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1
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He T, Zou Y, Grender J, Amini P, Kaminski M, Biesbrock AR. Randomized Controlled Trials Assessing Exposure Frequency Effects of Stannous Fluoride on Gingivitis. JDR Clin Trans Res 2025; 10:124-134. [PMID: 39118360 DOI: 10.1177/23800844241263031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVE To evaluate the exposure frequency effect of 0.454% stannous fluoride (SnF2) toothpaste in controlling gingivitis. METHODS Two randomized controlled trials enrolled generally healthy adults with gingivitis. The study duration was 1 mo (study 1) and 3 mo (study 2). Gingivitis was assessed using the Löe-Silness Gingival Index (LSGI) at baseline, 1 mo (both studies), and 3 mo (study 2); bleeding scores were derived from the LSGI. Study groups consisted of positive control (twice-daily use of 0.454% SnF2 toothpaste), experimental group (brushing in the morning with SnF2 toothpaste and in the evening with 0.76% sodium monofluorophosphate [SMFP] toothpaste), and negative control (twice-daily use of SMFP toothpaste). The primary endpoint was number of bleeding sites. RESULTS Study 1 and study 2 each enrolled and randomized 90 participants; 86 and 89 participants, respectively, completed the trials. At baseline, the mean (SD) number of bleeding sites was 47.6 (18.54) in study 1 and 41.5 (17.84) in study 2. At 3 mo (study 2), the positive control produced 51.3% fewer bleeding sites, and the experimental group produced 32.5% fewer bleeding sites versus the negative control (P < 0.001 for both). At 1 mo, the positive control produced 45.1% (study 1) and 45.8% (study 2) fewer bleeding sites versus the negative control (P < 0.001 for both), and the experimental group produced 33.0% (study 1) and 24.8% (study 2) fewer bleeding sites, respectively, versus the negative control (P ≤ 0.002 for both). The benefit was observed as early as 1 mo and was consistent with 3-mo results. CONCLUSION This research is to our knowledge the first to demonstrate a gingivitis-reduction response effect for the frequency of bioavailable SnF2 toothpaste use, with maximum benefit from twice-daily use, followed by a single-daily exposure versus the negative control. CLINICAL TRIAL REGISTRATION NUMBERS NCT05916508 and NCT05916521.Knowledge Transfer Statement:The results of this study can be used by dental professionals to guide their recommendations for therapeutic toothpaste for gingival health. Emphasis on the importance of twice-daily brushing with bioavailable stannous fluoride dentifrice will help patients optimize gingival health benefits achieved via self-care.
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Affiliation(s)
- T He
- The Procter & Gamble Company, Mason, OH, USA
| | - Y Zou
- The Procter & Gamble Company, Mason, OH, USA
| | - J Grender
- The Procter & Gamble Company, Mason, OH, USA
| | - P Amini
- Silverstone Research Group, Las Vegas, NV, USA
| | - M Kaminski
- The Procter & Gamble Company, Mason, OH, USA
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2
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Zang T, Zhang Z, Liu W, Yin L, Zhao S, Liu B, Ma L, Li Z, Tang X. Structural and functional changes in the oral microbiome of patients with craniofacial microsomia. Sci Rep 2025; 15:5400. [PMID: 39948426 PMCID: PMC11825945 DOI: 10.1038/s41598-025-86537-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 01/13/2025] [Indexed: 02/16/2025] Open
Abstract
Craniofacial microsomia (CFM) is the second most common congenital craniofacial deformity, presenting diverse clinical manifestations and treatments that may influence oral bacteria dysbiosis (OBD). However, research linking CFM to OBD is limited. Saliva samples were collected from 20 patients with CFM and 24 controls. We compared oral microflora and gene function using 16 S ribosomal RNA sequencing and metagenomics. We also evaluated the correlation between CFM clinical phenotypes and microbiota community structure. Patients with CFM demonstrated greater richness and evenness in their oral microflora. The dominant genera included several pathogenic species, such as Actinomyces, Fusobacterium, and Prevotella. Notably, the severity of CFM correlated positively with the abundance of Neisseria and Porphyromonas. Upregulated pathways were primarily linked to biotin and amino acid metabolism, such as Tryptophan metabolism and Lysine degradation, and further underscored the need for focused oral health interventions in this population. This study is the first to indicate that CFM patients exhibit unique oral bacterial dysbiosis, marked by a higher presence of opportunistic pathogens and increased pathways related to oral and systemic health. These findings highlight the importance of monitoring oral health in patients with CFM.
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Affiliation(s)
- Tianying Zang
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Zhiyong Zhang
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Wei Liu
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Lin Yin
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Shanbaga Zhao
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Bingyang Liu
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Lunkun Ma
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Zhifeng Li
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China
| | - Xiaojun Tang
- Maxillo-facial Surgery Center, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 33 Ba-Da-Chu Road, Beijing, China.
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Yan Q, Jia S, Li D, Yang J. The role and mechanism of action of microbiota-derived short-chain fatty acids in neutrophils: From the activation to becoming potential biomarkers. Biomed Pharmacother 2023; 169:115821. [PMID: 37952355 DOI: 10.1016/j.biopha.2023.115821] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023] Open
Abstract
Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, have emerged as critical mediators in the communication between the human microbiota and its host. As the first responder to the inflammatory site, neutrophils play an important role in protecting the host against bacterial infections. Recent investigations revealed that SCFAs generated from microbiota influence various neutrophil activities, including activation, migration, and generation of mediators of inflammatory processes. SCFAs have also been demonstrated to exhibit potential therapeutic benefits in a variety of disorders related to neutrophil dysfunction, including inflammatory bowel disease, viral infectious disorders, and cancer. This study aims to examine the molecular processes behind the complicated link between SCFAs and neutrophils, as well as their influence on neutrophil-driven inflammatory disorders. In addition, we will also provide an in-depth review of current research on the diagnostic and therapeutic value of SCFAs as possible biomarkers for neutrophil-related diseases.
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Affiliation(s)
- Qingzhu Yan
- Department of Ultrasound Medicine, the Second Hospital of Jilin University, Changchun 130000, China
| | - Shengnan Jia
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, the Second Hospital of Jilin University, Changchun 130000, China
| | - Dongfu Li
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, the Second Hospital of Jilin University, Changchun 130000, China.
| | - Junling Yang
- Department of Respiratory Medicine, the Second Hospital of Jilin University, Changchun 130000, China.
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4
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Robertsson C, Svensäter G, Davies JR, Bay Nord A, Malmodin D, Wickström C. Synergistic metabolism of salivary MUC5B in oral commensal bacteria during early biofilm formation. Microbiol Spectr 2023; 11:e0270423. [PMID: 37855449 PMCID: PMC10715109 DOI: 10.1128/spectrum.02704-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/05/2023] [Indexed: 10/20/2023] Open
Abstract
IMPORTANCE The study of bacterial interactions and salivary-mediated regulation of early dental biofilm activity is of interest for understanding oral microbial adaptation to environmental cues and biofilm maturation. Findings in oral commensals can prove useful from the perspectives of both oral and systemic health of the host, as well as the understanding of general microbial biofilm physiology. The knowledge may provide a basis for the development of prognostic biomarkers, or development of new treatment strategies, related to oral health and disease and possibly also to other biofilm-induced conditions. The study is also an important step toward developing the methodology for similar studies in other species and/or growth conditions.
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Affiliation(s)
- Carolina Robertsson
- Department of Oral Biology, Faculty of Odontology and Biofilms Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - Gunnel Svensäter
- Department of Oral Biology, Faculty of Odontology and Biofilms Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - Julia R. Davies
- Department of Oral Biology, Faculty of Odontology and Biofilms Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - Anders Bay Nord
- Swedish NMR Centre, Gothenburg University, Gothenburg, Sweden
| | - Daniel Malmodin
- Swedish NMR Centre, Gothenburg University, Gothenburg, Sweden
| | - Claes Wickström
- Department of Oral Biology, Faculty of Odontology and Biofilms Research Center for Biointerfaces, Malmö University, Malmö, Sweden
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Huang Q, Wu X, Zhou X, Sun Z, Shen J, Kong M, Chen N, Qiu JG, Jiang BH, Yuan C, Zheng Y. Association of cigarette smoking with oral bacterial microbiota and cardiometabolic health in Chinese adults. BMC Microbiol 2023; 23:346. [PMID: 37978427 PMCID: PMC10655299 DOI: 10.1186/s12866-023-03061-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 10/12/2023] [Indexed: 11/19/2023] Open
Abstract
The interplay among cigarette smoking status, oral microbiota, and cardiometabolic health is poorly understood. We aimed to examine the association of cigarette smoking status with oral microbiota and to assess the association of the identified microbial features with cardiometabolic risk factors in a Chinese population. This study included 587 participants within the Central China Cohort, including 111 smokers and 476 non-smokers, and their oral microbiota was profiled by 16S rRNA sequencing. Both oral microbial alpha- and beta-diversity were distinct between smokers and non-smokers (p < 0.05). With adjustment for sociodemographics, alcohol and tea drinking, tooth brushing frequency, and body mass index, the relative abundance of nine genera and 26 pathways, including the genus Megasphaera and two pathways involved in inositol degradation which have potentially adverse effects on cardiometabolic health, was significantly different between two groups (FDR q < 0.20). Multiple microbial features related to cigarette smoking were found to partly mediate the associations of cigarette smoking with serum triglycerides and C-reactive protein levels (p-mediation < 0.05). In conclusion, cigarette smoking status may have impacts on the oral microbial features, which may partially mediate the associations of cigarette smoking and cardiometabolic health.
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Affiliation(s)
- Qiumin Huang
- School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Xuemei Wu
- School of Public Health, Fudan University, Shanghai, 200032, China
| | - Xiaofeng Zhou
- School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Zhonghan Sun
- School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Jie Shen
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Mengmeng Kong
- School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Nannan Chen
- School of Medicine, Nantong University, Jiangsu, 226019, China
| | - Jian-Ge Qiu
- The Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China
| | - Bing-Hua Jiang
- The Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China
| | - Changzheng Yuan
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Yan Zheng
- School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, 200433, China.
- Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Balan P, Belibasakis G, Ivanovski S, Bostanci N, Seneviratne CJ. Community dynamics of subgingival microbiome in periodontitis and targets for microbiome modulation therapy. Crit Rev Microbiol 2023; 49:726-738. [PMID: 36260510 DOI: 10.1080/1040841x.2022.2133594] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 11/03/2022]
Abstract
The microbial aetiology for periodontitis has been widely studied and deciphered for more than a century. The evolving and changing concepts about periodontal microbiology can be attributed to continuously developing laboratory techniques. The current sequencing platforms have not only expanded the catalog of periodontal pathogens but have also facilitated the understanding of functional interactions of the ecological framework. However, the translation of this new knowledge to advance periodontal therapeutics is minimal. We contend that novel clinical interventions directed beyond conventional therapies need to be emphasized. A clear understanding of the structural and functional dynamics of subgingival microbiota is a pre-requisite for developing any microbiome-based interventions for applications in periodontal health care. In this review, we discuss the 16 s-rRNA gene sequencing-based knowledge of the subgingival microbial community structure, its interactions and functions, and our perspective on the potential to engineer it for periodontal therapeutics. Harnessing this next-generation sequencing-based knowledge, microbiome modulation therapies are poised to change microbiome therapeutics' face.
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Affiliation(s)
- Preethi Balan
- Singapore Oral Microbiomics Initiative, National Dental Research Institute Singapore, National Dental Center, Singapore, Singapore
- Oral Health Academic Clinical Program, Duke NUS Medical School, Singapore, Singapore
| | | | - Saso Ivanovski
- School of Dentistry, University of Queensland, Queensland, Australia
| | - Nagihan Bostanci
- Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Chaminda Jayampath Seneviratne
- Singapore Oral Microbiomics Initiative, National Dental Research Institute Singapore, National Dental Center, Singapore, Singapore
- Oral Health Academic Clinical Program, Duke NUS Medical School, Singapore, Singapore
- School of Dentistry, University of Queensland, Queensland, Australia
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7
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Miller A, Fantone KM, Tucker SL, Gokanapudi N, Goldberg JB, Rada B. Short chain fatty acids reduce the respiratory burst of human neutrophils in response to cystic fibrosis isolates of Staphylococcus aureus. J Cyst Fibros 2023; 22:756-762. [PMID: 37211502 PMCID: PMC10524534 DOI: 10.1016/j.jcf.2023.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/23/2023]
Abstract
Short chain fatty acids (SCFA) are produced by anaerobic bacteria. The most common SCFAs are acetate, propionate and butyrate. SCFAs have been implicated in several inflammatory diseases including cystic fibrosis (CF) where they are present in the airways at millimolar concentrations. Staphylococcus aureus is one of the main respiratory pathogens in CF. Polymorphonuclear neutrophil granulocytes (PMN) represent the most important immune defense the host uses against S. aureus. However, the reason why PMNs are unable to clear S. aureus in CF remains largely unclear. We hypothesized that SCFAs impair effector functions of PMNs in response to S. aureus. To test this, human PMNs were exposed to CF clinical isolates of S. aureus in vitro in the presence or absence of SCFAs and effector functions of PMNs were assessed. Our data show that SCFAs do not affect the viability of PMNs and do not stimulate the release of neutrophil extracellular traps (NET) from human PMNs. Production of reactive oxygen species (ROS), another important antimicrobial function of PMNs, on the other hand, was significantly inhibited by SCFAs in response to the bacterium. SCFAs did not compromise the ability of PMNs to kill CF isolates of S. aureus in vitro. Overall, our results provide new knowledge into the interactions between SCFAs and the immune system, and indicate that SCFAs produced by anaerobic bacteria in the CF lung could interfere with reactive oxidant production of PMNs in response to S. aureus, one of the prominent respiratory pathogens in this disease.
