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Cheng XY, Zou PH, Ma YM, Cai Y, Shi Q, Liu J, Luan QX. From gingiva to multiple organs in mice: The trace of Porphyromonas gingivalis via in vivo imaging. J Dent Sci 2025; 20:292-301. [PMID: 39873048 PMCID: PMC11762916 DOI: 10.1016/j.jds.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/11/2024] [Indexed: 01/30/2025] Open
Abstract
Background/purpose Periodontitis is associated with systemic health. One of the underlying mechanisms is the translocation of periodontal pathogens, among which Porphyromonas gingivalis (Pg) is the most common. Here, we aimed to illustrate the biodistribution and dynamics of Pg from gingiva to multiple organs through blood circulation. Materials and methods Pg tagged by Cyanine 7 (Cy7-Pg) was injected into the gingiva of healthy and periodontitis mice. In vivo imaging system (IVIS) was applied to monitor the distribution of Cy7-Pg in multiple organs which were isolated at serial timepoints. Polymerase chain reaction (PCR) was conducted to determine the Pg DNA copies in the gingiva, blood and organs. Cy7-Pg in the gingiva and organs was also confirmed by frozen section staining. Furthermore, to figure out whether the bacteremia derived from oral-gut axis, mice received gavage of Cy7-Pg. Then the blood and organ samples were detected in the similar way as above. Results Intra-gingival injection induced larger amounts of Cy7-Pg accumulating in the gingiva of periodontitis mice (P < 0.05) as confirmed by above three methods. Twenty minutes after injection, Pg DNA copies in the blood of periodontitis group were 36.3-fold higher than healthy group (P < 0.05). IVIS results, combined with PCR and frozen sections, demonstrated periodontitis induced longer retention with higher amounts of Cy7-Pg in the periodontitis group. Pg was enriched more significantly in the liver for the longer duration than the kidney and pancreas. Conclusion Our study showed Pg, which accumulated in the gingiva, could translocate through blood circulation to multiple organs with varied duration and amounts.
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Affiliation(s)
- Xin-Yi Cheng
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Pei-Hui Zou
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Yi-Ming Ma
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Yu Cai
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Qiao Shi
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Jia Liu
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Qing-Xian Luan
- Department of Periodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, China
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Ohno T, Kikuchi T, Suzuki Y, Goto R, Takeuchi D, Hayashi JI, Nishida E, Yamamoto G, Kondo S, Ono K, Nomoto S, Mitani A. Periodontitis promotes hepatocellular carcinoma in Stelic Animal model (STAM) mice. Sci Rep 2024; 14:17560. [PMID: 39080409 PMCID: PMC11289391 DOI: 10.1038/s41598-024-68422-7] [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: 02/24/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024] Open
Abstract
Periodontitis is a prevalent oral inflammatory disease that leads to alveolar bone loss and may exert an adverse impact on systemic health. Periodontal disease may be associated with hepatocellular carcinoma (HCC); however, the mechanism of such an association is unknown. In this study, Stelic Animal model (STAM) mice, a model of nonalcoholic steatohepatitis (NASH)-HCC, were induced to develop periodontitis and subjected to histopathological and immunological analyses. HCC progression was greater in STAM mice with experimental periodontitis compared with that in STAM mice without experimental periodontitis. Tumor necrosis factor-α (TNFα), matrix metalloproteinase-9 (MMP9), collagen 1, and angiopoietin-like protein 2 (ANGPTL2) gene expression was significantly increased in the liver of the periodontitis group. ANGPTL2 was previously reported to be involved in the pathogenesis of periodontitis, and HCC and ANGPTL2 protein tended to be more abundant in the pocket epithelium of STAM mice with experimental periodontitis than in control STAM mice. ANGPTL2 levels in the serum of STAM mice with experimental periodontitis tended to be higher than in control STAM mice. Our results indicate that ANGPTL2 is produced in chronically inflamed periodontal tissue and then travels to the liver via the bloodstream where it accumulates to promote the progression of hepatocellular carcinoma.
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Affiliation(s)
- Tasuku Ohno
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Takeshi Kikuchi
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan.
| | - Yuki Suzuki
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Ryoma Goto
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Daiki Takeuchi
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Jun-Ichiro Hayashi
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Eisaku Nishida
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Genta Yamamoto
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Shun Kondo
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Kouta Ono
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
| | - Shuji Nomoto
- Department of Surgery, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Akio Mitani
- Department of Periodontology, School of Dentistry, Aichi Gakuin University, 2-11 Suemoridori, Chikusa-ku, Nagoya, Aichi, 464-8651, Japan
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Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes 2024; 10:3. [PMID: 38233485 PMCID: PMC10794237 DOI: 10.1038/s41522-024-00476-x] [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: 04/17/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024] Open
Abstract
Oral microbiome dysbiosis mediates chronic periodontal disease, gut microbial dysbiosis, and mucosal barrier disfunction that leads to steatohepatitis via the enterohepatic circulation. Improving this dysbiosis towards health may improve liver disease. Treatment with antibiotics and probiotics have been used to modulate the microbial, immunological, and clinical landscape of periodontal disease with some success. The aim of the present investigation was to evaluate the potential for nisin, an antimicrobial peptide produced by Lactococcus lactis, to counteract the periodontitis-associated gut dysbiosis and to modulate the glycolipid-metabolism and inflammation in the liver. Periodontal pathogens, namely Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum, were administrated topically onto the oral cavity to establish polymicrobial periodontal disease in mice. In the context of disease, nisin treatment significantly shifted the microbiome towards a new composition, commensurate with health while preventing the harmful inflammation in the small intestine concomitant with decreased villi structural integrity, and heightened hepatic exposure to bacteria and lipid and malondialdehyde accumulation in the liver. Validation with RNA Seq analyses, confirmed the significant infection-related alteration of several genes involved in mitochondrial dysregulation, oxidative phosphorylation, and metal/iron binding and their restitution following nisin treatment. In support of these in vivo findings indicating that periodontopathogens induce gastrointestinal and liver distant organ lesions, human autopsy specimens demonstrated a correlation between tooth loss and severity of liver disease. Nisin's ability to shift the gut and liver microbiome towards a new state commensurate with health while mitigating enteritis, represents a novel approach to treating NAFLD-steatohepatitis-associated periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Changchang Ye
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Periodontology, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Chuanjiang Zhao
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Li Gao
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - April Martinez
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Yukihiro Miyashita
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Allan Radaic
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Pachiyappan Kamarajan
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Charles Le
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Ling Zhan
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Helene Range
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, University of Rennes, UFR of Odontology; Service d'Odontologie, CHU de Rennes, Rennes, France
- INSERM CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer); CIC 1414, Rennes, France
| | - Masataka Sunohara
- Department of Anatomy, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yvonne L Kapila
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA.
