|
1
|
Dhungana G, Srisai D, Sampath C, Soliman J, Kelly RM, Saleh HY, Sedik A, Raynes E, Ferguson A, Alluri LSC, Gangula PR. Unveiling the Molecular Crosstalk Between Periodontal and Cardiovascular Diseases: A Systematic Review. Dent J (Basel) 2025; 13:98. [PMID: 40136726 PMCID: PMC11941040 DOI: 10.3390/dj13030098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/13/2025] [Accepted: 02/23/2025] [Indexed: 03/27/2025] Open
Abstract
Background/Objectives: Periodontal disease (PD) is a chronic inflammatory condition caused by dysbiosis of the oral microbiome. PD is linked to systemic inflammation and endothelial dysfunction, which associate it with cardiovascular disease (CVD). This systematic review explores the molecular and microbial mechanisms through which periodontal pathogens, including "Red Complex" bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola) and Fusobacterium nucleatum, influence cardiovascular health via inflammatory pathways, immune modulation, and microbial dissemination. Methods: A systematic review was conducted following PRISMA guidelines. A literature search was conducted in the PubMed and ScienceDirect databases using relevant keywords, with strict inclusion and exclusion criteria, from the first week of September 2024 to the first week of October 2024. Studies addressing the relationship between PD and CVD were assessed for methodological rigor, relevance, and data availability. The outcomes were synthesized using a descriptive narrative approach. Out of 591 records screened, 421 full-text articles were sought for retrieval. The final review included 58 articles providing supplementary aggregated data after eligibility assessment. Results: The pathogenesis of PD involves the activation of immune cells and the release of pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α, and PGE2) and chemokines (including IL-8 and MCP-1) along with oxidative stress driven by reactive oxygen species (ROS). Periodontal pathogens trigger endothelial oxidative stress and systemic inflammation via Toll-like receptors (TLRs), NF-κB signaling, and nitric oxide (NO) dysregulation, contributing to endothelial dysfunction and atherogenesis. Biomarkers, such as C-reactive protein, interleukins, and matrix metalloproteinases (MMPs), further highlight the systemic inflammatory response. Conclusions: This review underscores the significant role of periodontal pathogens and inflammatory mediators in systemic health, particularly in the progression of CVD. Although existing evidence illustrates these associations, the underlying molecular mechanisms remain inadequately understood, indicating a need for further research to advance precision medicine and therapeutic strategies.
Collapse
Affiliation(s)
- Gunaraj Dhungana
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Dollada Srisai
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Chethan Sampath
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Jeremiah Soliman
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Regan M. Kelly
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Honar Y. Saleh
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Abdelrahman Sedik
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | - Edilberto Raynes
- Department of Professional and Medical Education, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA;
| | - Alexys Ferguson
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| | | | - Pandu R. Gangula
- Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA; (G.D.); (D.S.); (C.S.); (J.S.); (H.Y.S.); (A.S.); (A.F.)
| |
Collapse
|
|
2
|
Wu P, Bie M, Zhou J, Wang J, Zhao L. Periodontal pathogen Fusobacterium nucleatum infection accelerates hepatic steatosis in high-fat diet-fed ApoE knockout mice by inhibiting Nrf2/Keap1 signaling. J Periodontal Res 2024; 59:1220-1233. [PMID: 38795023 DOI: 10.1111/jre.13278] [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: 03/03/2024] [Revised: 03/31/2024] [Accepted: 04/12/2024] [Indexed: 05/27/2024]
Abstract
AIMS This study sought to explore the impact of Fusobacterium nucleatum on hepatic steatosis in apolipoprotein E (ApoE) knockout (KO) mice induced by a high-fat diet (HFD) and elucidate the underlying mechanism. METHODS ApoE KO mice, on a HFD, received F. nucleatum oral inoculation every other day. After 24 weeks, body weight, liver weight, and liver index were assessed. Serum biochemistry and pro-inflammatory factors in serum and liver were analyzed. The histopathology of right maxilla and live were performed. Oil red O, immunohistochemistry, and immunofluorescence staining for the liver were conducted. Myeloperoxidase (MPO) activity, apoptosis, lipid reactive oxygen species (ROS), ROS, lipid peroxides, and hepatic lipids were also evaluated. Liver inflammation, fibrosis, de novo lipogenesis (DNL)-related molecule, and Nrf2/Keap1-related signaling molecule gene/protein expression were determined by real-time PCR (RT-PCR) and/or Western blot (WB) analysis. RESULTS HFD-fed ApoE KO mice infected by F. nucleatum demonstrated significant changes, including increased body and liver weight, elevated proinflammatory factors and lipids in serum and liver, as well as neutrophil infiltration, fibrosis, apoptosis, oxidative stress, and lipid peroxidation in the liver. Additionally, F. nucleatum stimulates hepatic lipid accumulation and activates de novo lipogenesis (DNL), while simultaneously suppressing the Nrf2/Keap1 antioxidant pathway. CONCLUSION In conclusion, our study reveals that oral inoculation of F. nucleatum might promote hepatic steatosis by inhibiting Nrf2/Keap1 pathway.
Collapse
Affiliation(s)
- Peiyao Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Periodontics, West China School & Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mengyao Bie
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Periodontics, West China School & Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jieyu Zhou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Periodontics, West China School & Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jun Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Periodontics, West China School & Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lei Zhao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Periodontics, West China School & Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
3
|
Albuquerque-Souza E, Shelling B, Jiang M, Xia XJ, Rattanaprukskul K, Sahingur SE. Fusobacterium nucleatum triggers senescence phenotype in gingival epithelial cells. Mol Oral Microbiol 2024; 39:29-39. [PMID: 37718958 PMCID: PMC10939983 DOI: 10.1111/omi.12432] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/04/2023] [Accepted: 08/07/2023] [Indexed: 09/19/2023]
Abstract
The prevalence of periodontitis increases with physiological aging. However, whether bacteria associated with periodontal diseases foster aging and the mechanisms by which they may do so are unknown. Herein, we hypothesize that Fusobacterium nucleatum, a microorganism associated with periodontitis and several other age-related disorders, triggers senescence, a chief hallmark of aging responsible to reduce tissue repair capacity. Our study analyzed the senescence response of gingival epithelial cells and their reparative capacity upon long-term exposure to F. nucleatum. Specifically, we assessed (a) cell cycle arrest by analyzing the cyclin-dependent kinase inhibitors p16INK4a and p14ARF and their downstream cascade (pRb, p53, and p21) at both gene and protein levels, (b) lysosomal mediated dysfunction by using assays targeting the expression and activity of the senescence-associated β-galactosidase (SA-β-Gal) enzyme, and (c) nuclear envelope breakdown by assessing the expression of Lamin-B1. The consequences of the senescence phenotype mediated by F. nucleatum were further assessed using wound healing assays. Our results revealed that prolonged exposure to F. nucleatum promotes an aging-like phenotype as evidenced by the increased expression of pro-senescence markers (p16INK4a , p21, and pRb) and SA-β-Gal activity and reduced expression of the counter-balancing cascade (p14ARF and p53) and Lamin-B1. Furthermore, we also noted impaired wound healing capacity of gingival epithelial cells upon prolong bacterial exposure, which was consistent with the senescence-induced phenotype. Together, our findings provide a proof-of-concept evidence that F. nucleatum triggers a pro-senescence response in gingival epithelial cells. This might affect periodontal tissue homeostasis by reducing its repair capacity and, consequently, increasing susceptibility to periodontitis during aging.