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Affiliation(s)
- Arthur Miller
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Kayla M Fantone
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Samantha L Tucker
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Naveen Gokanapudi
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Joanna B Goldberg
- Division of Pulmonology, Asthma, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Balázs Rada
- Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA.
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Hyvärinen E, Kashyap B, Kullaa AM. Oral Sources of Salivary Metabolites. Metabolites 2023; 13:metabo13040498. [PMID: 37110157 PMCID: PMC10145445 DOI: 10.3390/metabo13040498] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/10/2023] [Accepted: 03/28/2023] [Indexed: 03/31/2023] Open
Abstract
The oral cavity is very diverse, where saliva plays an important role in maintaining oral health. The metabolism of saliva has been used to investigate oral diseases as well as general diseases, mainly to detect diagnostic biomarkers. There are many sources of salivary metabolites in the mouth. The online English language search and PubMed databases were searched to retrieve relevant studies on oral salivary metabolites. The physiological balance of the mouth is influenced by many factors that are reflected in the salivary metabolite profile. Similarly, the dysbiosis of microbes can alter the salivary metabolite profile, which may express oral inflammation or oral diseases. This narrative review highlights the factors to be considered when examining saliva and its use as a diagnostic biofluid for different diseases. Salivary metabolites, mainly small molecular metabolites may enter the bloodstream and cause illness elsewhere in the body. The importance of salivary metabolites produced in the oral cavity as risk factors for general diseases and their possible relationship to the body’s function are also discussed.
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9
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Liu Y, Wang J, Dong B, Zhai Y, Zhou L, Sun S, Li X, Wu L. Prediction and validation of microbial community function from normal pulp to pulpitis caused by deep dentinal caries. Int Endod J 2023; 56:608-621. [PMID: 36648366 DOI: 10.1111/iej.13890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Microbial function changes may be responsible for dental pulp transformation from normal to diseased. However, studies on the prediction and verification of the function of the microbial community in the deep dentine and pulp of caries-induced pulpitis are lacking. METHODS This study included 171 cases of deep dentinal caries divided into normal pulp (NP), reversible pulpitis (RP), and irreversible pulpitis (IRP). In Experiment I, the microbial community composition was identified in 111 samples using 16S ribosomal DNA. Function prediction was performed through phylogenetic investigation of communities by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States prediction and qPCR. In Experiment II, different microbiome functions were confirmed in 60 samples using liquid chromatography-tandem mass spectrometry. RESULTS In Experiment I, microbial abundance significantly differed in the IRP group compared to the other two groups. The RP and NP groups had the same microbiome composition, but the predicted functional difference between the RP and NP groups pertained to membrane transport (p < .010). The predicted functional difference between the IRP and NP groups pertained to amino-acid, co-factor, and vitamin metabolism (p < .010). In Experiment II, Kyoto Encyclopedia of Genes and Genomes functional annotation revealed that the differential metabolites between the RP and NP groups did not participate in membrane transport; however, the differential metabolites between the IRP and NP groups participated in amino-acid metabolism. CONCLUSIONS The near-pulp microbiome in RP and NP with deep dentinal caries had the same differential function. However, amino acid metabolism in near the pulp microbial community differed between IRP and NP with deep dentinal caries.
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Affiliation(s)
- Yimeng Liu
- Department of Endodontics, School of Stomatology, Tianjin Medical University, Tianjin, China.,Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, China
| | - Jiaojiao Wang
- Department of Endodontics, School of Stomatology, Tianjin Medical University, Tianjin, China
| | - Bojuan Dong
- Department of Stomatology, Wuqing People Hospital, Tianjin, China
| | - Yuanbin Zhai
- Department of Endodontics, School of Stomatology, Tianjin Medical University, Tianjin, China
| | - Liwen Zhou
- Department of Endodontics, School of Stomatology, Tianjin Medical University, Tianjin, China
| | - Siyuan Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xinyi Li
- Stomatology, Medical School of Nankai University, Tianjin, China
| | - Ligeng Wu
- Department of Endodontics, School of Stomatology, Tianjin Medical University, Tianjin, China
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10
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Chen Y, Zhao C, Zheng J, Su N, Ji H. Discovery of the mechanism of n-propylparaben-promoting the proliferation of human breast adenocarcinoma cells by activating human estrogen receptors via metabolomics analysis. Hum Exp Toxicol 2023; 42:9603271231171648. [PMID: 37121592 DOI: 10.1177/09603271231171648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
BACKGROUND N-propylparaben (PP), a type of paraben, is commonly used as a preservative or antibacterial agent in daily chemicals, medicine, food, cosmetics, feed, and various industrial preservatives. Although PP promotes the growth of human breast adenocarcinoma (MCF-7) cells by activating the human estrogen receptor (ER), the mechanism responsible for this type of programmed cell proliferation is poorly understood. OBJECTIVE To clarify the effect of PP on cell metabolic function and the potential molecular mechanism of PP induced MCF-7 cell proliferation from a new perspective. METHODS To use high-resolution mass spectrometry-based metabolomics combined with bioinformatics analysis to analyze the molecular mechanism. RESULTS The results illustrated that differential endogenous compounds related to the effects of PP on cell metabolic functions were detected. PP was found to promote glycolysis in MCF-7 cells and enhance the tricarboxylic acid cycle (TCA cycle) in mitochondria, thus improving the energy supply to these tumor cells for metabolic function and promotion of rapid proliferation. Moreover, we found that PP promoted cell proliferation by affecting the mitogen-activated protein kinase (MAPK) signaling pathway of MCF-7 cells. CONCLUSION Our results revealed the molecular mechanism of low concentration PP promoting MCF-7 cell proliferation by activating ER.
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Affiliation(s)
- Yunxia Chen
- Chinese Academy of Inspection and Quarantine, Cosmetic Technology Center, Beijing, China
| | - Chan Zhao
- Chinese Academy of Inspection and Quarantine, Institute of Chemicals Safety, Beijing, China
| | - Jun Zheng
- Chinese Academy of Inspection and Quarantine, Cosmetic Technology Center, Beijing, China
| | - Ning Su
- Chinese Academy of Inspection and Quarantine, Cosmetic Technology Center, Beijing, China
| | - Hainan Ji
- Chinese Academy of Inspection and Quarantine, Institute of Chemicals Safety, Beijing, China
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11
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Liu T, Yang R, Zhou J, Lu X, Yuan Z, Wei X, Guo L. Interactions Between Streptococcus gordonii and Fusobacterium nucleatum Altered Bacterial Transcriptional Profiling and Attenuated the Immune Responses of Macrophages. Front Cell Infect Microbiol 2022; 11:783323. [PMID: 35071038 PMCID: PMC8776643 DOI: 10.3389/fcimb.2021.783323] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022] Open
Abstract
Interspecies coaggregation promotes transcriptional changes in oral bacteria, affecting bacterial pathogenicity. Streptococcus gordonii (S. gordonii) and Fusobacterium nucleatum (F. nucleatum) are common oral inhabitants. The present study investigated the transcriptional profiling of S. gordonii and F. nucleatum subsp. polymorphum in response to the dual-species coaggregation using RNA-seq. Macrophages were infected with both species to explore the influence of bacterial coaggregation on both species' abilities to survive within macrophages and induce inflammatory responses. Results indicated that, after the 30-min dual-species coaggregation, 116 genes were significantly up-regulated, and 151 genes were significantly down-regulated in S. gordonii; 97 genes were significantly down-regulated, and 114 genes were significantly up-regulated in F. nucleatum subsp. polymorphum. Multiple S. gordonii genes were involved in the biosynthesis and export of cell-wall proteins and carbohydrate metabolism. F. nucleatum subsp. polymorphum genes were mostly associated with translation and protein export. The coaggregation led to decreased expression levels of genes associated with lipopolysaccharide and peptidoglycan biosynthesis. Coaggregation between S. gordonii and F. nucleatum subsp. polymorphum significantly promoted both species' intracellular survival within macrophages and attenuated the production of pro-inflammatory cytokines IL-6 and IL-1β. Physical interactions between these two species promoted a symbiotic lifestyle and repressed macrophage's killing and pro-inflammatory responses.
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Affiliation(s)
- Tingjun Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Ruiqi Yang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Jiani Zhou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xianjun Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Zijian Yuan
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xi Wei
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Lihong Guo
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
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12
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Updates and Original Case Studies Focused on the NMR-Linked Metabolomics Analysis of Human Oral Fluids Part I: Emerging Platforms and Perspectives. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12031235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
1H NMR-based metabolomics analysis of human saliva, other oral fluids, and/or tissue biopsies serves as a valuable technique for the exploration of metabolic processes, and when associated with ’state-of-the-art’ multivariate (MV) statistical analysis strategies, provides a powerful means of examining the identification of characteristic metabolite patterns, which may serve to differentiate between patients with oral health conditions (e.g., periodontitis, dental caries, and oral cancers) and age-matched heathy controls. This approach may also be employed to explore such discriminatory signatures in the salivary 1H NMR profiles of patients with systemic diseases, and to date, these have included diabetes, Sjörgen’s syndrome, cancers, neurological conditions such as Alzheimer’s disease, and viral infections. However, such investigations are complicated in view of quite a large number of serious inconsistencies between the different studies performed by independent research groups globally; these include differing protocols and routes for saliva sample collection (e.g., stimulated versus unstimulated samples), their timings (particularly the oral activity abstention period involved, which may range from one to 12 h or more), and methods for sample transport, storage, and preparation for NMR analysis, not to mention a very wide variety of demographic variables that may influence salivary metabolite concentrations, notably the age, gender, ethnic origin, salivary flow-rate, lifestyles, diets, and smoking status of participant donors, together with their exposure to any other possible convoluting environmental factors. In view of the explosive increase in reported salivary metabolomics investigations, in this update, we critically review a wide range of critical considerations for the successful performance of such experiments. These include the nature, composite sources, and biomolecular status of human saliva samples; the merits of these samples as media for the screening of disease biomarkers, notably their facile, unsupervised collection; and the different classes of such metabolomics investigations possible. Also encompassed is an account of the history of NMR-based salivary metabolomics; our recommended regimens for the collection, transport, and storage of saliva samples, along with their preparation for NMR analysis; frequently employed pulse sequences for the NMR analysis of these samples; the supreme resonance assignment benefits offered by homo- and heteronuclear two-dimensional NMR techniques; deliberations regarding salivary biomolecule quantification approaches employed for such studies, including the preprocessing and bucketing of multianalyte salivary NMR spectra, and the normalization, transformation, and scaling of datasets therefrom; salivary phenotype analysis, featuring the segregation of a range of different metabolites into ‘pools’ grouped according to their potential physiological sources; and lastly, future prospects afforded by the applications of LF benchtop NMR spectrometers for direct evaluations of the oral or systemic health status of patients at clinical ‘point-of-contact’ sites, e.g., dental surgeries. This commentary is then concluded with appropriate recommendations for the conduct of future salivary metabolomics studies. Also included are two original case studies featuring investigations of (1) the 1H NMR resonance line-widths of selected biomolecules and their possible dependence on biomacromolecular binding equilibria, and (2) the combined univariate (UV) and MV analysis of saliva specimens collected from a large group of healthy control participants in order to potentially delineate the possible origins of biomolecules therein, particularly host- versus oral microbiome-derived sources. In a follow-up publication, Part II of this series, we conduct censorious reviews of reported observations acquired from a diversity of salivary metabolomics investigations performed to evaluate both localized oral and non-oral diseases. Perplexing problems encountered with these again include those arising from sample collection and preparation protocols, along with 1H NMR spectral misassignments.
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Ishikawa T, Sasaki D, Aizawa R, Yamamoto M, Yaegashi T, Irié T, Sasaki M. The Role of Lactic Acid on Wound Healing, Cell Growth, Cell Cycle Kinetics, and Gene Expression of Cultured Junctional Epithelium Cells in the Pathophysiology of Periodontal Disease. Pathogens 2021; 10:pathogens10111507. [PMID: 34832662 PMCID: PMC8620665 DOI: 10.3390/pathogens10111507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/09/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022] Open
Abstract
Lactic acid (LA) is short-chain fatty acid, such as butyric acid and propionic acid, that is produced as a metabolite of lactic acid bacteria, including periodontopathic bacteria. These short-chain fatty acids have positive effects on human health but can also have negative effects, such as the promotion of periodontal disease (PD), which is caused by periodontal pathogens present in the gingival sulcus. PD is characterized by apical migration of junctional epithelium, deepening of pockets, and alveolar bone loss. Thus, the junctional epithelial cells that form the bottom of the gingival sulcus are extremely important in investigating the pathophysiology of PD. The aim of this study was to investigate the effect of LA on wound healing, cell growth, cell cycle kinetics, and gene expression of cultured junctional epithelium cells. The results showed that stimulation with 10 mM LA slowed wound healing of the junctional epithelial cell layer and arrested the cell cycle in the G0/G1 (early cell cycle) phase, thereby inhibiting cell growth. However, cell destruction was not observed. LA also enhanced mRNA expression of integrin α5, interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and receptor activator of nuclear factor kappa-B ligand. The results of this study suggest that stimulation of junctional epithelial cells with high concentrations of LA could exacerbate PD, similarly to butyric acid and propionic acid.