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Kim HY, Lim Y, Jang JS, Ko YK, Choi Y, Kim H, Choi B. Extracellular vesicles from periodontal pathogens regulate hepatic steatosis via Toll-like receptor 2 and plasminogen activator inhibitor-1. J Extracell Vesicles 2024; 13:e12407. [PMID: 38251423 PMCID: PMC10801670 DOI: 10.1002/jev2.12407] [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: 07/09/2023] [Accepted: 12/25/2023] [Indexed: 01/23/2024] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is associated with nonalcoholic fatty liver disease (NAFLD) by lipid accumulation in the liver. In this study, we showed that extracellular vesicles (EVs) from the periodontal pathogens Filifactor alocis and Porphyromonas gingivalis induced steatosis by inducing PAI-1 in the liver and serum of mice fed a low-fat diet. PAI-1 induction was not observed in TLR2-/- mice. When tested using HEK-Blue hTLR2 cells, human TLR2 reporter cells, the TLR2-activating ability of serum from NAFLD patients (n = 100) was significantly higher than that of serum from healthy subjects (n = 100). Correlation analysis confirmed that PAI-1 levels were positively correlated with the TLR2-activating ability of serum from NAFLD patients and healthy subjects. Amphiphilic molecules in EVs were involved in PAI-1 induction. Our data demonstrate that the TLR2/PAI-1 axis is important for hepatic steatosis by EVs of periodontal pathogens.
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Affiliation(s)
- Hyun Young Kim
- Department of Oral Microbiology and ImmunologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
- Dental Research InstituteSchool of DentistrySeoul National UniversitySeoulRepublic of Korea
| | - Younggap Lim
- Department of Oral Microbiology and ImmunologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
| | - Ji Sun Jang
- Department of Cell and Developmental BiologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
| | - Yeon Kyeong Ko
- Department of Immunology and Molecular MicrobiologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
| | - Youngnim Choi
- Department of Immunology and Molecular MicrobiologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
- Dental Research InstituteSchool of DentistrySeoul National UniversitySeoulRepublic of Korea
| | - Hong‐Hee Kim
- Department of Cell and Developmental BiologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
- Dental Research InstituteSchool of DentistrySeoul National UniversitySeoulRepublic of Korea
| | - Bong‐Kyu Choi
- Department of Oral Microbiology and ImmunologySchool of DentistrySeoul National UniversitySeoulRepublic of Korea
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Tan X, Wang Y, Gong T. The interplay between oral microbiota, gut microbiota and systematic diseases. J Oral Microbiol 2023; 15:2213112. [PMID: 37200866 PMCID: PMC10187086 DOI: 10.1080/20002297.2023.2213112] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 05/02/2023] [Accepted: 05/08/2023] [Indexed: 05/20/2023] Open
Abstract
Over the past two decades, the importance of microbiota in health and disease has become evident. The human gut microbiota and oral microbiota are the largest and second-largest microbiome in the human body, respectively, and they are physically connected as the oral cavity is the beginning of the digestive system. Emerging and exciting evidence has shown complex and important connections between gut microbiota and oral microbiota. The interplay of the two microbiomes may contribute to the pathological processes of many diseases, including diabetes, rheumatoid arthritis, nonalcoholic fatty liver disease, inflammatory bowel disease, pancreatic cancer, colorectal cancer, and so on. In this review, we discuss possible routes and factors of oral microbiota to affect gut microbiota, and the contribution of this interplay between oral and gut microbiota to systemic diseases. Although most studies are association studies, recently, there have been increasing mechanistic investigations. This review aims to enhance the interest in the connection between oral and gut microbiota, and shows the tangible impact of this connection on human health.