Collapse
Affiliation(s)
- Emmanuel Albuquerque-Souza
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Lipid Mediator Unit, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Benjamin Shelling
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Min Jiang
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xia-Juan Xia
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kantapon Rattanaprukskul
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sinem Esra Sahingur
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
4
|
Marroquin TY, Guauque-Olarte S. Integrative analysis of gene and protein expression in atherosclerosis-related pathways modulated by periodontal pathogens. Systematic review. JAPANESE DENTAL SCIENCE REVIEW 2023; 59:8-22. [PMID: 36654677 PMCID: PMC9841036 DOI: 10.1016/j.jdsr.2022.12.001] [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: 01/19/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 01/11/2023] Open
Abstract
The mechanisms modulated by periodontal pathogens in atherosclerosis are not fully understood. Aim: to perform an integrative analysis of gene and protein expression modulated by periodontal pathogens in cells and animal models for atherosclerosis. Methods Cochrane, PRISMA and AMSTAR2 guidelines for systematic reviews were followed. Data search was conducted in Pub-med, LILACS and Science Direct databases. Gene and protein expression data were collected from the included papers to perform an overrepresentation analysis using the Reactome Pathway Analysis tool and the KEGG database. Results Thirty-two papers were included in the review, they analyzed the effect of Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus anginosus, Streptococcus sanguinis, Tannerella forsythia, and Treponema denticola or/and their virulent factors on gene and protein expression in human cells and animal models of atherosclerosis. Some of the modulated pathways include the immune system, programmed cell death, cellular responses to external stimuli, transport of small molecules, and signal transduction (p < 0.05). Those pathways are known to be involved in different stages of atherosclerosis progression. Conclusion Based on the performed analysis, it is possible to state that periodontal pathogens have the potential to be a contributing factor for atherosclerosis even in absence of a high-fat diet or high shear stress.
Collapse
Affiliation(s)
| | - Sandra Guauque-Olarte
- GIOM group, Faculty of Dentistry, Universidad Cooperativa de Colombia, Envigado, Colombia
| |
Collapse
|
|
5
|
Zhou LJ, Lin WZ, Meng XQ, Zhu H, Liu T, Du LJ, Bai XB, Chen BY, Liu Y, Xu Y, Xie Y, Shu R, Chen FM, Zhu YQ, Duan SZ. Periodontitis exacerbates atherosclerosis through Fusobacterium nucleatum-promoted hepatic glycolysis and lipogenesis. Cardiovasc Res 2023; 119:1706-1717. [PMID: 36943793 DOI: 10.1093/cvr/cvad045] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 12/06/2022] [Accepted: 01/20/2023] [Indexed: 03/23/2023] Open
Abstract
AIMS Positive associations between periodontitis (PD) and atherosclerosis have been established, but the causality and mechanisms are not clear. We aimed to explore the causal roles of PD in atherosclerosis and dissect the underlying mechanisms. METHODS AND RESULTS A mouse model of PD was established by ligation of molars in combination with application of subgingival plaques collected from PD patients and then combined with atherosclerosis model induced by treating atheroprone mice with a high-cholesterol diet (HCD). PD significantly aggravated atherosclerosis in HCD-fed atheroprone mice, including increased en face plaque areas in whole aortas and lesion size at aortic roots. PD also increased circulating levels of triglycerides and cholesterol, hepatic levels of cholesterol, and hepatic expression of rate-limiting enzymes for lipogenesis. Using 16S ribosomal RNA (rRNA) gene sequencing, Fusobacterium nucleatum was identified as the most enriched PD-associated pathobiont that is present in both the oral cavity and livers. Co-culture experiments demonstrated that F. nucleatum directly stimulated lipid biosynthesis in primary mouse hepatocytes. Moreover, oral inoculation of F. nucleatum markedly elevated plasma levels of triglycerides and cholesterol and promoted atherogenesis in HCD-fed ApoE-/- mice. Results of RNA-seq and Seahorse assay indicated that F. nucleatum activated glycolysis, inhibition of which by 2-deoxyglucose in turn suppressed F. nucleatum-induced lipogenesis in hepatocytes. Finally, interrogation of the molecular mechanisms revealed that F. nucleatum-induced glycolysis and lipogenesis by activating PI3K/Akt/mTOR signalling pathway in hepatocytes. CONCLUSIONS PD exacerbates atherosclerosis and impairs lipid metabolism in mice, which may be mediated by F. nucleatum-promoted glycolysis and lipogenesis through PI3K/Akt/mTOR signalling in hepatocytes. Treatment of PD and specific targeting of F. nucleatum are promising strategies to improve therapeutic effectiveness of hyperlipidaemia and atherosclerosis.
Collapse
Affiliation(s)
- Lu-Jun Zhou
- Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Wen-Zhen Lin
- Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Xiao-Qian Meng
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Hong Zhu
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Ting Liu
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Lin-Juan Du
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Xue-Bing Bai
- Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Bo-Yan Chen
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Yan Liu
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Yuanzhi Xu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yufeng Xie
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
- Department of Periodontology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Rong Shu
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
- Department of Periodontology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Fa-Ming Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China
| | - Ya-Qin Zhu
- Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| | - Sheng-Zhong Duan
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Pudong New District, Shanghai 200125, China
- National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
| |
Collapse
|
|
6
|
Lu Y, Li Z, Peng X. Regulatory effects of oral microbe on intestinal microbiota and the illness. Front Cell Infect Microbiol 2023; 13:1093967. [PMID: 36816583 PMCID: PMC9928999 DOI: 10.3389/fcimb.2023.1093967] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/16/2023] [Indexed: 02/04/2023] Open
Abstract
Over the past decade, the association between oral health, intestinal microbiota, and systemic diseases has been further validated. Some oral microbial species have been isolated from pathological intestine mucosa or feces and identified as biomarkers for intestinal diseases. A small proportion of oral microbiome passes through or colonizes the lower gastrointestinal tract, even in healthy individuals. Opportunistic pathogens from the oral cavity may expand and participate in the occurrence and progression of intestinal diseases when the anatomical barrier is disrupted. These disruptors interact with the intestinal microbiota, disturbing indigenous microorganisms, and mucosal barriers through direct colonization, blood circulation, or derived metabolite pathways. While interacting with the host's immune system, oral-derived pathogens stimulate inflammation responses and guide the transition of the intestinal microenvironment from a healthy state to a pre-disease state. Therefore, the oral-gut microbiome axis sheds light on new clinical therapy options, and gastrointestinal tract ecology balance necessitates simultaneous consideration of both oral and gut microbiomes. This review summarizes possible routes of oral microbes entering the intestine and the effects of certain oral bacteria on intestinal microbiota and the host's immune responses.