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Affiliation(s)
- Taichi Ishikawa
- Division of Molecular Microbiology, Department of Microbiology, Iwate Medical University, 1-1-1 Idai-dori, Yahaba-Cho, Morioka 028-3694, Japan;
- Correspondence: ; Tel.: +81-19-651-5111; Fax: +81-19-908-8011
| | - Daisuke Sasaki
- Division of Periodontology, Department of Conservative Dentistry, School of Dentistry, Iwate Medical University, 1-3-27 Chuo-dori, Morioka 020-8505, Japan; (D.S.); (T.Y.)
| | - Ryo Aizawa
- Department of Periodontology, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo 145-8515, Japan; (R.A.); (M.Y.)
| | - Matsuo Yamamoto
- Department of Periodontology, School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ohta-ku, Tokyo 145-8515, Japan; (R.A.); (M.Y.)
| | - Takashi Yaegashi
- Division of Periodontology, Department of Conservative Dentistry, School of Dentistry, Iwate Medical University, 1-3-27 Chuo-dori, Morioka 020-8505, Japan; (D.S.); (T.Y.)
| | - Tarou Irié
- Division of Anatomical and Cellular Pathology, Department of Pathology, Iwate Medical University, 1-1-1 Idai-dori, Yahaba-Cho, Morioka 028-3694, Japan;
| | - Minoru Sasaki
- Division of Molecular Microbiology, Department of Microbiology, Iwate Medical University, 1-1-1 Idai-dori, Yahaba-Cho, Morioka 028-3694, Japan;
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Nechipurenko YD, Semyonov DA, Lavrinenko IA, Lagutkin DA, Generalov EA, Zaitceva AY, Matveeva OV, Yegorov YE. The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19. BIOLOGY 2021; 10:852. [PMID: 34571729 PMCID: PMC8469745 DOI: 10.3390/biology10090852] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/23/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022]
Abstract
COVID-19 has specific characteristics that distinguish this disease from many other infections. We suggest that the pathogenesis of severe forms of COVID-19 can be associated with acidosis. This review article discusses several mechanisms potentially linking the damaging effects of COVID-19 with acidosis and shows the existence of a vicious cycle between the development of hypoxia and acidosis in COVID-19 patients. At the early stages of the disease, inflammation, difficulty in gas exchange in the lungs and thrombosis collectively contribute to the onset of acidosis. In accordance with the Verigo-Bohr effect, a decrease in blood pH leads to a decrease in oxygen saturation, which contributes to the exacerbation of acidosis and results in a deterioration of the patient's condition. A decrease in pH can also cause conformational changes in the S-protein of the virus and thus lead to a decrease in the affinity and avidity of protective antibodies. Hypoxia and acidosis lead to dysregulation of the immune system and multidirectional pro- and anti-inflammatory reactions, resulting in the development of a "cytokine storm". In this review, we highlight the potential importance of supporting normal blood pH as an approach to COVID-19 therapy.
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Affiliation(s)
- Yury D. Nechipurenko
- Laboratory DNA-Protein Recognition, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Denis A. Semyonov
- Institute of Molecular Medicine and Pathobiochemistry, Voyno-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk 660022, Russia;
- Institute of Biophysics Siberian Branch of Russian Academy of Sciences, Krasnoyarsk 660036, Russia
| | - Igor A. Lavrinenko
- Department of Human and Animal Physiology, Faculty of Medicine and Biology, Voronezh State University, Voronezh 394018, Russia;
| | - Denis A. Lagutkin
- Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia;
| | - Evgenii A. Generalov
- Department of Biophysics, Faculty of Physics, Lomonosov Moscow State University, Moscow 119991, Russia;
| | - Anna Y. Zaitceva
- Laboratory of Medical Analytical Methods and Devices, Institute for Analytical Instrumentation of the Russian Academy of Sciences, St. Petersburg 198095, Russia;
| | | | - Yegor E. Yegorov
- Laboratory of Cellular Bases for the Development of Malignant Diseases, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
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Chang MC, Wang TM, Chien HH, Pan YH, Tsai YL, Jeng PY, Lin LD, Jeng JH. Effect of butyrate, a bacterial by-product, on the viability and ICAM-1 expression/production of human vascular endothelial cells: Role in infectious pulpal/periapical diseases. Int Endod J 2021; 55:38-53. [PMID: 34420220 DOI: 10.1111/iej.13614] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 08/19/2021] [Indexed: 01/21/2023]
Abstract
AIM To investigate the effects of butyric acid (BA), a metabolic product generated by pulp and root canal pathogens, on the viability and intercellular adhesion molecule-1 (ICAM-1) production of endothelial cells, which are crucial to angiogenesis and pulpal/periapical wound healing. METHODOLOGY Endothelial cells were exposed to butyrate with/without inhibitors. Cell viability, apoptosis and reactive oxygen species (ROS) were evaluated using an MTT assay, PI/annexin V and DCF fluorescence flow cytometry respectively. RNA and protein expression was determined using a polymerase chain reaction assay and Western blotting or immunofluorescent staining. Soluble ICAM-1 (sICAM-1) was measured using an enzyme-linked immunosorbent assay. The quantitative results were expressed as mean ± standard error (SE) of the mean. The data were analysed using a paired Student's t-test where necessary. A p-value ≤0.05 was considered to indicate a statistically significant difference between groups. RESULTS Butyrate (>4 mM) inhibited cell viability and induced cellular apoptosis and necrosis. It inhibited cyclin B1 but stimulated p21 and p27 expression. Butyrate stimulated ROS production and hemeoxygenase-1 (HO-1) expression as well as activated the Ac-H3, p-ATM, p-ATR, p-Chk1, p-Chk2, p-p38 and p-Akt expression of endothelial cells. Butyrate stimulated ICAM-1 mRNA/protein expression and significant sICAM-1 production (p < .05). Superoxide dismutase, 5z-7oxozeaenol, SB203580 and compound C (p < .05), but not ZnPP, CGK733, AZD7762 or LY294002, attenuated butyrate cytotoxicity to endothelial cells. Notably, little effect on butyrate-stimulated sICAM-1 secretion was found. Valproic acid, phenylbutyrate and trichostatin (three histone deacetylase inhibitors) significantly induced sICAM-1 production (p < .05). CONCLUSION Butyric acid inhibited proliferation, induced apoptosis, stimulated ROS and HO-1 production and increased ICAM-1 mRNA expression and protein synthesis in endothelial cells. Cell viability affected by BA was diminished by some inhibitors; however, the increased sICAM-1 secretion by BA was not affected by any of the tested inhibitors. These results facilitate understanding of the pathogenesis, prevention and treatment of pulpal/periapical diseases.
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Affiliation(s)
- Mei-Chi Chang
- Chang Gung University of Science and Technology, Taoyuan City, Taiwan.,Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Tong-Mei Wang
- School of Dentistry & Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
| | - Hua-Hong Chien
- Division of Periodontology, College of Dentistry, The Ohio State University, Columbus, Ohio, USA
| | - Yu-Hwa Pan
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yi-Ling Tsai
- School of Dentistry & Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
| | - Po-Yuan Jeng
- School of Dentistry & Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
| | - Li-Deh Lin
- School of Dentistry & Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
| | - Jiiang-Huei Jeng
- School of Dentistry & Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan.,School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
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Simas AM, Kramer CD, Weinberg EO, Genco CA. Oral infection with a periodontal pathogen alters oral and gut microbiomes. Anaerobe 2021; 71:102399. [PMID: 34090994 DOI: 10.1016/j.anaerobe.2021.102399] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 04/27/2021] [Accepted: 05/25/2021] [Indexed: 01/04/2023]
Abstract
Periodontal disease, an inflammatory bone disease of the oral cavity, affects more than 50% of the United States population over the age of 30. The Gram-negative, anaerobic bacterium Porphyromonas gingivalis, the etiological agent of periodontal disease, is known to induce dysbiosis of the oral microbiome while promoting inflammatory bone loss. We have recently reported that P. gingivalis can also alter the gut microbiota of mice prone to develop inflammatory atherosclerosis. However, it is still unknown whether P. gingivalis induces similar changes to the gut microbiome as it does to oral microbiome. In this study, we demonstrate that P. gingivalis infection increases the diversity of the oral microbiome, allowing for colonization of potentially opportunistic species in the oral microbiome and overgrowth of commensal species in both the oral and gut microbiomes. Since periodontal disease treatment in humans typically involves antibiotic treatment, we also examined the combined effect of P. gingivalis infection on mice pretreated with oral antibiotics. By correlating the oral and cecal microbiota of P. gingivalis-infected mice fed a normal chow diet, we identified blooms of the Gram-negative genera Barnesiella and Bacteroides and imbalances of mucin-degrading bacteria. These disrupted community structures were predicted to have increased detrimental functional capacities including increased flavonoid degradation and l-histidine fermentation. Though antibiotic pretreatment (without P. gingivlais) had a dominant impact on the cecal microbiome, P. gingivalis infection of mice with or without antibiotic pretreatment increased the abundance of the phylum Firmicutes and the Porphyromonadaceae family in the cecum. Collectively, our study demonstrates that P. gingivalis oral infection disrupted the oral and cecal microbiomes of otherwise unperturbed mice, altering their community membership and functional potential.
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Affiliation(s)
- Alexandra M Simas
- Graduate Program in Biochemical and Molecular Nutrition, Gerald J. and Dorothy R. Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA, 02111, USA; Department of Immunology, Tufts University School of Medicine, 136 Harrison Ave, M & V 701, Boston, MA, 02111, USA.
| | - Carolyn D Kramer
- Department of Immunology, Tufts University School of Medicine, 136 Harrison Ave, M & V 701, Boston, MA, 02111, USA.
| | - Ellen O Weinberg
- Department of Immunology, Tufts University School of Medicine, 136 Harrison Ave, M & V 701, Boston, MA, 02111, USA.
| | - Caroline A Genco
- Department of Immunology, Tufts University School of Medicine, 136 Harrison Ave, M & V 701, Boston, MA, 02111, USA; Graduate Program in Immunology and Molecular Microbiology, School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, M & V 701, Boston, MA, 02111, USA; Molecular Microbiology, School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, M & V 701, Boston, MA, 02111, USA.
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Adaptation by Ancient Horizontal Acquisition of Butyrate Metabolism Genes in Aggregatibacter actinomycetemcomitans. mBio 2021; 12:mBio.03581-20. [PMID: 33758084 PMCID: PMC8092312 DOI: 10.1128/mbio.03581-20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
There has been considerable interest in the impact of short-chain fatty acids (SCFAs) on inflammatory effects related to the microbiome. Here, we present evidence that SCFAs may also be important in disease by providing an energy source or disease-associated cue for colonizing pathogens. Like the bacterial residents of the human gut, it is likely that many of the species in the human oral microbiota have evolved to better occupy and persist in their niche. Aggregatibacter actinomycetemcomitans (Aa) is both a common colonizer of the oral cavity and has been implicated in the pathogenesis of periodontal disease. Here, we present a whole-genome phylogenetic analysis of Aa isolates from humans and nonhuman primates that revealed an ancient origin for this species and a long history of association with the Catarrhini, the lineage that includes Old World monkeys (OWM) and humans. Further genomic analysis showed a strong association with the presence of a short-chain fatty acid (SCFA) catabolism locus (atoRDAEB) in many human isolates that was absent in almost all nonhuman OWM isolates. We show that this locus was likely acquired through horizontal gene transfer. When grown under conditions that are similar to those at the subgingival site of periodontitis (anaerobic, SCFA replete), Aa strains with atoRDAEB formed robust biofilms and showed upregulation of genes involved in virulence, colonization, and immune evasion. Both an isogenic deletion mutant and nonhuman primate isolates lacking the ato locus failed to grow in a robust biofilm under these conditions, but grew well under the carbohydrate-rich conditions similar to those found above the gumline. We propose that the acquisition of the ato locus was a key evolutionary step allowing Aa to utilize SCFAs, adapt, and modulate subgingival disease.
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Kamel Oroumieh S, Naserian AA, Van Meulebroek L, De Paepe E, Valizadeh R, Vanhaecke L. Metabolic Fingerprinting of Feces from Calves, Subjected to Gram-Negative Bacterial Endotoxin. Metabolites 2021; 11:metabo11020108. [PMID: 33668448 PMCID: PMC7918135 DOI: 10.3390/metabo11020108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/03/2021] [Accepted: 02/09/2021] [Indexed: 11/23/2022] Open
Abstract
Gram-negative bacteria have a well-known impact on the disease state of neonatal calves and their mortality. This study was the first to implement untargeted metabolomics on calves’ fecal samples to unravel the effect of Gram-negative bacterial endotoxin lipopolysaccharide (LPS). In this context, calves were challenged with LPS and administered with fish oil, nanocurcumin, or dexamethasone to evaluate treatment effects. Ultra-high-performance liquid-chromatography high-resolution mass spectrometry (UHPLC-HRMS) was employed to map fecal metabolic fingerprints from the various groups before and after LPS challenge. Based on the generated fingerprints, including 9650 unique feature ions, significant separation according to LPS group was achieved through orthogonal partial least squares discriminant analysis (Q2 of 0.57 and p-value of 0.022), which allowed the selection of 37 metabolites as bacterial endotoxin markers. Tentative identification of these markers suggested that the majority belonged to the subclass of the carboxylic acid derivatives—amino acids, peptides, and analogs—and fatty amides, with these subclasses playing a role in the metabolism of steroids, histidine, glutamate, and folate. Biological interpretations supported the revealed markers’ potential to aid in disease diagnosis, whereas beneficial effects were observed following dexamethasone, fish oil, and nanocurcumin treatment.