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Affiliation(s)
- Xiujun Tan
- Stomatological Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Yizhong Wang
- Department of Research & Development, Zhejiang Charioteer Pharmaceutical CO. LTD, Taizhou, China
| | - Ting Gong
- Stomatological Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
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Pischke S, Shiprov A, Peters U, Schulze Zur Wiesch J, Kluwe J, Westphal T, Fischer F, Mader M, Fründt T, Horvatits K, Horvatits T, Aarabi G, Beikler T. High prevalence of periodontal disease in patients with NASH- possible association of poor dental health with NASH severity. Ann Hepatol 2023; 28:100887. [PMID: 36646168 DOI: 10.1016/j.aohep.2022.100887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/28/2022] [Accepted: 12/14/2022] [Indexed: 01/18/2023]
Abstract
INTRODUCTION AND OBJECTIVES Recent translational research indicated a bidirectional relationship between NASH (non-alcoholic steatohepatitis) and periodontitis; however, few clinical cohorts have studied this in detail. Thus we investigated this assumed association in a well-defined cohort. MATERIALS AND METHODS Data were generated prospectively for 132 patients (32 patients with NASH and 100 unselected, consecutively collected, anonymized controls from a local dental practice): detailed periodontal parameters, i.e., pocket-probing-depths (PPD), bleeding-on-probing (BOP), plaque-index, and utilization of dental care were assessed and correlated with relevant hepatic parameters (liver stiffness via fibroscan, AST, ALT, bilirubin, and MELD-score). Gingiva samples were tested for Porphyromonas gingvalis (P.g.) and Actinobacillus actinomyctemcomitans (A.a.) by PCR. RESULTS 87.5% of NASH patients and 47% of controls suffered from moderate to severe periodontitis (p=0.01). Liver stiffness was significantly correlated with elevated PPD (p=0.02) and BOP (p=0.03). 34 % of the NASH patients did not make use of regular dental health care. In these patients, AST (p=0.04), MELD score (p<0.01), and liver stiffness (p=0.01) were significantly elevated compared to those who see a dentist regularly. The severity of NASH was not associated with the intraoral detection of P.g. and A.a. CONCLUSIONS The present study suggests that NASH might be associated with periodontitis, irrespective of the intraoral presence of P.g. and A.a. Moreover, regular dental care utilization might mitigate the course of NASH, and patients should be reminded by their hepatologists of the importance of regular dental visits. Future studies should investigate the role of regular dental care and additional anti-inflammatory treatments of the oral cavity.
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Affiliation(s)
- Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner Sites, Germany.
| | - Anita Shiprov
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Periodontics, Preventive and Restorative Dentistry, University Medical Centre Hamburg-Eppendorf, Germany
| | - Ulrike Peters
- Department of Periodontics, Preventive and Restorative Dentistry, University Medical Centre Hamburg-Eppendorf, Germany
| | - Julian Schulze Zur Wiesch
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner Sites, Germany
| | - Johannes Kluwe
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tim Westphal
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Fischer
- Department of Periodontics, Preventive and Restorative Dentistry, University Medical Centre Hamburg-Eppendorf, Germany
| | - Maria Mader
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben Fründt
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karoline Horvatits
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Horvatits
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ghazal Aarabi
- Department of Periodontics, Preventive and Restorative Dentistry, University Medical Centre Hamburg-Eppendorf, Germany
| | - Thomas Beikler
- Department of Periodontics, Preventive and Restorative Dentistry, University Medical Centre Hamburg-Eppendorf, Germany
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Kuraji R, Shiba T, Dong TS, Numabe Y, Kapila YL. Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis. World J Gastroenterol 2023; 29:967-996. [PMID: 36844143 PMCID: PMC9950865 DOI: 10.3748/wjg.v29.i6.967] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/14/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-0071, Japan
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
| | - Takahiko Shiba
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, United States
- Department of Periodontology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
| | - Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-8159, Japan
| | - Yvonne L Kapila
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
- Sections of Biosystems and Function and Periodontics, Professor and Associate Dean of Research, Felix and Mildred Yip Endowed Chair in Dentistry, University of California Los Angeles, Los Angeles, CA 90095, United States
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8
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Kuraji R, Kapila Y, Numabe Y. Periodontal Disease and Nonalcoholic Fatty Liver Disease: New Microbiome-Targeted Therapy Based on the Oral–Gut–Liver Axis Concept. CURRENT ORAL HEALTH REPORTS 2022; 9:89-102. [DOI: 10.1007/s40496-022-00312-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/26/2022] [Indexed: 01/03/2025]
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Liu Y, Huang W, Dai K, Liu N, Wang J, Lu X, Ma J, Zhang M, Xu M, Long X, Liu J, Kou Y. Inflammatory response of gut, spleen, and liver in mice induced by orally administered Porphyromonas gingivalis. J Oral Microbiol 2022; 14:2088936. [PMID: 35756539 PMCID: PMC9225697 DOI: 10.1080/20002297.2022.2088936] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background Periodontitis is a chronic multifactorial inflammatory disease. Porphyromonas gingivalis is a primary periopathogen in the initiation and development of periodontal disease. Evidence has shown that P. gingivalis is associated with systemic diseases, including IBD and fatty liver disease. Inflammatory response is a key feature of diseases related to this species. Methods C57BL/6 mice were administered either PBS, or P. gingivalis. After 9 weeks, the inflammatory response in gut, spleen, and liver was analyzed. Results The findings revealed significant disturbance of the intestinal microbiota and increased inflammatory factors in the gut of P. gingivalis-administered mice. Administrated P. gingivalis remarkably promoted the secretion of IRF-1 and activated the inflammatory pathway IFN-γ/STAT1 in the spleen. Histologically, mice treated with P. gingivalis exhibited hepatocyte damage and lipid deposition. The inflammatory factors IL-17a, IL-6, and ROR-γt were also upregulated in the liver of mice fed with P. gingivalis. Lee’s index, spleen index, and liver index were also increased. Conclusion These results suggest that administrated P. gingivalis evokes inflammation in gut, spleen, and liver, which might promote the progression of various systemic diseases.