Collapse
|
|
7
|
Fan Z, Tang P, Li C, Yang Q, Xu Y, Su C, Li L. Fusobacterium nucleatum and its associated systemic diseases: epidemiologic studies and possible mechanisms. J Oral Microbiol 2023; 15:2145729. [PMID: 36407281 PMCID: PMC9673791 DOI: 10.1080/20002297.2022.2145729] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background Fusobacterium nucleatum (F. nucleatum) is an anaerobic oral commensal and the major coaggregation bridge organism linking early and late colonisers. In recent years, a large number of studies suggest that F. nucleatum is closely related to the development of various systemic diseases, such as cardiovascular diseases, adverse pregnancy outcomes, inflammatory bowel diseases, cancer, Alzheimer's disease, respiratory infection, rheumatoid arthritis, etc. Objective To review the effect of F. nucleatum on systemic diseases and its possible pathogenesis and to open new avenues for prevention and treatment of F. nucleatum-associated systemic diseases. Design The research included every article published up to July 2022 featuring the keywords 'Systemic diseases' OR 'Atherosclerotic cardiovascular diseases' OR 'Atherosclerosis' OR 'Adverse pregnancy outcomes' OR 'Inflammatory bowel disease' OR 'Ulcerative colitis' OR 'Crohn’s disease' OR 'Cancers' OR 'Oral squamous cell carcinomas' OR 'Gastrointestinal cancers' OR 'Colorectal cancer' OR 'Breast cancer' OR 'Genitourinary cancers' OR 'Alzheimer’s disease ' OR 'Rheumatoid arthritis' OR 'Respiratory diseases' AND 'Fusobacterium nucleatum' OR 'Periodontal pathogen' OR 'Oral microbiota' OR 'Porphyromonas gingivalis' and was conducted in the major medical databases. Results F. nucleatum can induce immune response and inflammation in the body through direct or indirect pathways, and thus affect the occurrence and development of systemic diseases. Only by continuing to investigate the pathogenic lifestyles of F. nucleatum will we discover the divergent pathways that may be leveraged for diagnostic, preventive and therapeutic purposes.
Collapse
Affiliation(s)
- Zixin Fan
- Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Shanghai road 1, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Pengzhou Tang
- Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Shanghai road 1, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Cheng Li
- Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Shanghai road 1, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qi Yang
- Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Shanghai road 1, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Xu
- Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Shanghai road 1, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuan Su
- State KeyLaboratory of Reproductive Medicine, Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu Li
- Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Shanghai road 1, Nanjing, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
8
|
Prevalence of Microorganisms in Atherosclerotic Plaques of Coronary Arteries: A Systematic Review and Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8678967. [PMID: 36506809 PMCID: PMC9731758 DOI: 10.1155/2022/8678967] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 07/05/2022] [Indexed: 12/02/2022]
Abstract
Background In this systematic review and meta-analysis, the existence of pathogens in atherosclerotic plaques of coronary arteries was investigated in coronary arteries diseases (CAD) patients. Methods This study was designed and implemented up to 31 August 2020. The findings present according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) checklist. Two independent reviewers (I.RJ and S.H) performed a comprehensive search on four different English databases including PubMed, ISI, Scopus, and Embase. In order to assess the quality of the articles, a checklist prepared by The Joanna Briggs Institute (JBI) was used. Results Finally, 44 studies were selected. The prevalence of different microorganisms in coronary arteries were as follows: Aggregatibacter actinomycetemcomitans (46.2%), Campylobacter rectus (43.0%), Chlamydia pneumonia (42.8%), Cytomegalovirus (29.1%), Helicobacter pylori (18.9%), Herpes simplex virus type 1 (5.9%), Porphyromonas gingivalis (42.6%), Prevotella intermedia (47.6%), Tannerella forsythia (43.7%), and Treponema denticola (32.9%). Conclusion Based on the result of this meta-analysis, Prevotella intermedia and Aggregatibacter actinomycetemcomitans are the most common microorganisms in atherosclerotic plaques of coronary arteries and may have an important role in the development of atherosclerosis.
Collapse
|
|
9
|
Curia MC, Pignatelli P, D’Antonio DL, D’Ardes D, Olmastroni E, Scorpiglione L, Cipollone F, Catapano AL, Piattelli A, Bucci M, Magni P. Oral Porphyromonas gingivalis and Fusobacterium nucleatum Abundance in Subjects in Primary and Secondary Cardiovascular Prevention, with or without Heterozygous Familial Hypercholesterolemia. Biomedicines 2022; 10:biomedicines10092144. [PMID: 36140246 PMCID: PMC9496065 DOI: 10.3390/biomedicines10092144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/26/2022] Open
Abstract
Background: Low-grade chronic inflammation, promoted by dysbiosis of the gut and oral microbiota, has been shown to contribute to individual susceptibility to atherosclerotic cardiovascular disease (ASCVD). High oral Porphyromonas gingivalis (Pg) and lower Fusobacterium nucleatum (Fn) concentrations have been associated with clinical and experimental atherosclerosis. We assessed oral Pg and Fn abundance in very high-risk patients with previously diagnosed ASCVD, with or without heterozygous familial hypercholesterolemia (HeFH), in subjects with HeFH in primary prevention and in healthy subjects. Methods: In this cross-sectional study, 40 patients with previously diagnosed ASCVD (10 with genetically proven HeFH, and 30 without FH), 26 subjects with HeFH in primary prevention, and 31 healthy subjects were selected to quantify oral Pg and Fn abundance by qPCR and assess oral health status. Results: Compared to healthy subjects, patients with previously diagnosed ASCVD showed greater Pg abundance (1101.3 vs. 192.4, p = 0.03), but similar Fn abundance. HeFH patients with ASCVD had an even greater Pg abundance than did non-HeFH patients and healthy subjects (1770.6 vs. 758.4 vs. 192.4, respectively; p = 0.048). No differences were found in the levels of Pg and Fn abundance in HeFH subjects in primary prevention, as compared to healthy subjects. Conclusions: Greater oral Pg abundance is present in very high-risk patients with previously diagnosed ASCVD, with or without FH, suggesting a potential relationship with CV events. Future studies will assess the predictive value of Pg abundance measurement in ASCVD risk stratification.