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Affiliation(s)
- Saeid Kamel Oroumieh
- Laboratory of Chemical Analysis, Department of Veterinary Public Health and Food Safety, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
- Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad P.O. Box 91775-1163, Iran
| | - Abbas Ali Naserian
- Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad P.O. Box 91775-1163, Iran
| | - Lieven Van Meulebroek
- Laboratory of Chemical Analysis, Department of Veterinary Public Health and Food Safety, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Ellen De Paepe
- Laboratory of Chemical Analysis, Department of Veterinary Public Health and Food Safety, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Reza Valizadeh
- Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad P.O. Box 91775-1163, Iran
| | - Lynn Vanhaecke
- Laboratory of Chemical Analysis, Department of Veterinary Public Health and Food Safety, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
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Mepham JR, MacFabe DF, Boon FH, Foley KA, Cain DP, Ossenkopp KP. Examining the non-spatial pretraining effect on a water maze spatial learning task in rats treated with multiple intracerebroventricular (ICV) infusions of propionic acid: Contributions to a rodent model of ASD. Behav Brain Res 2021; 403:113140. [PMID: 33508348 DOI: 10.1016/j.bbr.2021.113140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 01/06/2023]
Abstract
Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.
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Affiliation(s)
- Jennifer R Mepham
- Graduate Program in Neuroscience, Western University, London, Ontario, Canada; The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Western University, London, Ontario, Canada
| | - Derrick F MacFabe
- Department of Psychology, Western University, London, Ontario, Canada; The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Western University, London, Ontario, Canada
| | - Francis H Boon
- Department of Psychology, Western University, London, Ontario, Canada; The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Western University, London, Ontario, Canada
| | - Kelly A Foley
- Graduate Program in Neuroscience, Western University, London, Ontario, Canada; The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Western University, London, Ontario, Canada
| | - Donald P Cain
- Graduate Program in Neuroscience, Western University, London, Ontario, Canada; Department of Psychology, Western University, London, Ontario, Canada; The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Western University, London, Ontario, Canada
| | - Klaus-Peter Ossenkopp
- Graduate Program in Neuroscience, Western University, London, Ontario, Canada; Department of Psychology, Western University, London, Ontario, Canada; The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Western University, London, Ontario, Canada.
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Abstract
Butyrate is one of the most harmful metabolic end products found in the oral cavity. Thus, it would be important to characterize the enzymes responsible for production of this metabolite to elucidate the pathogenicity of periodontogenic bacteria. Here, a spectrophotometric assay for butyryl-CoA:acetate CoA transferase activity and gas chromatography-mass spectrometry measurement of butyrate and other short chain fatty acids such as acetate, propionate, isobutyrate, and isovalerate are described.
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Affiliation(s)
- Yasuo Yoshida
- Department of Microbiology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan.
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Aliashrafi M, Nasehi M, Zarrindast MR, Joghataei MT, Zali H, Siadat SD. Association of microbiota-derived propionic acid and Alzheimer's disease; bioinformatics analysis. J Diabetes Metab Disord 2020; 19:783-804. [PMID: 33553012 PMCID: PMC7843825 DOI: 10.1007/s40200-020-00564-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/06/2020] [Accepted: 06/02/2020] [Indexed: 12/29/2022]
Abstract
PURPOSE Microbiota-derived metabolites could alter the brain tissue toward the neurodegeneration disease. This study aims to select the genes associated with Propionic acid (PPA) and compromise Alzheimer's disease (AD) to find the possible roles of PPA in AD pathogenesis. METHODS Microbiota-derived metabolites could alter the brain tissue toward the neurodegeneration disease. This study aims to select the genes associated with Propionic acid (PPA) and compromise Alzheimer's disease (AD) to find the possible roles of PPA in AD pathogenesis. RESULTS Amongst all genes associated with PPA and AD, 284 genes to be shared by searching databases and were subjected to further analysis. AD-PPA genes mainly involved in cancer, bacterial and virus infection, and neurological and non-neurological diseases. Gene Ontology and pathway analysis covered the most AD hallmark, such as amyloid formation, apoptosis, proliferation, inflammation, and immune system. Network analysis revealed hub and bottleneck genes. MCODE analysis also indicated the seed genes represented in the significant subnetworks. ICAM1 and CCND1 were the hub, bottleneck, and seed genes. CONCLUSIONS PPA interacted genes implicated in AD act through pathways initiate neuronal cell death. In sum up, AD-PPA shared genes exhibited evidence that supports the idea PPA secreted from bacteria could alter brain physiology toward the emerging AD signs. This idea needs to confirm by more future investigation in animal models.
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Affiliation(s)
- Morteza Aliashrafi
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran
- Shahid Beheshti University, Tehran, Iran
| | - Mohammad Nasehi
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran
- Cognitive and Neuroscience Research Center, Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad-Reza Zarrindast
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Neuroendocrinology, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Molecular and Cellular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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22
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Balan P, Brandt BW, Chong YS, Crielaard W, Wong ML, Lopez V, He HG, Seneviratne CJ. Subgingival Microbiota during Healthy Pregnancy and Pregnancy Gingivitis. JDR Clin Trans Res 2020; 6:343-351. [PMID: 32777190 DOI: 10.1177/2380084420948779] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Previous studies have largely explored the microbial composition and pathogenesis of pregnancy gingivitis. However, the patterns of microbial colonization during pregnancy in the absence of pregnancy gingivitis have rarely been studied. Characterization of the oral microbiome in pregnant women with healthy gingiva is an important initial step in understanding the role of the microbiome in progression to pregnancy gingivitis. OBJECTIVES In this study, we compared the oral microbiome of pregnant women without gingivitis (healthy pregnancy) with pregnant women having gingivitis and nonpregnant healthy women to understand how pregnancy modifies the oral microbiome and induces progression to pregnancy gingivitis. METHODS Subgingival plaque samples were collected from Chinese pregnant women with gingivitis (n = 10), healthy pregnant women (n = 10), and nonpregnant healthy women (n = 10). The Illumina MiSeq platform was used to perform 16S rRNA gene sequencing targeting the V4 region. RESULTS The alpha and beta diversity was significantly different between pregnant and nonpregnant women, but minimal differences were observed between pregnant women with and without gingivitis. Interestingly, the oral bacterial community showed higher abundance of pathogenic taxa during healthy pregnancy as compared with nonpregnant women despite similar gingival and plaque index scores. However, when compared with overt pregnancy gingivitis, pathogenic taxa were less abundant during healthy pregnancy. PICRUSt analysis (phylogenetic investigation of communities by reconstruction of unobserved states) also suggested no difference in the functional capabilities of the microbiome during pregnancy, irrespective of gingival disease status. However, metabolic pathways related to amino acid metabolism were significantly increased in healthy pregnant women as compared with nonpregnant women. CONCLUSION The presence of pathogenic taxa in healthy pregnancy and pregnancy gingivitis suggests that bacteria may be necessary for initiating disease development but progression to gingivitis may be influenced by the host environmental factors. More efforts are required to plan interventions aimed at sustaining health before the appearance of overt gingivitis. KNOWLEDGE TRANSFER STATEMENT The results of this study draw attention to the importance of oral health maintenance during pregnancy, as women without any prenatal oral conditions are predisposed to the risk of developing pregnancy gingivitis. Hence, it is important to incorporate comprehensive assessment of oral health in the prenatal health care schedules. Pregnant woman should be screened for oral risks, counseled on proper oral hygiene and expected oral changes, and referred for dental treatment, when necessary.
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Affiliation(s)
- P Balan
- Singapore Oral Microbiomics Inititative, National Dental Research Institute Singapore, SingHealth, Singapore.,Oral Health ACP, Duke NUS Medical School, Singapore
| | - B W Brandt
- Department of Preventive Dentistry, Academic Centre for Dentistry, Amsterdam, the Netherlands
| | - Y S Chong
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Hospital, Singapore
| | - W Crielaard
- Department of Preventive Dentistry, Academic Centre for Dentistry, Amsterdam, the Netherlands
| | - M L Wong
- Discipline of Oral Sciences, Faculty of Dentistry, National University of Singapore, Singapore
| | - V Lopez
- School of Nursing, Hubei University of Medicine, Shiyan City, China
| | - H G He
- Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - C J Seneviratne
- Singapore Oral Microbiomics Inititative, National Dental Research Institute Singapore, SingHealth, Singapore.,Oral Health ACP, Duke NUS Medical School, Singapore
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Ji H, Song N, Ren J, Li W, Zhang L, Xu B, Li H, Shen G, Li H. Systems Toxicology Approaches Reveal the Mechanisms of Hepatotoxicity Induced by Diosbulbin B in Male Mice. Chem Res Toxicol 2020; 33:1389-1402. [PMID: 32148032 DOI: 10.1021/acs.chemrestox.9b00503] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diosbulbin B (DIOB) is an effective component of air potato yam with antitumor and anti-inflammatory activities, and it is the main toxic component leading to hepatotoxicity. However, the mechanism of its hepatotoxicity remains unclear. In this study, we aimed to systematically elucidate the molecular action of DIOB on liver metabolic function through systems toxicology approaches. C57BL/6 mice were orally treated with DIOB (10, 30, 60 mg/kg) for 28 days, and the liver metabonomics and histopathology, molecular docking, mRNA expression levels, and activities of enzymes were analyzed. The results illustrated that DIOB could affect fatty acid and glucose metabolism, block the TCA cycle, and DIOB also could disorder bile acid synthesis and transport and promote the occurrence of hyperbilirubinemia. In addition, DIOB increased Cyp3a11 expression in a dose-dependent manner. Thus, these results provide new insights into the mechanism of hepatotoxicity caused by DIOB.
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Affiliation(s)
- Hainan Ji
- Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, China
| | - Naining Song
- Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, China
| | - Juan Ren
- Pneumology Department, The Rocket Army General Hospital of the PLA, Beijing, China
| | - Wentao Li
- Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, China
| | - Lei Zhang
- Asia Regenerative Medicine Ltd., Shenzhen, China
| | - Baoliang Xu
- Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, China
| | - Haishan Li
- Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, China
| | - Guolin Shen
- Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, Beijing, China
| | - Hua Li
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
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24
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Magrin GL, Di Summa F, Strauss FJ, Panahipour L, Mildner M, Magalhães Benfatti CA, Gruber R. Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells. Int J Mol Sci 2020; 21:ijms21051679. [PMID: 32121422 PMCID: PMC7084181 DOI: 10.3390/ijms21051679] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/20/2020] [Accepted: 02/27/2020] [Indexed: 12/15/2022] Open
Abstract
Short-chain fatty acids (SCFA) are bacterial metabolites that can be found in periodontal pockets. The expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) within the epithelium pocket is considered to be a key event for the selective transmigration of leucocytes towards the gingival sulcus. However, the impact of SCFA on ICAM-1 expression by oral epithelial cells remains unclear. We therefore exposed the oral squamous carcinoma cell line HSC-2, primary oral epithelial cells and human gingival fibroblasts to SCFA, namely acetate, propionate and butyrate, and stimulated with known inducers of ICAM-1 such as interleukin-1-beta (IL1β) and tumor necrosis factor-alfa (TNFα). We report here that butyrate but not acetate or propionate significantly suppressed the cytokine-induced ICAM-1 expression in HSC-2 epithelial cells and primary epithelial cells. The G-protein coupled receptor-43 (GPR43/ FFAR2) agonist but not the histone deacetylase inhibitor, trichostatin A, mimicked the butyrate effects. Butyrate also attenuated the nuclear translocation of p65 into the nucleus on HSC-2 cells. The decrease of ICAM-1 was independent of Nrf2/HO-1 signaling and phosphorylation of JNK and p38. Nevertheless, butyrate could not reverse an ongoing cytokine-induced ICAM-1 expression in HSC-2 cells. Overall, these observations suggest that butyrate can attenuate cytokine-induced ICAM-1 expression in cells with epithelial origin.
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Affiliation(s)
- Gabriel Leonardo Magrin
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Sensengasse 2a, Vienna 1090, Austria; (G.L.M.); (F.D.S.); (F.-J.S.); (L.P.)
- Center for Education and Research on Dental Implants (CEPID), Department of Dentistry, School of Dentistry, Federal University of Santa Catarina, Campus Reitor João David Ferreira Lima s/n, Florianopolis – SC 88040-900, Brazil;
| | - Francesca Di Summa
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Sensengasse 2a, Vienna 1090, Austria; (G.L.M.); (F.D.S.); (F.-J.S.); (L.P.)
| | - Franz-Josef Strauss
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Sensengasse 2a, Vienna 1090, Austria; (G.L.M.); (F.D.S.); (F.-J.S.); (L.P.)
- Department of Conservative Dentistry, School of Dentistry, University of Chile, Av. Sergio Livingstone 943, Santiago 7500566, Chile
- Clinic of Reconstructive Dentistry, University of Zurich, 8032 Zurich, Switzerland
| | - Layla Panahipour
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Sensengasse 2a, Vienna 1090, Austria; (G.L.M.); (F.D.S.); (F.-J.S.); (L.P.)