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Affiliation(s)
- Yingman Liu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Wenkai Huang
- Department of Orthodontics, School of Stomatology, China Medical University, Shenyang, Liaoning, China
| | - Ke Dai
- Department of Stomatology, Lishui University School of Medicine, Lishui, Zhejing, China
| | - Ni Liu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Jiaqi Wang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Xiaoying Lu
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Jiaojiao Ma
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Manman Zhang
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Mengqi Xu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Xu Long
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
| | - Jie Liu
- Department of Stomatology, Science Experiment Center, China Medical University, Shenyang, Liaoning, China
| | - Yurong Kou
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China.,Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, China
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10
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Shin HS, Hong MH, Moon JY, Sim SJ. Periodontal disease could be a potential risk factor for non-alcoholic fatty liver disease: An 11-year retrospective follow-up study. Clin Oral Investig 2022; 26:5503-5514. [PMID: 35556175 DOI: 10.1007/s00784-022-04518-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 04/23/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVE This study aimed to evaluate the association of periodontal disease with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS A retrospective follow-up study using the National Health Insurance Service-National Sample Cohort was performed from 2002 to 2015 in the Korean population. A total of 165,032 subjects were followed up for incident NAFLD during 11 years. Periodontal disease and NAFLD were defined by a diagnosis using the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) codes. Periodontal status was used as the severity of periodontal status and the number of dental visit due to PD. RESULTS Periodontitis was associated with a 4% increase in risk for NAFLD after adjusting for socio-demographic factor, health behaviors, and systemic diseases (adjusted hazard ratio [aHR] = 1.04, 95% CI = 1.01 to 1.07). Between the number of dental visit due to PD and the risk for NAFLD was observed a dose-effect association (aHR = 1.02, 95% CI = 0.99 to 1.05 for once; aHR = 1.10, 95% CI = 1.06 to 1.15 for two times; aHR = 1.14, 95% CI = 1.06 to 1.24 for three times). CONCLUSIONS Our data confirmed that periodontitis showed an association with a higher incidence of NAFLD. CLINICAL RELEVANCE Prevention and management of periodontal disease could be beneficial for reducing the risk of NAFLD.
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Affiliation(s)
- Hye-Sun Shin
- Department of Dental Hygiene, Baekseok University, (31065) 1 Baekseokdehak-Ro, Dongnam-Gu, Cheonan, Chungnam, South Korea.,Big Data Statistics Institute, Cheonan, South Korea
| | - Min-Hee Hong
- Department of Dental Hygiene, Baekseok University, (31065) 1 Baekseokdehak-Ro, Dongnam-Gu, Cheonan, Chungnam, South Korea
| | - Ja-Young Moon
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, (03722) 50-1, Yonsei-Ro, Seodaemun-gu, Seoul, South Korea.
| | - Seon-Ju Sim
- Department of Dental Hygiene, Baekseok University, (31065) 1 Baekseokdehak-Ro, Dongnam-Gu, Cheonan, Chungnam, South Korea.,Big Data Statistics Institute, Cheonan, South Korea
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11
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Albuquerque-Souza E, Sahingur SE. Periodontitis, chronic liver diseases, and the emerging oral-gut-liver axis. Periodontol 2000 2022; 89:125-141. [PMID: 35244954 PMCID: PMC9314012 DOI: 10.1111/prd.12427] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver carries out a wide range of functions ranging from the control of metabolites, nutrient storage, and detoxification to immunosurveillance. While inflammation is essential for the tissue remodeling and maintenance of homeostasis and normal liver physiology, constant exposure to dietary and microbial products creates a niche for potentially prolonged immune activation and unresolved inflammation in susceptible host. Failure to restrain inflammation can lead to development of chronic liver diseases characterized by fibrosis, cirrhosis and eventually liver failure. The liver maintains close interactions with numerous organs which can influence its metabolism and physiology. It is also known that oral cavity microenvironment can influence the physiological conditions of other organs and emerging evidence implicates that this could be true for the liver as well. Presence of chronic inflammation and dysbiotic microbiota is a common feature leading to clinical pathology both in periodontitis and chronic liver diseases (CLDs). In fact, known CLDs appear to have some relationship with periodontitis, which impacts the onset or progression of these conditions in a bidirectional crosstalk. In this review, we explore the emerging association between oral‐gut‐liver axis focusing on periodontitis and common CLDs including nonalcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and hepatocellular cancer. We highlight the immune pathways and oral microbiome interactions which can link oral cavity and liver health and offer perspectives for future research.
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Affiliation(s)
- Emmanuel Albuquerque-Souza
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sinem E Sahingur
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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12
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Oral Health and Liver Disease: Bidirectional Associations—A Narrative Review. Dent J (Basel) 2022; 10:dj10020016. [PMID: 35200242 PMCID: PMC8870998 DOI: 10.3390/dj10020016] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/11/2022] [Accepted: 01/18/2022] [Indexed: 12/04/2022] Open
Abstract
Several links between chronic liver disease and oral health have been described and are discussed in this narrative review. Oral manifestations such as lichen planus, ulcers, xerostomia, erosion and tongue abnormalities seem to be particularly prevalent among patients with chronic liver disease. These may be causal, coincidental, secondary to therapeutic interventions, or attributable to other factors commonly observed in liver disease patients. In addition, findings from both experimental and epidemiological studies suggest that periodontitis can induce liver injury and contribute to the progression of chronic liver disease through periodontitis-induced systemic inflammation, endotoxemia, and gut dysbiosis with increased intestinal translocation. This has brought forward the hypothesis of an oral-gut-liver axis. Preliminary clinical intervention studies indicate that local periodontal treatments may lead to beneficial liver effects, but more human studies are needed to clarify if treatment of periodontitis truly can halt or reverse progression of liver disease and improve liver-related outcomes.