Collapse
Affiliation(s)
- Maria Cristina Curia
- Department of Medical, Oral and Biotechnological Sciences, Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
- Correspondence: (M.C.C.); (M.B.); (P.M.)
| | - Pamela Pignatelli
- Department of Medical, Oral and Biotechnological Sciences, Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
- Department of Oral and Maxillofacial Sciences, “Sapienza” University of Rome, 00185 Rome, Italy
| | - Domenica Lucia D’Antonio
- Department of Medical, Oral and Biotechnological Sciences, Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
| | - Damiano D’Ardes
- Regional Center for the Study of Atherosclerosis, Hypertension and Dyslipidemia, “SS Annunziata” Hospital—ASL, 66100 Chieti, Italy
- C.A.S.T., Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
| | - Elena Olmastroni
- Epidemiology and Preventive Pharmacology Service (SEFAP), Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Luca Scorpiglione
- Regional Center for the Study of Atherosclerosis, Hypertension and Dyslipidemia, “SS Annunziata” Hospital—ASL, 66100 Chieti, Italy
- C.A.S.T., Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
| | - Francesco Cipollone
- Regional Center for the Study of Atherosclerosis, Hypertension and Dyslipidemia, “SS Annunziata” Hospital—ASL, 66100 Chieti, Italy
- C.A.S.T., Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
| | - Alberico Luigi Catapano
- Epidemiology and Preventive Pharmacology Service (SEFAP), Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
- IRCCS MultiMedica, Sesto S. Giovanni, 20099 Milan, Italy
| | - Adriano Piattelli
- Master Course in Microsurgery in Odontostomatology, Saint Camillus International University for Health Sciences (Unicamillus), 00131 Rome, Italy
- Fondazione Villaserena per la Ricerca, 65013 Città Sant’Angelo, Pescara, Italy
- Casa di Cura Villa Serena, 65013 Città Sant’Angelo, Pescara, Italy
| | - Marco Bucci
- Regional Center for the Study of Atherosclerosis, Hypertension and Dyslipidemia, “SS Annunziata” Hospital—ASL, 66100 Chieti, Italy
- C.A.S.T., Università degli Studi “Gabriele d’Annunzio” di Chieti-Pescara, 66100 Chieti, Italy
- Correspondence: (M.C.C.); (M.B.); (P.M.)
| | - Paolo Magni
- Epidemiology and Preventive Pharmacology Service (SEFAP), Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
- IRCCS MultiMedica, Sesto S. Giovanni, 20099 Milan, Italy
- Correspondence: (M.C.C.); (M.B.); (P.M.)
| |
Collapse
|
|
10
|
Cross Talk between Synthetic Food Colors (Azo Dyes), Oral Flora, and Cardiovascular Disorders. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12147084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Synthetic food colors are important ingredients in the food industry. These synthetic food colorants are azo dyes, majorly acidic in nature such as Allura red and Tartrazine. They are present in sweets, carbonated drinks, meat products, and candies to attract the consumers. This review article is an attempt to explain the adverse effects of azo dyes and their association with oral cavities and cardiovascular disorders. These synthetic dyes (azo dyes) have staining effects on dentin. Poor dental care accelerates the bacterial accumulation on the dental crown (Gram-negative bacteria P. gingivalis, T. denticola, and T. forsythia and Gram-positive bacteria Strep. Gordonii), causing the washing of enamel, forming dental plaque. Bacterial pathogens (P. ginigivalis and F. nacleatum) release different chemicals (FadA and Fap2) that bind to protein on the cell by producing an inflammatory response through different line-host defenses, such as Gingival epithelial cells (ECs), Hemi-desmosomes, and desmosomes, which helps the bacterium migration from the cell–cell junction. This makes the junctions slightly open up and makes the whole vessel permeable, through which the bacterium enters into the blood stream line. This leads to different major arteries, such as the carotid artery, and causes the accumulation of plaque in major cardiac arteries, which causes different cardiovascular disorders. These bacterial species present in gums cause cardiovascular diseases, such as ischemic heart disease, coronary artery disease, heart attacks and strokes, and arrhythmias, which can lead to death.
Collapse
|
|
11
|
Xu AA, Kennedy LK, Hoffman K, White DL, Kanwal F, El-Serag HB, Petrosino JF, Jiao L. Dietary Fatty Acid Intake and the Colonic Gut Microbiota in Humans. Nutrients 2022; 14:2722. [PMID: 35807903 PMCID: PMC9268849 DOI: 10.3390/nu14132722] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/19/2022] [Accepted: 06/28/2022] [Indexed: 11/16/2022] Open
Abstract
A high-fat diet has been associated with systemic diseases in humans and alterations in gut microbiota in animal studies. However, the influence of dietary fatty acid intake on gut microbiota in humans has not been well studied. In this cross-sectional study, we examined the association between intake of total fatty acids (TFAs), saturated fatty acids (SFAs), trans fatty acids (TrFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), n3-FAs, and n6-FAs, and the community composition and structure of the adherent colonic gut microbiota. We obtained 97 colonic biopsies from 34 participants with endoscopically normal colons. Microbial DNA was used to sequence the 16S rRNA V4 region. The DADA2 and SILVA database were used for amplicon sequence variant assignment. Dietary data were collected using the Block food frequency questionnaire. The biodiversity and the relative abundance of the bacterial taxa by higher vs. lower fat intake were compared using the Mann−Whitney test followed by multivariable negative binomial regression model. False discovery rate−adjusted p-values (q value) < 0.05 indicated statistical significance. The beta diversity of gut bacteria differed significantly by intake of all types of fatty acids. The relative abundance of Sutterella was significantly higher with higher intake of TFAs, MUFAs, PUFAs, and n6-FAs. The relative abundance of Tyzzerella and Fusobacterium was significantly higher with higher intake of SFAs. Tyzzerella was also higher with higher intake of TrFA. These observations were confirmed by multivariate analyses. Dietary fat intake was associated with bacterial composition and structure. Sutterella, Fusobacterium, and Tyzzerella were associated with fatty acid intake.
Collapse
Affiliation(s)
- Anthony A. Xu
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; (A.A.X.); (L.K.K.); (D.L.W.); (F.K.); (H.B.E.-S.)
| | - Luke K. Kennedy
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; (A.A.X.); (L.K.K.); (D.L.W.); (F.K.); (H.B.E.-S.)
| | - Kristi Hoffman
- The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; (K.H.); (J.F.P.)
| | - Donna L. White
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; (A.A.X.); (L.K.K.); (D.L.W.); (F.K.); (H.B.E.-S.)
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
- Texas Medical Center Digestive Disease Center, Houston, TX 77030, USA
| | - Fasiha Kanwal
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; (A.A.X.); (L.K.K.); (D.L.W.); (F.K.); (H.B.E.-S.)
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
- Texas Medical Center Digestive Disease Center, Houston, TX 77030, USA
- Section of Gastroenterology, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
| | - Hashem B. El-Serag
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; (A.A.X.); (L.K.K.); (D.L.W.); (F.K.); (H.B.E.-S.)