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Spitalgasse 23, Vienna 1090, Austria;
| | - Cesar Augusto Magalhães Benfatti
- Center for Education and Research on Dental Implants (CEPID), Department of Dentistry, School of Dentistry, Federal University of Santa Catarina, Campus Reitor João David Ferreira Lima s/n, Florianopolis – SC 88040-900, Brazil;
| | - Reinhard Gruber
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Sensengasse 2a, Vienna 1090, Austria; (G.L.M.); (F.D.S.); (F.-J.S.); (L.P.)
- Department of Periodontology, University Bern, Hochschulstrasse 4, 3012 Bern, Switzerland
- Correspondence:
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25
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Nyvad B, Takahashi N. Integrated hypothesis of dental caries and periodontal diseases. J Oral Microbiol 2020; 12:1710953. [PMID: 32002131 PMCID: PMC6968559 DOI: 10.1080/20002297.2019.1710953] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/24/2019] [Accepted: 12/27/2019] [Indexed: 12/14/2022] Open
Abstract
This review considers an integrated hypothesis of dental caries and periodontal diseases that builds on theoretical ecological principles. The backbone of the hypothesis is based on the dynamic stability stage of the oral microbiota, at which intrinsic (mainly saliva and gingival crevicular fluid) and bacterial (mainly metabolic) resilience factors maintain ecological dynamic stability, compatible with clinical health. However, loss of intrinsic resilience factors and/or prolonged changes in the availability of microbial metabolic substrates may shift the ecological balance of the microbiota into either saccharolytic (acidogenic) or amino acid-degrading/proteolytic (alkalinogenic) stages, depending on the nature of the predominant substrates, leading to clinical diseases. Therefore, to maintain and restore the dynamic stability of the oral microbiota, it is necessary to control the drivers of disease, such as salivary flow and influx of bacterial nutrients into the oral cavity. Contrary to conventional wisdom, excessive intake of fermentable carbohydrates may contribute to inflammation in periodontal tissues resulting from hyperglycaemia. An integrated hypothesis emphasizes that both dental caries and periodontal diseases originate in the dynamic stability stage and emerge in response to nutritional imbalances in the microbiota. Periodontal diseases may belong to the sugar driven inflammatory diseases, similar to diabetes, obesity, and cardiovascular diseases.
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Affiliation(s)
- Bente Nyvad
- Section of Dental Pathology, Operative Dentistry and Endodontics, Department of Dentistry and Oral Health, Aarhus University, Aarhus, Denmark
| | - Nobuhiro Takahashi
- Division of Oral Ecology and Biochemistry, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan
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Liu J, Wang Y, Meng H, Yu J, Lu H, Li W, Lu R, Zhao Y, Li Q, Su L. Butyrate rather than LPS subverts gingival epithelial homeostasis by downregulation of intercellular junctions and triggering pyroptosis. J Clin Periodontol 2019; 46:894-907. [PMID: 31241781 DOI: 10.1111/jcpe.13162] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 06/16/2019] [Accepted: 06/23/2019] [Indexed: 12/20/2022]
Abstract
AIM To investigate the effects of sodium butyrate (NaB) and lipopolysaccharide (LPS) on gingival epithelial barrier. MATERIAL AND METHODS We cultured human primary gingival epithelial cells and investigated the effects of NaB and LPS on gingival epithelial barrier and involved mechanisms at in vitro and in vivo levels by immunostaining, confocal microscopy, field emission scanning electron microscopy (FE-SEM), transmission electronic microscopy (TEM), transepithelial electrical resistance (TEER), FTIC-dextran flux, flow cytometry, real-time PCR and Western blot assays. RESULTS Our results showed that NaB, rather than LPS, destroyed the epithelial barrier by breaking down cell-cell junctions and triggering gingival epithelial cell pyroptosis with characteristic morphological changes, including swollen cells, large bubbles, pore formation in the plasma membrane and subcellular organelles changes. The upregulated expression of pyroptosis-related markers, caspase-3 and gasdermin-E (GSDME) contributed to this effect. Pyroptosis aroused by NaB is a pro-inflammatory cell death. Pyroptotic cell death provoked inflammatory responses by upregulation of IL-8 and MCP-1, and releasing intracellular contents into the extracellular microenvironment after pyroptotic rupture of the plasma membrane. CONCLUSIONS Our new findings indicate that butyrate is a potent destructive factor of gingival epithelial barrier and pro-inflammatory mediator, which shed a new light on our understanding of periodontitis initiation.
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Affiliation(s)
- Juan Liu
- Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yixiang Wang
- Central Laboratory, Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Huanxin Meng
- Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Jingting Yu
- Department of General Dentistry II, Peking University School and Hospital of Stomatology, Beijing, China
| | - Hongye Lu
- Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Wenjing Li
- Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Ruifang Lu
- Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yibing Zhao
- Department of Periodontology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Qiqiang Li
- Department of Periodontology, Capital Medical University School of Stomatology, Beijing, China
| | - Li Su
- Center of Medical and Health Analysis, Peking University, Beijing, China
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27
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Importance of Virulence Factors for the Persistence of Oral Bacteria in the Inflamed Gingival Crevice and in the Pathogenesis of Periodontal Disease. J Clin Med 2019; 8:jcm8091339. [PMID: 31470579 PMCID: PMC6780532 DOI: 10.3390/jcm8091339] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 08/22/2019] [Indexed: 01/18/2023] Open
Abstract
Periodontitis is a chronic inflammation that develops due to a destructive tissue response to prolonged inflammation and a disturbed homeostasis (dysbiosis) in the interplay between the microorganisms of the dental biofilm and the host. The infectious nature of the microbes associated with periodontitis is unclear, as is the role of specific bacterial species and virulence factors that interfere with the host defense and tissue repair. This review highlights the impact of classical virulence factors, such as exotoxins, endotoxins, fimbriae and capsule, but also aims to emphasize the often-neglected cascade of metabolic products (e.g., those generated by anaerobic and proteolytic metabolism) that are produced by the bacterial phenotypes that survive and thrive in deep, inflamed periodontal pockets. This metabolic activity of the microbes aggravates the inflammatory response from a low-grade physiologic (homeostatic) inflammation (i.e., gingivitis) into more destructive or tissue remodeling processes in periodontitis. That bacteria associated with periodontitis are linked with a number of systemic diseases of importance in clinical medicine is highlighted and exemplified with rheumatoid arthritis, The unclear significance of a number of potential "virulence factors" that contribute to the pathogenicity of specific bacterial species in the complex biofilm-host interaction clinically is discussed in this review.
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28
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Zeller I, Malovichko MV, Hurst HE, Renaud DE, Scott DA. Cigarette smoke reduces short chain fatty acid production by a Porphyromonas gingivalis clinical isolate. J Periodontal Res 2019; 54:566-571. [PMID: 30982987 PMCID: PMC6776670 DOI: 10.1111/jre.12660] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 02/13/2019] [Accepted: 03/18/2019] [Indexed: 01/13/2023]
Abstract
Objectives We hypothesized that short chain fatty acid (SCFA) production by oral pathogens is suppressed by exposure to cigarette smoke extract (CSE). Background Tobacco smoking is a major risk factor for plaque‐induced periodontal diseases. Despite increased disease susceptibility, overt oral inflammation is suppressed in smokers, presenting a diagnostic conundrum. Bacterial‐derived SCFAs can penetrate into oral tissues where they influence multiple components of immune and healing responses. Indeed, the SCFA burden has been correlated with the inflammatory condition of the gingiva. However, the influence of cigarette consumption on SCFA production is unknown. Methods GC/MS was employed to monitor the production of several SCFAs (propionic acid, isobutyric acid, butyric acid, and isovaleric acid) by representative anaerobic oral pathogens (Filifactor alocis 35896, Fusobacterium nucleatum 25586, Porphyromonas gingivalis 33277) that were exposed, or not, to a physiologically relevant dose of CSE (2000 ng/ml nicotine equivalents) generated from 3R4F reference cigarettes. Results The growth of all three bacterial species was unaffected by CSE. The capacity to produce SCFAs by these bacteria was highly varied. F alocis produced the highest concentration of a specific SCFA (butyrate); P gingivalis provided the most robust overall SCFA signal, while F alocis and F nucleatum did not release detectable levels of isobutyrate or isovalerate. As P gingivalis 33277 was the broadest SCFA producer, three low‐passage clinical isolates (10208C, 5607, and 10512) were also examined. Compared to unconditioned microbes, reduced SCFA release was apparent in CSE‐exposed low‐passage clinical isolates of P gingivalis which reached significance for one of the three isolates (propionic, isobutyric, butyric, and isovaleric acids, all P < 0.05). Conclusions There is high disparity in the SCFA profiles of variant chronic periodontitis‐associated bacteria, while CSE exposure reduces SCFA production by a specific clinical strain of P gingivalis. If the latter phenomenon occurs in vivo, a reduced SCFA burden may help explain the reduced vascular response to dental plaque in tobacco smokers.
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Affiliation(s)
- Iris Zeller
- Departments of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, Kentucky
| | - Marina V Malovichko
- University of Louisville Superfund Research Center and Envirome Institute, University of Louisville, Louisville, Kentucky.,American Heart Association Tobacco Regulatory Science and Addiction Center, University of Louisville, Louisville, Kentucky
| | - Harrell E Hurst
- Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
| | - Diane E Renaud
- Departments of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, Kentucky
| | - David A Scott
- Departments of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, Kentucky
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29
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Impaired Spatial Cognition in Adult Rats Treated with Multiple Intracerebroventricular (ICV) Infusions of the Enteric Bacterial Metabolite, Propionic Acid, and Return to Baseline After 1 Week of No Treatment: Contribution to a Rodent Model of ASD. Neurotox Res 2019; 35:823-837. [DOI: 10.1007/s12640-019-0002-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/23/2018] [Accepted: 01/15/2019] [Indexed: 02/07/2023]
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30
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Jiang M, Li Z, Zhu G. The role of autophagy in the pathogenesis of periodontal disease. Oral Dis 2019; 26:259-269. [PMID: 30674085 DOI: 10.1111/odi.13045] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 01/13/2019] [Accepted: 01/16/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Ming Jiang
- Department of Stomatology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology Wuhan China
| | - Zhuoneng Li
- Centers for Disease Control and Prevention of Wuhan Wuhan China
| | - Guangxun Zhu
- Department of Stomatology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology Wuhan China
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Unravelling the Interplay between Extracellular Acidosis and Immune Cells. Mediators Inflamm 2018; 2018:1218297. [PMID: 30692870 PMCID: PMC6332927 DOI: 10.1155/2018/1218297] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 11/28/2018] [Indexed: 01/18/2023] Open
Abstract
The development of an acidic tissue environment is a hallmark of a variety of inflammatory processes and solid tumors. However, little attention has been paid so far to analyze the influence exerted by extracellular pH on the immune response. Tissue acidosis (pH 6.0 to 7.0) is usually associated with the course of infectious processes in peripheral tissues. Moreover, it represents a prominent feature of solid tumors. In fact, values of pH ranging from 5.7 to 7.0 are usually found in a number of solid tumors such as breast cancer, brain tumors, sarcomas, malignant melanoma, squamous cell carcinomas, and adenocarcinomas. Both the innate and adaptive arms of the immune response appear to be finely regulated by extracellular acidosis in the range of pH values found at inflammatory sites and tumors. Low pH has been shown to delay neutrophil apoptosis, promoting their differentiation into a proangiogenic profile. Acting on monocytes and macrophages, it induces the activation of the inflammasome and the production of IL-1β, while the exposure of conventional dendritic cells to low pH promotes the acquisition of a mature phenotype. Overall, these observations suggest that high concentrations of protons could be recognized by innate immune cells as a danger-associated molecular pattern (DAMP). On the other hand, by acting on T lymphocytes, low pH has been shown to suppress the cytotoxic response mediated by CD8+ T cells as well as the production of IFN-γ by TH1 cells. Interestingly, modulation of tumor microenvironment acidity has been shown to be able not only to reverse anergy in human and mouse tumor-infiltrating T lymphocytes but also to improve the antitumor immune response induced by checkpoint inhibitors. Here, we provide an integrated view of the influence exerted by low pH on immune cells and discuss its implications in the immune response against infectious agents and tumor cells.