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13
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Thalla S, Kamaraj R, Kavitha A. Increasing risk factors of non-alcoholic fatty liver disease, a look into chronic periodontitis and insulin resistance. Endocr Metab Immune Disord Drug Targets 2022; 22:807-814. [PMID: 34983354 DOI: 10.2174/1871530322666220104095534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/21/2021] [Accepted: 10/27/2021] [Indexed: 11/22/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is marked by the excessive intrusion of triglycerides into hepatocytes without any role of alcohol consumption. Various risk factors have been attributed to this disease pathogenesis which involves metabolic disorders, immune response, and even an intricate relationship between the two. The role of insulin resistance (IR) in NAFLD has long been known; however, the molecular basis of disease progression under this metabolic backdrop is still being investigated. Similarly, the periodontitis-mediated immune response is another major factor involved in NAFLD manifestation which has generated huge interest. The prevalence of pathogenic bacteria elicits a strong immune response which according to studies shows a strong correlation with NAFLD state. Such pre-existing conditions have a strong probability of explaining the disease onset. Additionally, increasing reports of inflammatory response and its links to insulin resistance have further increased the scope of understanding NAFLD. Through this review, we aim to elaborate on these factors explaining their role in the disease progression.
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Affiliation(s)
- Sreenu Thalla
- Department of Pharmacology, SRM College of Pharmacy, SRMIST, Kattankalathur, Tamil Nadu - 603203
| | - Kamaraj R
- SRM College of Pharmacy, SRMIST, Kattankalathur, Tamil Nadu - 603203
| | - Kavitha A
- Department of Gastroenterology, Guntur Medical College & Government General Hospital, Guntur, Andhra Pradesh - 522004
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14
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Wang T, Ishikawa T, Sasaki M, Chiba T. Oral and Gut Microbial Dysbiosis and Non-alcoholic Fatty Liver Disease: The Central Role of Porphyromonas gingivalis. Front Med (Lausanne) 2022; 9:822190. [PMID: 35308549 PMCID: PMC8924514 DOI: 10.3389/fmed.2022.822190] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/19/2022] [Indexed: 02/05/2023] Open
Abstract
Gut microbiota play many important roles, such as the regulation of immunity and barrier function in the intestine, and are crucial for maintaining homeostasis in living organisms. The disruption in microbiota is called dysbiosis, which has been associated with various chronic inflammatory conditions, food allergies, colorectal cancer, etc. The gut microbiota is also affected by several other factors such as diet, antibiotics and other medications, or bacterial and viral infections. Moreover, there are some reports on the oral-gut-liver axis indicating that the disruption of oral microbiota affects the intestinal biota. Non-alcoholic fatty liver disease (NAFLD) is one of the systemic diseases caused due to the dysregulation of the oral-gut-liver axis. NAFLD is the most common liver disease reported in the developed countries. It includes liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Recently, accumulating evidence supports an association between NAFLD and dysbiosis of oral and gut microbiota. Periodontopathic bacteria, especially Porphyromonas gingivalis, have been correlated with the pathogenesis and development of NAFLD based on the clinical and basic research, and immunology. P. gingivalis was detected in the liver, and lipopolysaccharide from this bacteria has been shown to be involved in the progression of NAFLD, thereby indicating a direct role of P. gingivalis in NAFLD. Moreover, P. gingivalis induces dysbiosis of gut microbiota, which promotes the progression of NAFLD, through disrupting both metabolic and immunologic pathways. Here, we review the roles of microbial dysbiosis in NAFLD. Focusing on P. gingivalis, we evaluate and summarize the most recent advances in our understanding of the relationship between oral-gut microbiome symbiosis and the pathogenesis and progression of non-alcoholic fatty liver disease, as well as discuss novel strategies targeting both P. gingivalis and microbial dysbiosis.
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Affiliation(s)
- Ting Wang
- Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University, Morioka, Japan
- Ting Wang
| | - Taichi Ishikawa
- Division of Molecular Microbiology, Department of Microbiology, Iwate Medical University, Morioka, Japan
| | - Minoru Sasaki
- Division of Molecular Microbiology, Department of Microbiology, Iwate Medical University, Morioka, Japan
| | - Toshimi Chiba
- Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University, Morioka, Japan
- *Correspondence: Toshimi Chiba
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15
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Jiang J, Xiong J, Ni J, Chen C, Wang K. Live Combined B. subtilis and E. faecium Alleviate Liver Inflammation, Improve Intestinal Barrier Function, and Modulate Gut Microbiota in Mice with Non-Alcoholic Fatty Liver Disease. Med Sci Monit 2021; 27:e931143. [PMID: 34482357 PMCID: PMC8428156 DOI: 10.12659/msm.931143] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic, progressive liver disease with an increasing incidence rate. This study investigated the protective effects of live combined Bacillus subtilis and Enterococcus faecium (LCBE) on NAFLD, and its possible mechanisms. Material/Methods Five-week-old C57BL/6 mice were randomly divided into 3 groups: chow, HFD, and HFD+LCBE groups. The levels of serum biochemical markers, glucose tolerance, insulin, the inflammatory cytokines IL-1β, IL-6, and TNF-α, LPS, and histological staining were measured using commercial kits. qPCR was used to examine the mRNA expression levels of inflammatory cytokines in the liver. Western blotting was used to determine the protein levels of TLR4, NF-κB p65, PPAR-α, and CPT-1 in the liver, and occludin and Claudin1 in the intestine. The intestinal flora of the mice was analyzed by high-throughput sequencing of the V3–V4 region of 16S rDNA. Results LCBE significantly lowered the body weight, liver/body weight ratio, and serum glucose level, and increased the serum insulin level in NAFLD mice. In addition, LCBE treatment improved the liver function and lipid profile, decreased the levels of LPS and inflammatory cytokines, and downregulated the expression of TLR4 and NF-κB p65. Moreover, LCBE enhanced the intestinal barrier function by increasing the expression of occludin and Claudin1. Furthermore, LCBE modulated the composition of the gut microbiota by reducing the Firmicutes to Bacteroidetes ratio, and the proportion of inflammation-related and LPS-producing bacteria, thus re-arranging the structure of the gut microbiota. Conclusions LCBE protects against NAFLD by alleviating inflammation, restoring the intestinal barrier, and modulating gut microbiota composition.