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
- Texas Medical Center Digestive Disease Center, Houston, TX 77030, USA
- Section of Gastroenterology, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
| | - Joseph F. Petrosino
- The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; (K.H.); (J.F.P.)
| | - Li Jiao
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; (A.A.X.); (L.K.K.); (D.L.W.); (F.K.); (H.B.E.-S.)
| |
Collapse
|
|
12
|
Zhou J, Liu L, Wu P, Zhao L, Wu Y. Fusobacterium nucleatum Accelerates Atherosclerosis via Macrophage-Driven Aberrant Proinflammatory Response and Lipid Metabolism. Front Microbiol 2022; 13:798685. [PMID: 35359716 PMCID: PMC8963492 DOI: 10.3389/fmicb.2022.798685] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/03/2022] [Indexed: 12/18/2022] Open
Abstract
Periodontitis, an oral chronic inflammatory disease, is reported to show an association with atherosclerotic vascular disease. Fusobacterium nucleatum is an oral commensal bacterium that is abundantly implicated in various forms of periodontal diseases; however, its role in the pathogenesis of atherosclerosis is unclear. This study aimed to elucidate the underlying pathogenic mechanisms of atherosclerosis induced by F. nucleatum to provide new insight on the prevention and treatment of atherosclerosis. We used an animal model, that is, ApoE–/– mice were infected with F. nucleatum by oral gavage, and in vitro co-culture models to assess the pathogenicity of F. nucleatum. The results indicate that F. nucleatum ATCC 25586 invaded aortic tissues and substantially increased the progression of atherosclerotic lesions. In addition, F. nucleatum changed plaque composition into a less-stable phenotype, characterized with increased subcutaneous macrophage infiltration, M1 polarization, lipid deposition, cell apoptosis, and reduced extracellular matrix and collagen content. The serum levels of pro-atherosclerotic factors, such as interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), c-reactive protein, and oxidized low-density lipoprotein (ox-LDL) and microRNAs (miR-146a, miR-155, and miR-23b) were considerably increased after F. nucleatum stimulation, whereas HDL-c level was reduced. F. nucleatum induced in vitro macrophage apoptosis in a time- and dose-dependent manner. F. nucleatum facilitated ox-LDL–induced cholesterol phagocytosis and accumulation by regulating the expression of lipid metabolism-related genes (AR-A1, ACAT1, ABCA1, and ABCG1). F. nucleatum further worsened the atherosclerotic plaque microenvironment by considerably increasing the levels of IL-6; IL-1β; TNF-α; MCP-1; and MMP-2, 8, and 9 and by suppressing fibronectin (FN) 1 levels during foam cell formation. This study shows that F. nucleatum ATCC 25586 is implicated in atherosclerosis by causing aberrant activation and lipid metabolism in macrophage.
Collapse
Affiliation(s)
- Jieyu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Peiyao Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lei Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yafei Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
13
|
De Seta F, Lonnee-Hoffmann R, Campisciano G, Comar M, Verstraelen H, Vieira-Baptista P, Ventolini G, Lev-Sagie A. The Vaginal Microbiome: III. The Vaginal Microbiome in Various Urogenital Disorders. J Low Genit Tract Dis 2022; 26:85-92. [PMID: 34928258 PMCID: PMC8719503 DOI: 10.1097/lgt.0000000000000645] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE This series of articles, titled The Vaginal Microbiome (VMB), written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the recent findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders. MATERIALS AND METHODS A search of PubMed database was performed, using the search terms "vaginal microbiome" with "Candida," "vaginitis," "urinary microbiome," "recurrent urinary tract infections," "sexually transmitted infections," "human immunodeficiency virus," "human papillomavirus," "nonspecific vaginitis," "vulvodynia," and "vulvovaginal symptoms." Full article texts were reviewed. Reference lists were screened for additional articles. The third article in this series describes VMB in various urogenital disorders. RESULTS Variable patterns of the VMB are found in patients with vulvovaginal candidiasis, challenging the idea of a protective role of lactobacilli. Highly similar strains of health-associated commensal bacteria are shared in both the bladder and vagina of the same individual and may provide protection against urinary tract infections. Dysbiotic VMB increases the risk of urinary tract infection. Loss of vaginal lactic acid-producing bacteria combined with elevated pH, increase the risk for sexually transmitted infections, although the exact protective mechanisms of the VMB against sexually transmitted infections are still unknown. CONCLUSIONS The VMB may constitute a biological barrier to pathogenic microorganisms. When the predominance of lactobacilli community is disrupted, there is an increased risk for the acquisition of various vaginal pathogents. Longitudinal studies are needed to describe the association between the host, bacterial, and fungal components of the VMB.
Collapse
Affiliation(s)
- Francesco De Seta
- Institute for Maternal and Child Health “IRCCS Burlo Garofolo,” Trieste, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Risa Lonnee-Hoffmann
- Department of Obstetrics and Gynecology, St Olavs University Hospital, Trondheim, Norway
- Institute for Clinical and Molecular Medicine, Norwegian University for Science and Technology, Trondheim, Norway
| | | | - Manola Comar
- Institute for Maternal and Child Health “IRCCS Burlo Garofolo,” Trieste, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Hans Verstraelen
- Department of Obstetrics & Gynaecology, Ghent University Hospital, Ghent, Belgium
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Pedro Vieira-Baptista
- Hospital Lusíadas Porto, Porto, Portugal
- Lower Genital Tract Unit, Centro Hospitalar de São João, Porto, Portugal
- LAP, a Unilabs Company, Porto, Portugal
| | - Gary Ventolini
- Department of Obstetrics and Gynecology, Distinguish University Professor, School of Medicine, Texas Tech University Health Sciences Center, Permian Basin, Odessa, TX
| | - Ahinoam Lev-Sagie
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| |
Collapse
|
|
14
|
Porphyromonas gingivalis exacerbates ulcerative colitis via Porphyromonas gingivalis peptidylarginine deiminase. Int J Oral Sci 2021; 13:31. [PMID: 34593756 PMCID: PMC8484350 DOI: 10.1038/s41368-021-00136-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 08/18/2021] [Accepted: 08/29/2021] [Indexed: 11/09/2022] Open
Abstract
Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0-40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31-40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.