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Chang MC, Chen YJ, Lian YC, Chang BE, Huang CC, Huang WL, Pan YH, Jeng JH. Butyrate Stimulates Histone H3 Acetylation, 8-Isoprostane Production, RANKL Expression, and Regulated Osteoprotegerin Expression/Secretion in MG-63 Osteoblastic Cells. Int J Mol Sci 2018; 19:4071. [PMID: 30562925 PMCID: PMC6321057 DOI: 10.3390/ijms19124071] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 12/13/2018] [Accepted: 12/14/2018] [Indexed: 12/31/2022] Open
Abstract
Butyric acid as a histone deacetylase (HDAC) inhibitor is produced by a number of periodontal and root canal microorganisms (such as Porphyromonas, Fusobacterium, etc.). Butyric acid may affect the biological activities of periodontal/periapical cells such as osteoblasts, periodontal ligament cells, etc., and thus affect periodontal/periapical tissue destruction and healing. The purposes of this study were to study the toxic effects of butyrate on the matrix and mineralization marker expression in MG-63 osteoblasts. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cellular apoptosis and necrosis were analyzed by propidium iodide/annexin V flow cytometry. The protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) were analyzed by Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). OPG, soluble RANKL (sRANKL), 8-isoprostane, pro-collagen I, matrix metalloproteinase-2 (MMP-2), osteonectin (SPARC), osteocalcin and osteopontin (OPN) secretion into culture medium were measured by enzyme-linked immunosorbant assay. Alkaline phosphatase (ALP) activity was checked by ALP staining. Histone H3 acetylation levels were evaluated by immunofluorescent staining (IF) and Western blot. We found that butyrate activated the histone H3 acetylation of MG-63 cells. Exposure of MG-63 cells to butyrate partly decreased cell viability with no marked increase in apoptosis and necrosis. Twenty-four hours of exposure to butyrate stimulated RANKL protein expression, whereas it inhibited OPG protein expression. Butyrate also inhibited the secretion of OPG in MG-63 cells, whereas the sRANKL level was below the detection limit. However, 3 days of exposure to butyrate (1 to 8 mM) or other HDAC inhibitors such as phenylbutyrate, valproic acid and trichostatin stimulated OPG secretion. Butyrate stimulated 8-isoprostane, MMP-2 and OPN secretion, but not procollagen I, or osteocalcin in MG-63 cells. Exposure to butyrate (2⁻4 mM) for 3 days markedly stimulated osteonectin secretion and ALP activity. In conclusion, higher concentrations of butyric acid generated by periodontal and root canal microorganisms may potentially induce bone destruction and impair bone repair by the alteration of OPG/RANKL expression/secretion, 8-isoprostane, MMP-2 and OPN secretion, and affect cell viability. However, lower concentrations of butyrate (1⁻4 mM) may stimulate ALP, osteonectin and OPG. These effects are possibly related to increased histone acetylation. These events are important in the pathogenesis and repair of periodontal and periapical destruction.
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Grants
- NSC102-2314-B-255-003-MY2, NSC102-2628-B-255-001-MY3, NSC101-2320-B-255-002, NSC-100-2314-B-002-094, NSC-101-2320- B-255-002, MOST104-2314-B-255-010-MY3, MOST106-2314-B-002-034-MY2, and MOST106- 2314-B-002-033-MY2 Ministry of Science and Technology, Taiwan
- CMRPF1H0061, CMRPF1F0071, CMRPF1G0101, CMRPF1G0102, CMRPF3E0021, CMRPF3E0022, CMRPF3E0023, NMRPF3C0091, NMRPF3C0061, CMRPG1B0031, CMRPF170053, NMRPF370033, CMRPF3E0021, NMRPF3B0071, NMRPF3E0041, NMRPF3E0042, NMRPF3E0043, NMRPF3C0093, NMRPF3H0071, NMRPF3H0 Chang Gung Memorial Hospital
- NTUH 101-001937, NTUH102-002259, NTUH101-S1862 & NTUH102-S2180, NTUH103-S2368, NTUH104-S2658, NTUH106-S3467, NTUH106-UN-001 National Taiwan University Hospital
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Affiliation(s)
- Mei-Chi Chang
- Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan 333, Taiwan.
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei Branch, 6th Floor, 199, Tung-Hwa North Road, Taipei 105, Taiwan.
| | - Yunn-Jy Chen
- School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei 100, Taiwan.
| | - Yun-Chia Lian
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei Branch, 6th Floor, 199, Tung-Hwa North Road, Taipei 105, Taiwan.
| | - Bei-En Chang
- Graduate Institute of Oral Biology, National Taiwan University Medical College, Taipei 100, Taiwan.
| | - Chih-Chia Huang
- Department of Dentistry, Cardinal Tien Hospital, New Taipei City 234, Taiwan.
| | - Wei-Ling Huang
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei Branch, 6th Floor, 199, Tung-Hwa North Road, Taipei 105, Taiwan.
| | - Yu-Hwa Pan
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei Branch, 6th Floor, 199, Tung-Hwa North Road, Taipei 105, Taiwan.
- Graduate Department of Craniofacial Dentistry, Chang-Gung University Medical College, Taoyuan 333, Taiwan.
| | - Jiiang-Huei Jeng
- School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei 100, Taiwan.
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Ramirez-Mora T, Retana-Lobo C, Valle-Bourrouet G. Biochemical characterization of extracellular polymeric substances from endodontic biofilms. PLoS One 2018; 13:e0204081. [PMID: 30457998 PMCID: PMC6245677 DOI: 10.1371/journal.pone.0204081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 11/02/2018] [Indexed: 11/20/2022] Open
Abstract
Apical periodontitis is frequently associated with the presence of bacteria biofilm, which has an indisputable impact on the prognosis of endodontic therapy due to the high resistance to adverse environmental conditions, chemicals, and antibiotic therapy that characterize bacteria within biofilm. The biofilm matrix acts as a protective shield over the encased microorganisms. The aim of this investigation was to identify the main biochemical components of biofilm matrix from endodontic mono- and dual-species biofilms. Enterococcus faecalis and Actinomyces naeslundii were cultured as mono- and dual-species biofilms for 14 days. Crude extracellular polymeric substances (EPSs) from biofilm matrices were extracted using chemical and physical methods. High-performance liquid chromatography, gas chromatography, and mass spectrometry were used to determine the carbohydrate, protein, and fatty acid components. Chemical analysis of the biofilm matrices revealed that they were mainly composed of stachyose, maltose, and mannose carbohydrates. The protein profile in all biofilm samples showed abundant oxidoreductases and chaperone proteins and some virulence- associated proteins mainly located in the membrane surface. High percentages of saturated and monounsaturated fatty acids were identified in all biofilm matrices, with a major prevalence of palmitic, stearic, and oleic acids. Based on the results, it was possible to obtain for the first time a general overview of the biochemical profile of endodontic biofilm matrices.
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Affiliation(s)
- Tatiana Ramirez-Mora
- Section of Endodontics, Restorative Department, Faculty of Dentistry, University of Costa Rica, Montes de Oca, San José, Costa Rica
- * E-mail:
| | - Cristina Retana-Lobo
- Section of Endodontics, Restorative Department, Faculty of Dentistry, University of Costa Rica, Montes de Oca, San José, Costa Rica
| | - Grettel Valle-Bourrouet
- Inorganic Chemistry Department, Chemistry Faculty, University of Costa Rica, Montes de Oca, San José, Costa Rica
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The making of a miscreant: tobacco smoke and the creation of pathogen-rich biofilms. NPJ Biofilms Microbiomes 2017; 3:26. [PMID: 29081982 PMCID: PMC5655325 DOI: 10.1038/s41522-017-0033-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 08/29/2017] [Accepted: 09/25/2017] [Indexed: 02/03/2023] Open
Abstract
We have previously reported that oral biofilms in clinically healthy smokers are pathogen-rich, and that this enrichment occurs within 24 h of biofilm formation. The present investigation aimed to identify a mechanism by which smoking creates this altered community structure. By combining in vitro microbial–mucosal interface models of commensal (consisting of Streptococcus oralis, Streptococcus sanguis, Streptococcus mitis, Actinomyces naeslundii, Neisseria mucosa and Veillonella parvula) and pathogen-rich (comprising S.oralis, S.sanguis, S.mitis, A.naeslundii, N.mucosa and V.parvula, Fusobacterium nucleatum, Porphyromonas gingivalis, Filifactor alocis, Dialister pneumosintes, Selenonomas sputigena, Selenominas noxia, Catonella morbi, Parvimonas micra and Tannerella forsythia) communities with metatranscriptomics, targeted proteomics and fluorescent microscopy, we demonstrate that smoke exposure significantly downregulates essential metabolic functions within commensal biofilms, while significantly increasing expression of virulence genes, notably lipopolysaccharide (LPS), flagella and capsule synthesis. By contrast, in pathogen-rich biofilms several metabolic pathways were over-expressed in response to smoke exposure. Under smoke-rich conditions, epithelial cells mounted an early and amplified pro-inflammatory and oxidative stress response to these virulence-enhanced commensal biofilms, and a muted early response to pathogen-rich biofilms. Commensal biofilms also demonstrated early and widespread cell death. Similar results were observed when smoke-free epithelial cells were challenged with smoke-conditioned biofilms, but not vice versa. In conclusion, our data suggest that smoke-induced transcriptional shifts in commensal biofilms triggers a florid pro-inflammatory response, leading to early commensal death, which may preclude niche saturation by these beneficial organisms. The cytokine-rich, pro-oxidant, anaerobic environment sustains inflammophilic bacteria, and, in the absence of commensal antagonism, may promote the creation of pathogen-rich biofilms in smokers. Tobacco smoke inhibits the metabolism of beneficial bacteria in biofilms, while activating specific genes in pathogenic bacteria. This suggests a mechanism to explain how smoking quickly leads to the formation of damaging biofilms in the mouth and respiratory tract. Purnima Kumar and colleagues at Ohio State University, USA studied the effect of tobacco smoke on cultured biofilms used to model those that form on mucous membranes. They detected specific and varied changes in the activity of genes, proteins and metabolism that allowed pathogenic bacteria to displace beneficial “commensal” bacteria. The research suggests the transition toward pathogen-rich biofilms may contribute to the health effects of smoking by causing increased inflammation of mucous membranes and the production of damaging oxidant chemicals. Further research should investigate the chemical constituents of smoke responsible for these effects.
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Rzeznik M, Triba MN, Levy P, Jungo S, Botosoa E, Duchemann B, Le Moyec L, Bernaudin JF, Savarin P, Guez D. Identification of a discriminative metabolomic fingerprint of potential clinical relevance in saliva of patients with periodontitis using 1H nuclear magnetic resonance (NMR) spectroscopy. PLoS One 2017; 12:e0182767. [PMID: 28837579 PMCID: PMC5570357 DOI: 10.1371/journal.pone.0182767] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 07/24/2017] [Indexed: 12/31/2022] Open
Abstract
Periodontitis is characterized by the loss of the supporting tissues of the teeth in an inflammatory-infectious context. The diagnosis relies on clinical and X-ray examination. Unfortunately, clinical signs of tissue destruction occur late in the disease progression. Therefore, it is mandatory to identify reliable biomarkers to facilitate a better and earlier management of this disease. To this end, saliva represents a promising fluid for identification of biomarkers as metabolomic fingerprints. The present study used high-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical analysis to identify the metabolic signature of active periodontitis. The metabolome of stimulated saliva of 26 patients with generalized periodontitis (18 chronic and 8 aggressive) was compared to that of 25 healthy controls. Principal Components Analysis (PCA), performed with clinical variables, indicated that the patient population was homogeneous, demonstrating a strong correlation between the clinical and the radiological variables used to assess the loss of periodontal tissues and criteria of active disease. Orthogonal Projection to Latent Structure (OPLS) analysis showed that patients with periodontitis can be discriminated from controls on the basis of metabolite concentrations in saliva with satisfactory explained variance (R2X = 0.81 and R2Y = 0.61) and predictability (Q2Y = 0.49, CV-AUROC = 0.94). Interestingly, this discrimination was irrespective of the type of generalized periodontitis, i.e. chronic or aggressive. Among the main discriminating metabolites were short chain fatty acids as butyrate, observed in higher concentrations, and lactate, γ-amino-butyrate, methanol, and threonine observed in lower concentrations in periodontitis. The association of lactate, GABA, and butyrate to generate an aggregated variable reached the best positive predictive value for diagnosis of periodontitis. In conclusion, this pilot study showed that 1H-NMR spectroscopy analysis of saliva could differentiate patients with periodontitis from controls. Therefore, this simple, robust, non-invasive method, may offer a significant help for early diagnosis and follow-up of periodontitis.
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Affiliation(s)
- Matthias Rzeznik
- Paris 13 University, Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France.,APHP, Department of Periodontology, Bretonneau Hospital, Paris-Descartes University, Paris, France
| | - Mohamed Nawfal Triba
- Paris 13 University, Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| | - Pierre Levy
- APHP, Department of Public Health, Tenon Hospital, Paris, France.,UMR-S1136 (EPAR team), INSERM UPMC, Sorbonne Universités, Paris, France
| | - Sébastien Jungo
- APHP, Department of Periodontology, Bretonneau Hospital, Paris-Descartes University, Paris, France
| | - Eliot Botosoa
- Paris 13 University, Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| | - Boris Duchemann
- Paris 13 University, Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France.,APHP, Department of Pneumology, Avicenne Hospital, Bobigny, France
| | | | - Jean-François Bernaudin
- APHP, Department of Pneumology, Avicenne Hospital, Bobigny, France.,UPMC Paris 6, Sorbonne Universités, Paris, France.,Paris 13 University, Sorbonne Paris Cité, EA2363, Bobigny, France
| | - Philippe Savarin
- Paris 13 University, Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| | - Dominique Guez
- APHP, Department of Periodontology, Bretonneau Hospital, Paris-Descartes University, Paris, France
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Kuru BE, Laleman I, Yalnızoğlu T, Kuru L, Teughels W. The Influence of a Bifidobacterium animalis Probiotic on Gingival Health: A Randomized Controlled Clinical Trial. J Periodontol 2017; 88:1115-1123. [PMID: 28753102 DOI: 10.1902/jop.2017.170213] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND There is growing interest in the use of probiotics in periodontal therapy; however, until now, most research has focused on lactobacilli probiotics. The aim of this study is to evaluate the effect of 4-week use of yogurt supplemented with Bifidobacterium animalis subsp. lactis DN-173010 versus a placebo yogurt, followed by a 5-day non-brushing period. METHODS Individuals were included in this single-mask, randomized, controlled study if probing depth (PD) was ≤3 mm and attachment loss was ≤2 mm. After professional prophylaxis, they were randomized into two groups receiving yogurt containing either placebo or B. animalis for 28 days, followed by a 5-day non-brushing period. Outcome measures were plaque index (PI), gingival index (GI), bleeding on probing (BOP), PD, gingival crevicular fluid (GCF) volume, and total amount and concentration of interleukin (IL)-1β in GCF. These were measured at baseline, after 28 days of study product use, and subsequently after 5 days of plaque accumulation. RESULTS Fifty-one patients were analyzed. No intergroup differences could be detected before and after intake of study products. However, after plaque accumulation, significantly better results for all parameters were seen in the probiotic group compared with the control group (P <0.001): lower PI and GI, less BOP, less increase in GCF volume, and lower IL-1β total amount/concentration. CONCLUSION The use of a probiotic yogurt supplemented with B. animalis can have a positive effect on plaque accumulation and gingival inflammatory parameters after refraining from oral hygiene practices.
