelial barrier impairment in the intestines. Herein, we examined the effect of HYA on gingival epithelial barrier function and its possible application for the prevention and treatment of periodontal disease. We found that GPR40, a fatty acid receptor, was expressed on gingival epithelial cells; activation of GPR40 by HYA significantly inhibited barrier impairment induced by Porphyromonas gingivalis, a representative periodontopathic bacterium. The degradation of E-cadherin and beta-catenin, basic components of the epithelial barrier, was prevented in a GPR40-dependent manner in vitro. Oral inoculation of HYA in a mouse experimental periodontitis model suppressed the bacteria-induced degradation of E-cadherin and subsequent inflammatory cytokine production in the gingival tissue. Collectively, these results suggest that HYA exerts a protective function, through GPR40 signaling, against periodontopathic bacteria-induced gingival epithelial barrier impairment and contributes to the suppression of inflammatory responses in periodontal diseases.