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Affiliation(s)
- Jie Jiang
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China (mainland)
| | - Jie Xiong
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China (mainland)
| | - Jianbo Ni
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Congying Chen
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Kezhou Wang
- Department of Pathology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
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16
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Kuraji R, Sekino S, Kapila Y, Numabe Y. Periodontal disease-related nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: An emerging concept of oral-liver axis. Periodontol 2000 2021; 87:204-240. [PMID: 34463983 PMCID: PMC8456799 DOI: 10.1111/prd.12387] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Periodontal disease, a chronic inflammatory disease of the periodontal tissues, is not only a major cause of tooth loss, but it is also known to exacerbate/be associated with various metabolic disorders, such as obesity, diabetes, dyslipidemia, and cardiovascular disease. Recently, growing evidence has suggested that periodontal disease has adverse effects on the pathophysiology of liver disease. In particular, nonalcoholic fatty liver disease, a hepatic manifestation of metabolic syndrome, has been associated with periodontal disease. Nonalcoholic fatty liver disease is characterized by hepatic fat deposition in the absence of a habitual drinking history, viral infections, or autoimmune diseases. A subset of nonalcoholic fatty liver diseases can develop into more severe and progressive forms, namely nonalcoholic steatohepatitis. The latter can lead to cirrhosis and hepatocellular carcinoma, which are end‐stage liver diseases. Extensive research has provided plausible mechanisms to explain how periodontal disease can negatively affect nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, namely via hematogenous or enteral routes. During periodontitis, the liver is under constant exposure to various pathogenic factors that diffuse systemically from the oral cavity, such as bacteria and their by‐products, inflammatory cytokines, and reactive oxygen species, and these can be involved in disease promotion of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Also, gut microbiome dysbiosis induced by enteral translocation of periodontopathic bacteria may impair gut wall barrier function and promote the transfer of hepatotoxins and enterobacteria to the liver through the enterohepatic circulation. Moreover, in a population with metabolic syndrome, the interaction between periodontitis and systemic conditions related to insulin resistance further strengthens the association with nonalcoholic fatty liver disease. However, most of the pathologic links between periodontitis and nonalcoholic fatty liver disease in humans are provided by epidemiologic observational studies, with the causal relationship not yet being established. Several systematic and meta‐analysis studies also show conflicting results. In addition, the effect of periodontal treatment on nonalcoholic fatty liver disease has hardly been studied. Despite these limitations, the global burden of periodontal disease combined with the recent nonalcoholic fatty liver disease epidemic has important clinical and public health implications. Emerging evidence suggests an association between periodontal disease and liver diseases, and thus we propose the term periodontal disease–related nonalcoholic fatty liver disease or periodontal disease–related nonalcoholic steatohepatitis. Continued efforts in this area will pave the way for new diagnostic and therapeutic approaches based on a periodontologic viewpoint to address this life‐threatening liver disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Life Science Dentistry, The Nippon Dental University, Tokyo, Japan.,Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, California, USA
| | - Satoshi Sekino
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yvonne Kapila
- Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, California, USA
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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17
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Marcano R, Rojo MÁ, Cordoba-Diaz D, Garrosa M. Pathological and Therapeutic Approach to Endotoxin-Secreting Bacteria Involved in Periodontal Disease. Toxins (Basel) 2021; 13:533. [PMID: 34437404 PMCID: PMC8402370 DOI: 10.3390/toxins13080533] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 07/26/2021] [Indexed: 12/16/2022] Open
Abstract
It is widely recognized that periodontal disease is an inflammatory entity of infectious origin, in which the immune activation of the host leads to the destruction of the supporting tissues of the tooth. Periodontal pathogenic bacteria like Porphyromonas gingivalis, that belongs to the complex net of oral microflora, exhibits a toxicogenic potential by releasing endotoxins, which are the lipopolysaccharide component (LPS) available in the outer cell wall of Gram-negative bacteria. Endotoxins are released into the tissues causing damage after the cell is lysed. There are three well-defined regions in the LPS: one of them, the lipid A, has a lipidic nature, and the other two, the Core and the O-antigen, have a glycosidic nature, all of them with independent and synergistic functions. Lipid A is the "bioactive center" of LPS, responsible for its toxicity, and shows great variability along bacteria. In general, endotoxins have specific receptors at the cells, causing a wide immunoinflammatory response by inducing the release of pro-inflammatory cytokines and the production of matrix metalloproteinases. This response is not coordinated, favoring the dissemination of LPS through blood vessels, as well as binding mainly to Toll-like receptor 4 (TLR4) expressed in the host cells, leading to the destruction of the tissues and the detrimental effect in some systemic pathologies. Lipid A can also act as a TLRs antagonist eliciting immune deregulation. Although bacterial endotoxins have been extensively studied clinically and in a laboratory, their effects on the oral cavity and particularly on periodontium deserve special attention since they affect the connective tissue that supports the tooth, and can be linked to advanced medical conditions. This review addresses the distribution of endotoxins associated with periodontal pathogenic bacteria and its relationship with systemic diseases, as well as the effect of some therapeutic alternatives.