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Affiliation(s)
- Bahar Eren Kuru
- Department of Periodontology, School of Dentistry, Marmara University, Istanbul, Turkey.,Department of Periodontology, School of Dentistry, Yeditepe University, Istanbul, Turkey
| | - Isabelle Laleman
- Department of Oral Health Sciences, KU Leuven Dentistry, University Hospitals Leuven, Leuven, Belgium
| | - Tuğçe Yalnızoğlu
- Department of Periodontology, School of Dentistry, Marmara University, Istanbul, Turkey
| | - Leyla Kuru
- Department of Periodontology, School of Dentistry, Marmara University, Istanbul, Turkey
| | - Wim Teughels
- Department of Oral Health Sciences, KU Leuven Dentistry, University Hospitals Leuven, Leuven, Belgium
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Goodson JM, Hartman ML, Shi P, Hasturk H, Yaskell T, Vargas J, Song X, Cugini M, Barake R, Alsmadi O, Al-Mutawa S, Ariga J, Soparkar P, Behbehani J, Behbehani K. The salivary microbiome is altered in the presence of a high salivary glucose concentration. PLoS One 2017; 12:e0170437. [PMID: 28249034 PMCID: PMC5331956 DOI: 10.1371/journal.pone.0170437] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 01/04/2017] [Indexed: 01/30/2023] Open
Abstract
Background Type II diabetes (T2D) has been associated with changes in oral bacterial diversity and frequency. It is not known whether these changes are part of the etiology of T2D, or one of its effects. Methods We measured the glucose concentration, bacterial counts, and relative frequencies of 42 bacterial species in whole saliva samples from 8,173 Kuwaiti adolescents (mean age 10.00 ± 0.67 years) using DNA probe analysis. In addition, clinical data related to obesity, dental caries, and gingivitis were collected. Data were compared between adolescents with high salivary glucose (HSG; glucose concentration ≥ 1.0 mg/d, n = 175) and those with low salivary glucose (LSG, glucose concentration < 0.1 mg/dL n = 2,537). Results HSG was associated with dental caries and gingivitis in the study population. The overall salivary bacterial load in saliva decreased with increasing salivary glucose concentration. Under HSG conditions, the bacterial count for 35 (83%) of 42 species was significantly reduced, and relative bacterial frequencies in 27 species (64%) were altered, as compared with LSG conditions. These alterations were stronger predictors of high salivary glucose than measures of oral disease, obesity, sleep or fitness. Conclusions HSG was associated with a reduction in overall bacterial load and alterations to many relative bacterial frequencies in saliva when compared with LSG in samples from adolescents. We propose that hyperglycemia due to obesity and/or T2D results in HSG and subsequent acidification of the oral environment, leading to a generalized perturbation in the oral microbiome. This suggests a basis for the observation that hyperglycemia is associated with an increased risk of dental erosion, dental caries, and gingivitis. We conclude that HSG in adolescents may be predicted from salivary microbial diversity or frequency, and that the changes in the oral microbial composition seen in adolescents with developing metabolic disease may the consequence of hyperglycemia.
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Affiliation(s)
- J. Max Goodson
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
- * E-mail:
| | - Mor-Li Hartman
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Ping Shi
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Hatice Hasturk
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Tina Yaskell
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Jorel Vargas
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Xiaoqing Song
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Maryann Cugini
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Roula Barake
- The Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | | | | | - Pramod Soparkar
- Department of Applied Oral Sciences, the Forsyth Research Institute, Cambridge, Massachusetts, United States of America
| | - Jawad Behbehani
- Kuwait University, Faculty of Dentistry, Kuwait City, Kuwait
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Corrêa R, Vieira A, Sernaglia E, Lancellotti M, Vieira A, Avila-Campos M, Rodrigues H, Vinolo M. Bacterial short-chain fatty acid metabolites modulate the inflammatory response against infectious bacteria. Cell Microbiol 2017; 19. [DOI: 10.1111/cmi.12720] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/04/2017] [Accepted: 01/05/2017] [Indexed: 12/27/2022]
Affiliation(s)
- R. O. Corrêa
- Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas; Campinas São Paulo Brazil
| | - A. Vieira
- Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas; Campinas São Paulo Brazil
| | - E. M. Sernaglia
- Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas; Campinas São Paulo Brazil
| | - M. Lancellotti
- Laboratory of Biotechnology, Department of Biochemistry, Institute of Biology; University of Campinas; Campinas São Paulo Brazil
| | - A. T. Vieira
- Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences; Federal University of Minas Gerais; Belo Horizonte Minas Gerais Brazil
| | - M. J. Avila-Campos
- Anaerobe Laboratory, Department of Microbiology, Institute of Biomedical Sciences; University of São Paulo; São Paulo Brazil
| | - H. G. Rodrigues
- Laboratory of Nutrients and Tissue Repair, School of Applied Sciences; University of Campinas; Limeira São Paulo Brazil
| | - M. A. R. Vinolo
- Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology; University of Campinas; Campinas São Paulo Brazil
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Comparative metagenomics reveals taxonomically idiosyncratic yet functionally congruent communities in periodontitis. Sci Rep 2016; 6:38993. [PMID: 27991530 PMCID: PMC5172196 DOI: 10.1038/srep38993] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 11/15/2016] [Indexed: 02/07/2023] Open
Abstract
The phylogenetic characteristics of microbial communities associated with periodontitis have been well studied, however, little is known about the functional endowments of this ecosystem. The present study examined 73 microbial assemblages from 25 individuals with generalized chronic periodontitis and 25 periodontally healthy individuals using whole genome shotgun sequencing. Core metabolic networks were computed from taxa and genes identified in at least 80% of individuals in each group. 50% of genes and species identified in health formed part of the core microbiome, while the disease-associated core microbiome contained 33% of genes and only 1% of taxa. Clinically healthy sites in individuals with periodontitis were more aligned with sites with disease than with health. 68% of the health-associated metagenome was dedicated to energy utilization through oxidative pathways, while in disease; fermentation and methanogenesis were predominant energy transfer mechanisms. Expanded functionality was observed in periodontitis, with unique- or over-representation of genes encoding for fermentation, antibiotic resistance, detoxification stress, adhesion, invasion and intracellular resistance, proteolysis, quorum sensing, Type III/IV secretion systems, phages and toxins in the disease-associated core microbiome. However, different species or consortia contributed to these functions in each individual. Several genes, but not species, demonstrated robust discriminating power between health and disease.
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40
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Chang MC, Tsai YL, Liou EJW, Tang CM, Wang TM, Liu HC, Liao MW, Yeung SY, Chan CP, Jeng JH. Effect of Butyrate on Collagen Expression, Cell Viability, Cell Cycle Progression and Related Proteins Expression of MG-63 Osteoblastic Cells. PLoS One 2016; 11:e0165438. [PMID: 27893752 PMCID: PMC5125573 DOI: 10.1371/journal.pone.0165438] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 10/11/2016] [Indexed: 01/20/2023] Open
Abstract
AIMS Butyric acid is one major metabolic product generated by anaerobic Gram-negative bacteria of periodontal and root canal infection. Butyric acid affects the activity of periodontal cells such as osteoblasts. The purposes of this study were to investigate the effects of butyrate on MG-63 osteoblasts. METHODS MG-63 cells were exposed to butyrate and cell viability was estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mRNA and protein expression of type I collagen and cell cycle-related proteins were measured by reverse-transcriptase polymerase chain reaction (RT-PCR), western blotting or immunofluorescent staining. Cellular production of reactive oxygen species (ROS) was analyzed by 2',7'-dichlorofluorescein (DCF) fluorescence flow cytometry. RESULTS Exposure to butyrate suppressed cell proliferation, and induced G2/M (8 and 16 mM) cell cycle arrest of MG-63 cells. Some cell apoptosis was noted. The mRNA expression of cdc2 and cyclin-B1 decreased after exposure to butyrate. The protein expression of type I collagen, cdc2 and cyclin B1 were decreased, whereas the expression of p21, p27 and p57 was stimulated. Under the treatment of butyrate, ROS production in MG-63 cells markedly increased. CONCLUSIONS The secretion of butyric acid by periodontal and root canal microorganisms may inhibit bone cell growth and matrix turnover. This is possibly due to induction of cell cycle arrest and ROS generation and inhibition of collagen expression. These results suggest the involvement of butyric acid in the pathogenesis of periodontal and periapical tissue destruction by impairing bone healing responses.
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Affiliation(s)
- Mei-Chi Chang
- Biomedical Science Team, Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan City, Taiwan
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yi-Ling Tsai
- Graduate Institute of Clinical Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan
| | | | - Chia-Mei Tang
- Graduate Institute of Clinical Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan
| | - Tong-Mei Wang
- Graduate Institute of Clinical Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan
| | | | - Ming-Wei Liao
- Graduate Institute of Clinical Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan
| | - Sin-Yuet Yeung
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chiu-Po Chan
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Jiiang-Huei Jeng
- Graduate Institute of Clinical Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan
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Izumigawa M, Hasegawa Y, Ikai R, Horie T, Inomata M, Into T, Kitai N, Yoshimura F, Murakami Y. Separation of novel phosphoproteins of Porphyromonas gingivalis using phosphate-affinity chromatography. Microbiol Immunol 2016; 60:702-707. [PMID: 27663267 DOI: 10.1111/1348-0421.12441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 09/06/2016] [Accepted: 09/19/2016] [Indexed: 11/28/2022]
Abstract
Phosphorylation of serine, threonine and tyrosine is a central mechanism for regulating the structure and function of proteins in both eukaryotes and prokaryotes. However, the action of phosphorylated proteins present in Porphyromonas gingivalis, a major periodontopathogen, is not fully understood. Here, six novel phosphoproteins that possess metabolic activities were identified, namely PGN_0004, PGN_0375, PGN_0500, PGN_0724, PGN_0733 and PGN_0880, having been separated by phosphate-affinity chromatography. The identified proteins were detectable by immunoblotting specific to phosphorylated Ser (P-Ser), P-Thr, and/or P-Tyr. These results imply that novel phosphorylated proteins might play an important role for regulation of metabolism in P. gingivalis.
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Affiliation(s)
- Masashi Izumigawa
- Department of Oral Microbiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
| | - Yoshiaki Hasegawa
- Department of Microbiology, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Aichi, Japan.