Collapse
|
|
15
|
Liu Y, Huang W, Wang J, Ma J, Zhang M, Lu X, Liu J, Kou Y. Multifaceted Impacts of Periodontal Pathogens in Disorders of the Intestinal Barrier. Front Immunol 2021; 12:693479. [PMID: 34386004 PMCID: PMC8353228 DOI: 10.3389/fimmu.2021.693479] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Periodontal disease, a common inflammatory disease, is considered a hazardous factor that contributes to the development of diseases of the digestive system as well as other systems. The bridge between periodontitis and systemic diseases is believed to be periodontal pathogens. The intestine, as part of the lower gastrointestinal tract, has a close connection with the oral cavity. Within the intestine, the intestinal barrier acts as a multifunctional system including microbial, mucous, physical and immune barrier. The intestinal barrier forms the body's first line of defense against external pathogens; its breakdown can lead to pathological changes in the gut and other organs or systems. Reports in the literature have described how oral periodontal pathogens and pathobiont-reactive immune cells can transmigrate to the intestinal mucosa, causing the destruction of intestinal barrier homeostasis. Such findings might lead to novel ideas for investigating the relationship between periodontal disease and other systemic diseases. This review summarizes studies on the effects of periodontal pathogens on the intestinal barrier, which might contribute to understanding the link between periodontitis and gastrointestinal diseases.
Collapse
Affiliation(s)
- Yingman Liu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Wenxuan Huang
- School of Stomatology, Shenyang Medical College, Shenyang, China
| | - Jiaqi Wang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Jiaojiao Ma
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Manman Zhang
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xiaoying Lu
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Jie Liu
- Science Experiment Center, China Medical University, Shenyang, China
| | - Yurong Kou
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
- Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| |
Collapse
|
|
16
|
Li L, Zhang YL, Liu XY, Meng X, Zhao RQ, Ou LL, Li BZ, Xing T. Periodontitis Exacerbates and Promotes the Progression of Chronic Kidney Disease Through Oral Flora, Cytokines, and Oxidative Stress. Front Microbiol 2021; 12:656372. [PMID: 34211440 PMCID: PMC8238692 DOI: 10.3389/fmicb.2021.656372] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/01/2021] [Indexed: 12/25/2022] Open
Abstract
Periodontitis is a type of systemic immune inflammation that is caused by the complex infection of a variety of microorganisms in the subgingival plaque and the imbalance of the microbial ecological environment in the mouth. Periodontitis and chronic kidney disease (CKD) share many risk factors, such as obesity, smoking, and age. A growing body of data supports a strong correlation between periodontitis and kidney disease. Evidence supports the role of periodontal inflammation and elevated serum inflammatory mediators in renal atherosclerosis, renal deterioration, and end-stage renal disease (ESRD) development. Periodontitis is a risk factor for kidney disease. However, to our knowledge, there are few studies detailing the possible link between periodontitis and CKD. This review summarizes the possible mechanisms underlying periodontitis and CKD. More importantly, it highlights novel and potential pathogenic factors for CKD, including bacteria, pro-inflammatory mediators and oxidative stress. However, most research on the relationship between periodontitis and systemic disease has not determined causality, and these diseases are largely linked by bidirectional associations. Future research will focus on exploring these links to contribute to new treatments for CKD.
Collapse
Affiliation(s)
- Ling Li
- School of Stomatology, Anhui Medical University, Hefei, China
| | - Ya-Li Zhang
- School of Stomatology, Anhui Medical University, Hefei, China
| | - Xing-Yu Liu
- School of Stomatology, Anhui Medical University, Hefei, China
| | - Xiang Meng
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
| | - Rong-Quan Zhao
- School of Stomatology, Anhui Medical University, Hefei, China
| | - Lin-Lin Ou
- School of Stomatology, Anhui Medical University, Hefei, China
| | - Bao-Zhu Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Tian Xing
- School of Stomatology, Anhui Medical University, Hefei, China
- Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China
| |
Collapse
|
|
17
|
Alkharaan H, Lu L, Gabarrini G, Halimi A, Ateeb Z, Sobkowiak MJ, Davanian H, Fernández Moro C, Jansson L, Del Chiaro M, Özenci V, Sällberg Chen M. Circulating and Salivary Antibodies to Fusobacterium nucleatum Are Associated With Cystic Pancreatic Neoplasm Malignancy. Front Immunol 2020; 11:2003. [PMID: 32983143 PMCID: PMC7484485 DOI: 10.3389/fimmu.2020.02003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/24/2020] [Indexed: 12/21/2022] Open
Abstract
Objectives Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic cancer. The presence of oral microbes in pancreatic tissue or cyst fluid has been associated with high-grade dysplasia (HGD) and cancer. The present study aims at investigating if humoral immunity to pancreas-associated oral microbes reflects IPMN severity. Design Paired plasma (n = 109) and saliva (n = 65) samples were obtained from IPMN pancreatic cystic tumor cases and controls, for anti-bacterial antibody analysis and DNA quantification by enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. Tumor severity was graded by histopathology, laboratory, and clinical data. Circulating plasma and salivary antibody reactivity to a pancreas-associated oral microbe panel were measured by ELISA and correlated to tumor severity. Results The patient group with high-risk cystic tumors (HGD and/or associated invasive cancer) shows ample circulating IgG reactivity to Fusobacterium nucleatum (F. nucleatum) but not to Granulicatella adiacens (G. adiacens), which is independent of the salivary bacteria DNA levels. This group also shows higher salivary IgA reactivity to F. nucleatum, Fap2 of F. nucleatum, and Streptococcus gordonii (S. gordonii) compared to low-risk IPMN and controls. The salivary antibody reactivity to F. nucleatum and Fap2 are found to be highly correlated, and cross-competition assays further confirm that these antibodies appear cross-reactive. Conclusion Our findings indicate that humoral reactivity against pancreas-associated oral microbes may reflect IPMN severity. These findings are beneficial for biomarker development.
Collapse
Affiliation(s)
- Hassan Alkharaan
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
- College of Dentistry, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Liyan Lu
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
- Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Giorgio Gabarrini
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Asif Halimi
- Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Huddinge, Sweden
| | - Zeeshan Ateeb
- Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Huddinge, Sweden
| | | | - Haleh Davanian
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Carlos Fernández Moro
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
- Department of Clinical Pathology/Cytology, Karolinska University Hospital, Huddinge, Sweden
| | - Leif Jansson
- Clinic of Endodontics and Periodontology, Eastman Institute Stockholm, Stockholm, Sweden
| | - Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, CO, United States
| | - Volkan Özenci
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Margaret Sällberg Chen
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
- Tenth People’s Hospital, Tongji University, Shanghai, China
| |
Collapse
|
|
18
|
Li B, Xia Y, Hu B. Infection and atherosclerosis: TLR-dependent pathways. Cell Mol Life Sci 2020; 77:2751-2769. [PMID: 32002588 PMCID: PMC7223178 DOI: 10.1007/s00018-020-03453-7] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 12/15/2022]
Abstract
Atherosclerotic vascular disease (ASVD) is a chronic process, with a progressive course over many years, but it can cause acute clinical events, including acute coronary syndromes (ACS), myocardial infarction (MI) and stroke. In addition to a series of typical risk factors for atherosclerosis, like hyperlipidemia, hypertension, smoking and obesity, emerging evidence suggests that atherosclerosis is a chronic inflammatory disease, suggesting that chronic infection plays an important role in the development of atherosclerosis. Toll-like receptors (TLRs) are the most characteristic members of pattern recognition receptors (PRRs), which play an important role in innate immune mechanism. TLRs play different roles in different stages of infection of atherosclerosis-related pathogens such as Chlamydia pneumoniae (C. pneumoniae), periodontal pathogens including Porphyromonas gingivalis (P. gingivalis), Helicobacter pylori (H. pylori) and human immunodeficiency virus (HIV). Overall, activation of TLR2 and 4 seems to have a profound impact on infection-related atherosclerosis. This article reviews the role of TLRs in the process of atherosclerosis after C. pneumoniae and other infections and the current status of treatment, with a view to providing a new direction and potential therapeutic targets for the study of ASVD.