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Affiliation(s)
- Rosalia Marcano
- Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine and INCYL, University of Valladolid, 47005 Valladolid, Spain;
| | - M. Ángeles Rojo
- Area of Experimental Sciences, Miguel de Cervantes European University, 47012 Valladolid, Spain;
| | - Damián Cordoba-Diaz
- Area of Pharmaceutics and Food Technology, Faculty of Pharmacy, and IUFI, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Manuel Garrosa
- Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine and INCYL, University of Valladolid, 47005 Valladolid, Spain;
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18
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Hatasa M, Yoshida S, Takahashi H, Tanaka K, Kubotsu Y, Ohsugi Y, Katagiri T, Iwata T, Katagiri S. Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response. Int J Mol Sci 2021; 22:3728. [PMID: 33918456 PMCID: PMC8038294 DOI: 10.3390/ijms22073728] [Citation(s) in RCA: 21] [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: 02/26/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, Porphyromonas gingivalis lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD.
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Affiliation(s)
- Masahiro Hatasa
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Sumiko Yoshida
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
| | - Yoshihito Kubotsu
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
| | - Yujin Ohsugi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Takaharu Katagiri
- Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan;
- Division of Rheumatology, Department of Internal Medicine, Ohashi Medical Center, Tokyo 153-8515, Japan
| | - Takanori Iwata
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Sayaka Katagiri
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
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19
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Carreres L, Jílková ZM, Vial G, Marche PN, Decaens T, Lerat H. Modeling Diet-Induced NAFLD and NASH in Rats: A Comprehensive Review. Biomedicines 2021; 9:biomedicines9040378. [PMID: 33918467 PMCID: PMC8067264 DOI: 10.3390/biomedicines9040378] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, characterized by hepatic steatosis without any alcohol abuse. As the prevalence of NAFLD is rapidly increasing worldwide, important research activity is being dedicated to deciphering the underlying molecular mechanisms in order to define new therapeutic targets. To investigate these pathways and validate preclinical study, reliable, simple and reproducible tools are needed. For that purpose, animal models, more precisely, diet-induced NAFLD and nonalcoholic steatohepatitis (NASH) models, were developed to mimic the human disease. In this review, we focus on rat models, especially in the current investigation of the establishment of the dietary model of NAFLD and NASH in this species, compiling the different dietary compositions and their impact on histological outcomes and metabolic injuries, as well as external factors influencing the course of liver pathogenesis.
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Affiliation(s)
- Lydie Carreres
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
| | - Zuzana Macek Jílková
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
| | - Guillaume Vial
- Université Grenoble-Alpes, 38000 Grenoble, France;
- Inserm U 1300, Hypoxia PathoPhysiology (HP2), 38000 Grenoble, France
| | - Patrice N. Marche
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
| | - Thomas Decaens
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
- Service D’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Hervé Lerat
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
- Unité Mixte de Service UGA hTAG, Inserm US 046, CNRS UAR 2019, 38700 La Tronche, France
- Correspondence:
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20
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Non-alcoholic steatohepatitis caused by oral bacteria. PEDIATRIC DENTAL JOURNAL 2021. [DOI: 10.1016/j.pdj.2020.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Kuraji R, Wu YH, Hashimoto S, Miyashita Y, Mishiro S, Ito H, Kamarajan P, Kapila Y, Numabe Y. Periodontal inflammation triggers a site-specific and wide radius of calcium metabolic effects on alveolar bone. J Periodontal Res 2020; 56:314-329. [PMID: 33314132 DOI: 10.1111/jre.12824] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/30/2020] [Accepted: 10/28/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVE There is a close relationship between inflammation and bone remodeling in the periodontium. However, previous studies have not delineated the alterations in calcium (Ca) metabolism during periodontitis progression. The aim of this current investigation was to examine Ca dynamics in alveolar bone of rats during progression of ligature-induced periodontal inflammation by using 45 Ca, which is an index of hard tissue neogenesis. MATERIAL AND METHODS To induce periodontitis, the maxillary right first molar (M1) of 8-week-old male rats was ligated with a silk suture for 1, 3, 7, and 28 days. The left M1 was not ligated as a control. To evaluate resultant changes in bone neogenesis, 45 CaCl2 was injected intraperitoneally 24 hours before euthanasia. The left-and-right palatal mucosa, molar teeth (M1 and M2), and alveolar bone were harvested for evaluation of 45 Ca radioactivity using a liquid scintillation counter. The distribution of 45 Ca in maxillary tissues was evaluated using autoradiography (ARG). In addition, we analyzed the bone volume fraction (BV/TV) and bone mineral density (BMD) of the alveolar bone by micro-computed tomography. To investigate the number of osteoclasts and osteoblasts, tartrate-resistant acid phosphatase (TRAP) and bone-specific alkaline phosphatase (BAP) were measured by an enzymatic assay and immunohistochemistry, respectively. RESULTS 45 Ca radioactivity in the alveolar bone of the ligature side decreased by 8% compared to the unligated control-side on day 1, whereas on day 7, it markedly increased by 33%. The 45 Ca levels in the gingival tissue and molar teeth were slightly but significantly lower than the control-side on day 1 and higher from day 3 to 28. The variation in 45 Ca levels for the alveolar bone was greater and specific compared with other tissues. Furthermore, on day 7, ARG data revealed that 45 Ca on the control side was primarily localized to the periodontal ligament (PDL) space