| | - Ryota Ikai
- Department of Community Oral Health, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
| | - Toshi Horie
- Department of Oral Microbiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
| | - Megumi Inomata
- Department of Oral Microbiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
| | - Takeshi Into
- Department of Oral Microbiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
| | - Noriyuki Kitai
- Department of Orthodontic, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
| | - Fuminobu Yoshimura
- Department of Microbiology, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Aichi, Japan
| | - Yukitaka Murakami
- Department of Oral Microbiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan
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Evans M, Murofushi T, Tsuda H, Mikami Y, Zhao N, Ochiai K, Kurita-Ochiai T, Yamamoto M, Otsuka K, Suzuki N. Combined effects of starvation and butyrate on autophagy-dependent gingival epithelial cell death. J Periodontal Res 2016; 52:522-531. [DOI: 10.1111/jre.12418] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2016] [Indexed: 12/15/2022]
Affiliation(s)
- M. Evans
- Nihon University School of Dentistry; Tokyo Japan
| | - T. Murofushi
- Department of Biochemistry; Nihon University School of Dentistry; Tokyo Japan
| | - H. Tsuda
- Department of Biochemistry; Nihon University School of Dentistry; Tokyo Japan
- Division of Functional Morphology; Dental Research Center; Nihon University School of Dentistry; Tokyo Japan
| | - Y. Mikami
- Division of Microscopic Anatomy; Niigata University Graduate School of Medical and Dental Sciences; Niigata Japan
| | - N. Zhao
- Department of Biochemistry; Nihon University School of Dentistry; Tokyo Japan
- Department of Endodontics; School of Dentistry; Shandong University; Jinan Shandong China
| | - K. Ochiai
- Department of Oral Microbiology; Nihon University School of Dentistry; Tokyo Japan
- Divisions of Immunology and Pathobiology; Dental Research Center; Nihon University School of Dentistry; Tokyo Japan
| | - T. Kurita-Ochiai
- Department of Microbiology and Immunology; Nihon University School of Dentistry at Matsudo; Chiba Japan
| | - M. Yamamoto
- Department of Microbiology and Immunology; Nihon University School of Dentistry at Matsudo; Chiba Japan
| | - K. Otsuka
- Department of Biochemistry; Nihon University School of Dentistry; Tokyo Japan
- Division of Functional Morphology; Dental Research Center; Nihon University School of Dentistry; Tokyo Japan
| | - N. Suzuki
- Department of Biochemistry; Nihon University School of Dentistry; Tokyo Japan
- Division of Functional Morphology; Dental Research Center; Nihon University School of Dentistry; Tokyo Japan
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Levine M, Lohinai Z, Teles RP. Low Biofilm Lysine Content in Refractory Chronic Periodontitis. J Periodontol 2016; 88:181-189. [PMID: 27620654 DOI: 10.1902/jop.2016.160302] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Chronic periodontitis is controlled without antibiotics by scaling and root planing (SRP) to remove dental biofilm. It has been previously reported that the epithelial barrier to bacterial proinflammatory products is impaired when biofilm lysine falls below the minimal content of normal blood plasma. Aims were to examine whether being refractory and requiring antibiotics to supplement SRP were associated with low biofilm lysine contents. METHODS Sixteen patients with periodontitis and six periodontally healthy volunteers (HVs) (respective mean ages: 57 ± 6 and 36 ± 8 years) were examined. Patients with periodontitis received SRP and surgery, and HVs received prophylaxis. At quarterly maintenance or prophylaxis visits during the subsequent year, therapeutic response was good (GR, n = 9) or poor (PR, n = 7; including five cigarette smokers). Biofilm cadaverine, lysine, and other amino acid (AA) contents were determined by liquid chromatography. Cadaverine mole fraction of lysine plus cadaverine (CF) indicated biofilm lysine decarboxylase activity. RESULTS Biofilm lysine was 0.19 ± 0.10 and 0.20 ± 0.09 μmol/mg in GRs and HVs, but 0.07 ± 0.03 μmol/mg in PRs (Kruskal-Wallis: P <0.01). All AAs were depleted in biofilm from smokers, but only lysine was depleted in biofilm from non-smokers. CF was inversely associated with clinical attachment level (CAL) at baseline before therapy in all patients (R2 = 0.28, P <0.01) and with CAL change after therapy in GR (R2 = 0.49, P <0.05). Lysine and cadaverine contents discriminated PRs from GRs and HVs (Wilks' λ = 0.499, P <0.012). CONCLUSIONS Refractory responses requiring antibiotic therapy result from smoking and/or microbial infections that starve the biofilm and epithelial attachment of lysine. Biofilm CF is associated with periodontitis severity pretherapy and extent of therapeutic response post-therapy.
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Affiliation(s)
- Martin Levine
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Zsolt Lohinai
- Department of Conservative Dentistry, Semmelweis University, Budapest, Hungary
| | - Ricardo P Teles
- Department of Periodontology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Takahashi N, Nyvad B. Ecological Hypothesis of Dentin and Root Caries. Caries Res 2016; 50:422-31. [PMID: 27458979 DOI: 10.1159/000447309] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/31/2016] [Indexed: 11/19/2022] Open
Abstract
Recent advances regarding the caries process indicate that ecological phenomena induced by bacterial acid production tilt the de- and remineralization balance of the dental hard tissues towards demineralization through bacterial acid-induced adaptation and selection within the microbiota - from the dynamic stability stage to the aciduric stage via the acidogenic stage [Takahashi and Nyvad, 2008]. Dentin and root caries can also be partly explained by this hypothesis; however, the fact that these tissues contain a considerable amount of organic material suggests that protein degradation is involved in caries formation. In this review, we compiled relevant histological, biochemical, and microbiological information about dentin/root caries and refined the hypothesis by adding degradation of the organic matrix (the proteolytic stage) to the abovementioned stages. Bacterial acidification not only induces demineralization and exposure of the organic matrix in dentin/root surfaces but also activation of dentin-embedded and salivary matrix metalloproteinases and cathepsins. These phenomena initiate degradation of the demineralized organic matrix in dentin/root surfaces. While a bacterial involvement has never been confirmed in the initial degradation of organic material, the detection of proteolytic/amino acid-degrading bacteria and bacterial metabolites in dentin and root caries suggests a bacterial digestion and metabolism of partly degraded matrix. Moreover, bacterial metabolites might induce pulpitis as an inflammatory/immunomodulatory factor. Root and dentin surfaces are always at risk of becoming demineralized in the oral cavity, and exposed organic materials can be degraded by host-derived proteases contained in saliva and dentin itself. New approaches to the prevention and treatment of root/dentin caries are required.
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Affiliation(s)
- Nobuhiro Takahashi
- Division of Oral Ecology and Biochemistry, Tohoku University Graduate School of Dentistry, Sendai, Japan
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Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, Van't Klooster G. Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol 2016; 82:139-48. [PMID: 26852904 PMCID: PMC4917808 DOI: 10.1111/bcp.12900] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 01/21/2016] [Accepted: 02/03/2016] [Indexed: 01/14/2023] Open
Abstract
Aims Free fatty acids (FFA) can act as direct signalling molecules through activation of several membrane‐bound G‐protein coupled receptors. The FFA2 receptor (known as GPR43) is activated by short chain fatty acids (SCFA) such as acetate and has been shown to play a major role in SCFA‐induced neutrophil activation and migration and to contribute in the development and control of inflammation. GLPG0974 is a potent and selective antagonist of the human FFA2. The main objectives of the two phase 1 trials were to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG0974. Methods Two consecutive randomized, double‐blind, placebo‐controlled, single centre trials in healthy subjects were performed. In the first, GLPG0974 was administered as single doses up to 250 mg and in the second, multiple daily doses up to 400 mg for 14 days were evaluated. Non‐compartmental analysis was used to determine GLPG0974 pharmacokinetics while target engagement was investigated through the inhibition of neutrophils in acetate‐simulated whole blood samples using surface expression of CD11b activated epitope as a marker of neutrophil activation. Results The investigation of safety/tolerability and pharmacokinetics in the early development phase showed that GLPG0974 was safe and well tolerated up to a daily dose of 400 mg. GLPG0974 showed good and dose proportional exposure up to 400 mg daily as well as a substantial and sustained inhibition of acetate‐stimulated neutrophil activation. Conclusion Based on these results, a proof‐of‐concept study was initiated to evaluate the safety, tolerability and efficacy of GLPG0974 in patients with mild to moderate ulcerative colitis.
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Richards L, Li M, van Esch B, Garssen J, Folkerts G. The effects of short-chain fatty acids on the cardiovascular system. PHARMANUTRITION 2016. [DOI: 10.1016/j.phanu.2016.02.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Yoshida Y, Sato M, Nagano K, Hasegawa Y, Okamoto T, Yoshimura F. Production of 4-hydroxybutyrate from succinate semialdehyde in butyrate biosynthesis in Porphyromonas gingivalis. Biochim Biophys Acta Gen Subj 2015; 1850:2582-91. [DOI: 10.1016/j.bbagen.2015.09.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 09/04/2015] [Accepted: 09/24/2015] [Indexed: 01/14/2023]
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Szafrański SP, Deng ZL, Tomasch J, Jarek M, Bhuju S, Meisinger C, Kühnisch J, Sztajer H, Wagner-Döbler I. Functional biomarkers for chronic periodontitis and insights into the roles of Prevotella nigrescens and Fusobacterium nucleatum; a metatranscriptome analysis. NPJ Biofilms Microbiomes 2015; 1:15017. [PMID: 28721234 PMCID: PMC5515211 DOI: 10.1038/npjbiofilms.2015.17] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 08/07/2015] [Accepted: 08/20/2015] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND/OBJECTIVES Periodontitis is the most prevalent inflammatory disease worldwide and is caused by a dysbiotic subgingival biofilm. Here we used metatranscriptomics to determine the functional shift from health to periodontitis, the response of individual species to dysbiosis and to discover biomarkers. METHODS Sixteen individuals were studied, from which six were diagnosed with chronic periodontitis. Illumina sequencing of the total messenger RNA (mRNA) yielded ~42 million reads per sample. A total of 324 human oral taxon phylotypes and 366,055 open reading frames from the HOMD database reference genomes were detected. RESULTS The transcriptionally active community shifted from Bacilli and Actinobacteria in health to Bacteroidia, Deltaproteobacteria, Spirochaetes and Synergistetes in periodontitis. Clusters of orthologous groups (COGs) related to carbohydrate transport and catabolism dominated in health, whereas protein degradation and amino acid catabolism dominated in disease. The LEfSe, random forest and support vector machine methods were applied to the 2,000 most highly expressed genes and discovered the three best functional biomarkers, namely haem binding protein HmuY from Porphyromonas gingivalis, flagellar filament core protein FlaB3 from Treponema denticola, and repeat protein of unknown function from Filifactor alocis. They predicted the diagnosis correctly for 14 from 16 individuals, and when applied to an independent study misclassified one out of six subjects only. Prevotella nigrescens shifted from commensalism to virulence by upregulating the expression of metalloproteases and the haem transporter. Expression of genes for the synthesis of the cytotoxic short-chain fatty acid butyrate was observed by Fusobacterium nucleatum under all conditions. Four additional species contributed to butyrate synthesis in periodontitis and they used an additional pathway. CONCLUSION Gene biomarkers of periodontitis are highly predictive. The pro-inflammatory role of F. nucelatum is not related to butyrate synthesis.
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Affiliation(s)
- Szymon P Szafrański
- Research Group Microbial Communication, Department of Molecular Infection Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Zhi-Luo Deng
- Research Group Microbial Communication, Department of Molecular Infection Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Jürgen Tomasch
- Research Group Microbial Communication, Department of Molecular Infection Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Michael Jarek
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Sabin Bhuju
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Christa Meisinger
- Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Jan Kühnisch
- Department of Conservative Dentistry, Ludwig-Maximilians-University, München, Germany
| | - Helena Sztajer
- Research Group Microbial Communication, Department of Molecular Infection Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Irene Wagner-Döbler
- Research Group Microbial Communication, Department of Molecular Infection Biology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
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Abstract
Recent advances in molecular biology have facilitated analyses of the oral microbiome ("Who are they?"); however, its functions (e.g., metabolic activities) are poorly understood ("What are they doing?"). This review aims to summarize our current understanding of the metabolism of the oral microbiome. Saccharolytic bacteria-including Streptococcus, Actinomyces, and Lactobacillus species-degrade carbohydrates into organic acids via the Embden-Meyerhof-Parnas pathway and several of its branch pathways, resulting in dental caries, while alkalization and acid neutralization via the arginine deiminase system, urease, and so on, counteract acidification. Proteolytic/amino acid-degrading bacteria, including Prevotella and Porphyromonas species, break down proteins and peptides into amino acids and degrade them further via specific pathways to produce short-chain fatty acids, ammonia, sulfur compounds, and indole/skatole, which act as virulent and modifying factors in periodontitis and oral malodor. Furthermore, it is suggested that ethanol-derived acetaldehyde can cause oral cancer, while nitrate-derived nitrite can aid caries prevention and systemic health. Microbial metabolic activity is influenced by the oral environment; however, it can also modify the oral environment, enhance the pathogenicity of bacteria, and induce microbial selection to create more pathogenic microbiome. Taking a metabolomic approach to analyzing the oral microbiome is crucial to improving our understanding of the functions of the oral microbiome.
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Affiliation(s)
- N Takahashi
- Division of Oral Ecology and Biochemistry, Tohoku University Graduate School of Dentistry, Sendai, Japan
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MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. MICROBIAL ECOLOGY IN HEALTH AND DISEASE 2015; 26:28177. [PMID: 26031685 PMCID: PMC4451098 DOI: 10.3402/mehd.v26.28177] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Clinical observations suggest that gut and dietary factors transiently worsen and, in some cases, appear to improve behavioral symptoms in a subset of persons with autism spectrum disorders (ASDs), but the reason for this is unclear. Emerging evidence suggests ASDs are a family of systemic disorders of altered immunity, metabolism, and gene expression. Pre- or perinatal infection, hospitalization, or early antibiotic exposure, which may alter gut microbiota, have been suggested as potential risk factors for ASD. Can a common environmental agent link these disparate findings? This review outlines basic science and clinical evidence that enteric short-chain fatty acids (SCFAs), present in diet and also produced by opportunistic gut bacteria following fermentation of dietary carbohydrates, may be environmental triggers in ASD. Of note, propionic acid, a major SCFA produced by ASD-associated gastrointestinal bacteria (clostridia, bacteroides, desulfovibrio) and also a common food preservative, can produce reversible behavioral, electrographic, neuroinflammatory, metabolic, and epigenetic changes closely resembling those found in ASD when administered to rodents. Major effects of these SCFAs may be through the alteration of mitochondrial function via the citric acid cycle and carnitine metabolism, or the epigenetic modulation of ASD-associated genes, which may be useful clinical biomarkers. It discusses the hypothesis that ASDs are produced by pre- or post-natal alterations in intestinal microbiota in sensitive sub-populations, which may have major implications in ASD cause, diagnosis, prevention, and treatment.
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Affiliation(s)
- Derrick F MacFabe
- The Kilee Patchell-Evans Autism Research Group, Departments of Psychology (Neuroscience) and Psychiatry, Division of Developmental Disabilities, University of Western Ontario, Ontario, Canada;
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