Collapse
Affiliation(s)
- Bowei Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuanpeng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
19
|
Hashizume-Takizawa T, Yamaguchi Y, Kobayashi R, Shinozaki-Kuwahara N, Saito M, Kurita-Ochiai T. Oral challenge with Streptococcus sanguinis induces aortic inflammation and accelerates atherosclerosis in spontaneously hyperlipidemic mice. Biochem Biophys Res Commun 2019; 520:507-513. [DOI: 10.1016/j.bbrc.2019.10.057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/05/2019] [Indexed: 12/11/2022]
|
|
20
|
Targeting Programmed Fusobacterium nucleatum Fap2 for Colorectal Cancer Therapy. Cancers (Basel) 2019; 11:cancers11101592. [PMID: 31635333 PMCID: PMC6827134 DOI: 10.3390/cancers11101592] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/13/2019] [Accepted: 10/14/2019] [Indexed: 12/18/2022] Open
Abstract
Colorectal patients generally have the maximum counts of Fusobacterium nucleatum (F. nucleatum) in tumors and elevate colorectal adenomas and carcinomas, which show the lowest rate of human survival. Hence, F. nucleatum is a diagnostic marker of colorectal cancer (CRC). Studies demonstrated that targeting fusobacterial Fap2 or polysaccharide of the host epithelium may decrease fusobacteria count in the CRC. Attenuated F. nucleatum-Fap2 prevents transmembrane signals and inhibits tumorigenesis inducing mechanisms. Hence, in this review, we hypothesized that application of genetically programmed fusobacterium can be skillful and thus reduce fusobacterium in the CRC. Genetically programmed F. nucleatum is a promising antitumor strategy.
Collapse
|
|
21
|
Yang Z, Ji G. Fusobacterium nucleatum-positive colorectal cancer. Oncol Lett 2019; 18:975-982. [PMID: 31423156 PMCID: PMC6607099 DOI: 10.3892/ol.2019.10433] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 05/17/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is an important threat to human health and the fourth leading cause of mortality worldwide. Accumulating evidence indicates that the composition of the intestinal flora is associated with the occurrence of CRC. Fusobacterium nucleatum (Fn), one of the highly enriched bacteria in CRC tissues, invades the mucosa with adhesion factors and virulence proteins, interacts with the host immune system and promotes the occurrence and development of CRC and chemoresistance. Fn infection is prevalent in human colorectal carcinoma, although the infection rate varies in different regions. Fn may be used as a prognostic indicator of CRC. It is important to understand the multi-pathway carcinogenic mechanisms associated with CRC in order to develop novel antibacterial drugs against Fn. The current review summarizes the role of Fn and relevant research concerning CRC published in recent years, focusing on Fn infection in CRC, pathogenesis of Fn, Fn-positive CRC treatment, screening and prevention strategies against Fn-positive CRC.
Collapse
Affiliation(s)
- Zhenhua Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China.,Department of Digestive Endoscopy, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| |
Collapse
|
|
22
|
Proença MA, Biselli JM, Succi M, Severino FE, Berardinelli GN, Caetano A, Reis RM, Hughes DJ, Silva AE. Relationship between Fusobacterium nucleatum, inflammatory mediators and microRNAs in colorectal carcinogenesis. World J Gastroenterol 2018; 24:5351-5365. [PMID: 30598580 PMCID: PMC6305535 DOI: 10.3748/wjg.v24.i47.5351] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/29/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the effect of Fusobacterium nucleatum (F. nucleatum) on the microenvironment of colonic neoplasms and the expression of inflammatory mediators and microRNAs (miRNAs).
METHODS Levels of F. nucleatum DNA, cytokine gene mRNA (TLR2, TLR4, NFKB1, TNF, IL1B, IL6 and IL8), and potentially interacting miRNAs (miR-21-3p, miR-22-3p, miR-28-5p, miR-34a-5p, miR-135b-5p) were measured by quantitative polymerase chain reaction (qPCR) TaqMan® assays in DNA and/or RNA extracted from the disease and adjacent normal fresh tissues of 27 colorectal adenoma (CRA) and 43 colorectal cancer (CRC) patients. KRAS mutations were detected by direct sequencing and microsatellite instability (MSI) status by multiplex PCR. Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network.
RESULTS Overabundance of F. nucleatum in neoplastic tissue compared to matched normal tissue was detected in CRA (51.8%) and more markedly in CRC (72.1%). We observed significantly greater expression of TLR4, IL1B, IL8, and miR-135b in CRA lesions and TLR2, IL1B, IL6, IL8, miR-34a and miR-135b in CRC tumours compared to their respective normal tissues. Only two transcripts for miR-22 and miR-28 were exclusively downregulated in CRC tumour samples. The mRNA expression of IL1B, IL6, IL8 and miR-22 was positively correlated with F. nucleatum quantification in CRC tumours. The mRNA expression of miR-135b and TNF was inversely correlated. The miRNA:mRNA interaction network suggested that the upregulation of miR-34a in CRC proceeds via a TLR2/TLR4-dependent response to F. nucleatum. Finally, KRAS mutations were more frequently observed in CRC samples infected with F. nucleatum and were associated with greater expression of miR-21 in CRA, while IL8 was upregulated in MSI-high CRC.
CONCLUSION Our findings indicate that F. nucleatum is a risk factor for CRC by increasing the expression of inflammatory mediators through a possible miRNA-mediated activation of TLR2/TLR4.