and alveolar bone crest and barely detected in the gingival tissues and deeper parts of the alveolar bone. On the ligature side, 45 Ca disappeared from the PDL and alveolar crest, but instead was broadly and significantly increased within the deeper zones of the alveolar bone and furcation areas and distant from the site of ligature placement and periodontal inflammation. In the shallow zone of the alveolar bone, these changes in 45 Ca levels on day 7 were consistent with decreases in the bone structural parameters (BV/TV and BMD), enhanced osteoclast presence, and suppressed levels of BAP expression in osteoblasts. In contrast, the deep zone and furcation area showed that TRAP-positive cells increased, but BAP expression was maintained in the resorption lacunae of the alveolar bone. CONCLUSION During periodontitis progression in rats, 45 Ca levels in the alveolar bone exhibited biphasic alterations, namely decreases and increases. These data indicate that periodontitis induces a wide range of site-specific Ca metabolism alterations within the alveolar bone.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Life Science Dentistry, The Nippon Dental University, Tokyo, Japan.,Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Orofacial Sciences, University of California San Francisco, School of Dentistry, San Francisco, CA, USA
| | - Ya-Hsin Wu
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Periodontology, China Medical University Hospital, Taichung City, Taiwan
| | | | - Yukihiro Miyashita
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Saki Mishiro
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Hiroshi Ito
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Pachiyappan Kamarajan
- Department of Orofacial Sciences, University of California San Francisco, School of Dentistry, San Francisco, CA, USA
| | - Yvonne Kapila
- Department of Orofacial Sciences, University of California San Francisco, School of Dentistry, San Francisco, CA, USA
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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Yue Y, Liu X, Li Y, Xia B, Yu W. The role of TLR4/MyD88/NF-κB pathway in periodontitis-induced liver inflammation of rats. Oral Dis 2020; 27:1012-1021. [PMID: 32853444 PMCID: PMC8247295 DOI: 10.1111/odi.13616] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 07/24/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The aim of this study was to clarify the immune mechanism of hepatic injury induced by periodontitis using a rat model. METHODS Twenty-four SPF male Wistar rats were randomly divided into two groups: control group (CG) and periodontitis group (PG). In order to induce experimental periodontitis, we tied the wire ligature around bilateral maxillary first molar of rats. After 8 weeks, the following indicators were valued: gingival index, tooth mobility, probing pocket depth; indexes about oxidative stress and circulating biomarkers; bone retraction by micro-CT analysis; Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and nuclear factor kappa B (NF-κB) by qRT-PCR and Western blotting; tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) by qRT-PCR and immunohistochemical staining; inflammation of periodontal and hepatic tissues by histopathological observation. RESULTS Periodontal indicators and micro-CT results showed the raised levels of inflammatory response and bone retraction in PG compared with CG. The mRNA and protein levels of TLR4, MyD88, NF-κB, TNF-α, and IL-6 have indicated high values in PG versus CG. Histopathological analysis revealed a correlation between periodontitis and hepatic injury. CONCLUSION TLR4/MyD88/NF-κB pathway may play a role in periodontitis-induced liver inflammation of rats.
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Affiliation(s)
- Yiyun Yue
- Department of Periodontology, Jilin University, Changchun, China
| | - Xinchan Liu
- Department of Geriatric Stomatology, Jilin University, Changchun, China
| | - Yan Li
- Department of Periodontology, Jilin University, Changchun, China
| | - Boyuan Xia
- Department of Periodontology, Jilin University, Changchun, China
| | - Weixian Yu
- Department of Geriatric Stomatology, Jilin University, Changchun, China.,Jilin Provincial Laboratory of Biomedical Engineering, School and Hospital of Stomatology, Jilin University, Changchun, China
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A Diet Rich in Saturated Fat and Cholesterol Aggravates the Effect of Bacterial Lipopolysaccharide on Alveolar Bone Loss in a Rabbit Model of Periodontal Disease. Nutrients 2020; 12:nu12051405. [PMID: 32422858 PMCID: PMC7284766 DOI: 10.3390/nu12051405] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/09/2020] [Accepted: 05/10/2020] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence connects periodontitis with a variety of systemic diseases, including metabolic syndrome, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). The proposal of this study was to evaluate the role of diets rich in saturated fat and cholesterol in some aspects of periodontal diseases in a lipopolysaccharide (LPS)-induced model of periodontal disease in rabbits and to assess the influence of a periodontal intervention on hyperlipidemia, atherosclerosis, and NAFLD progression to non-alcoholic steatohepatitis. Male rabbits were maintained on a commercial standard diet or a diet rich in saturated fat (3% lard w/w) and cholesterol (1.3% w/w) (HFD) for 40 days. Half of the rabbits on each diet were treated 2 days per week with intragingival injections of LPS from Porphyromonas gingivalis. Morphometric analyses revealed that LPS induced higher alveolar bone loss (ABL) around the first premolar in animals receiving standard diets, which was exacerbated by the HFD diet. A higher score of acinar inflammation in the liver and higher blood levels of triglycerides and phospholipids were found in HFD-fed rabbits receiving LPS. These results suggest that certain dietary habits can exacerbate some aspects of periodontitis and that bad periodontal health can contribute to dyslipidemia and promote NAFLD progression, but only under certain conditions.
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Kuraji R, Hashimoto S, Ito H, Sunada K, Numabe Y. Development and use of a mouth gag for oral experiments in rats. Arch Oral Biol 2019; 98:68-74. [DOI: 10.1016/j.archoralbio.2018.11.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/18/2018] [Accepted: 11/10/2018] [Indexed: 12/12/2022]
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