Collapse
Affiliation(s)
- Marcela Alcântara Proença
- Department of Biology, UNESP, Univ. Estadual Paulista, Campus of São José do Rio Preto, São José do Rio Preto, São Paulo 15054-000, Brazil
| | - Joice Matos Biselli
- Department of Biology, UNESP, Univ. Estadual Paulista, Campus of São José do Rio Preto, São José do Rio Preto, São Paulo 15054-000, Brazil
| | - Maysa Succi
- Department of Biology, UNESP, Univ. Estadual Paulista, Campus of São José do Rio Preto, São José do Rio Preto, São Paulo 15054-000, Brazil
| | - Fábio Eduardo Severino
- Department of Surgery and Orthopedics, Faculty of Medicine, UNESP, Univ. Estadual Paulista, Campus of Botucatu, Botucatu, São Paulo 18618-687, Brazil
| | | | - Alaor Caetano
- Endoscopy Center of Rio Preto, São José do Rio Preto, São Paulo 15015-700, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo 14784-400, Brazil
- Life and Health Sciences Research Institute, University of Minho, Campus Gualtar, Braga 4710-057, Portugal
- ICVS/3B’s-PT Government Associate Laboratory, Campus Gualtar, Braga 4710-057, Portugal
| | - David J Hughes
- Cancer Biology and Therapeutics Group, UCD Conway Institute, University College Dublin, Dublin D04 V1W8, Ireland
| | - Ana Elizabete Silva
- Department of Biology, UNESP, Univ. Estadual Paulista, Campus of São José do Rio Preto, São José do Rio Preto, São Paulo 15054-000, Brazil
| |
Collapse
|
|
23
|
Pereira LC, Nascimento JCR, Rêgo JMC, Canuto KM, Crespo-Lopez ME, Alvarez-Leite JI, Baysan A, Oriá RB. Apolipoprotein E, periodontal disease and the risk for atherosclerosis: a review. Arch Oral Biol 2018; 98:204-212. [PMID: 30503976 DOI: 10.1016/j.archoralbio.2018.11.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 09/25/2018] [Accepted: 11/10/2018] [Indexed: 12/26/2022]
Abstract
The association between cardiovascular and periodontal diseases is characterized by chronic inflammatory processes, with a high prevalence worldwide and complex genetic-environment interactions. Although apolipoprotein E4 (ApoE4), one of the isoforms coded by a polymorphic APOE gene, has been widely recognized as a risk factor for cardiovascular diseases and as an immunoinflammatory factor, less is known regarding how ApoE4 affects atherosclerosis in periodontitis patients. The aim of this review was to investigate the potential underlying mechanisms related to APOE4 that could increase the risk of periodontal disease and, ultimately, of atherosclerosis. There have only been a few studies addressing apoE polymorphisms in patients with chronic periodontitis. To date, no studies have been performed that have assessed how ApoE4 affects atherosclerotic disease in chronic periodontitis patients. Although clinical studies are warranted, experimental studies have consistently documented the presence of periodontal pathogens, which are usually found in the oral cavity and saliva, in the atherosclerotic plaques of ApoE-deficient mice. In addition, in this review, the potential role of the APOE4 allele as an example of antagonistic pleiotropy during human evolution and its relation to oral health is discussed.
Collapse
Affiliation(s)
- L C Pereira
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - J C R Nascimento
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - J M C Rêgo
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - K M Canuto
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - M E Crespo-Lopez
- Laboratory of Molecular Pharmacology, Institute of Biological Sciences, Federal University of Para, Belém, PA, Brazil
| | - J I Alvarez-Leite
- Institute of Biological Sciences, Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - A Baysan
- Institute of Dentistry, Barts and the London, School of Medicine and Dentistry, Queen Mary University, London, UK
| | - R B Oriá
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
| |
Collapse
|
|
24
|
Chukkapalli SS, Ambadapadi S, Varkoly K, Jiron J, Aguirre JI, Bhattacharyya I, Morel LM, Lucas AR, Kesavalu L. Impaired innate immune signaling due to combined Toll-like receptor 2 and 4 deficiency affects both periodontitis and atherosclerosis in response to polybacterial infection. Pathog Dis 2018; 76:5142697. [PMID: 30351354 DOI: 10.1093/femspd/fty076] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 10/22/2018] [Indexed: 12/15/2022] Open
Abstract
Plasma membrane-associated Toll-like receptor (TLR2 and TLR4) signaling contributes to oral microbe infection-induced periodontitis and atherosclerosis. We recently reported that either TLR2 or TLR4 receptor deficiency alters recognition of a consortium of oral pathogens, modifying host responses in periodontitis and atherosclerosis. We evaluated the effects of combined TLR2-/-TLR4-/- double knockout mice on innate immune signaling and induction of periodontitis and atherosclerosis after polybacterial infection with Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum in a mouse model. Multispecies infections established gingival colonization in all TLR2-/-TLR4-/- mice and induced production of bacterial-specific IgG antibodies. In combined TLR2-/-TLR4-/- deficiency there was, however, reduced alveolar bone resorption and mild gingival inflammation with minimal migration of junctional epithelium and infiltration of inflammatory cells. This indicates a central role for TLR2 and TLR4 in periodontitis. Atherosclerotic plaque progression was markedly reduced in infected TLR2-/-TLR4-/- mice or in heterozygotes indicating a profound effect on plaque growth. However, bacterial genomic DNA was detected in multiple organs in TLR2-/-TLR4-/- mice indicating an intravascular dissemination from gingival tissue to heart, aorta, kidney and lungs. TRL2 and TLR4 were dispensable for systemic spread after polybacterial infections but TLR2 and 4 deficiency markedly reduces atherosclerosis induced by oral bacteria.
Collapse
Affiliation(s)
- Sasanka S Chukkapalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| | - Sriram Ambadapadi
- Biodesign Institute, Arizona State University, Tempe, 727 E Tyler St 85287, AZ, USA
| | - Kyle Varkoly
- Biodesign Institute, Arizona State University, Tempe, 727 E Tyler St 85287, AZ, USA
| | - Jessica Jiron
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jose Ignacio Aguirre
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Indraneel Bhattacharyya
- Department of Oral Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| | - Laurence M Morel
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Alexandra R Lucas
- Biodesign Institute, Arizona State University, Tempe, 727 E Tyler St 85287, AZ, USA
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA.,Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
| |
Collapse
|
|
25
|
Velsko IM, Shaddox LM. Consistent and reproducible long-term in vitro growth of health and disease-associated oral subgingival biofilms. BMC Microbiol 2018; 18:70. [PMID: 29996764 PMCID: PMC6042318 DOI: 10.1186/s12866-018-1212-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 06/27/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Several in vitro oral biofilm growth systems can reliably construct oral microbiome communities in culture, yet their stability and reproducibility through time has not been well characterized. Long-term in vitro growth of natural biofilms would enable use of these biofilms in both in vitro and in vivo studies that require complex microbial communities with minimal variation over a period of time. Understanding biofilm community dynamics in continuous culture, and whether they maintain distinct signatures of health and disease, is necessary to determine the reliability and applicability of such models to broader studies. To this end, we performed next-generation sequencing on biofilms grown from healthy and disease-site subgingival plaque for 80 days to assess stability and reliability of continuous oral biofilm growth. RESULTS Biofilms were grown from subgingival plaque collected from periodontitis-affected sites and healthy individuals for ten eight-day long generations, using hydroxyapatite disks. The bacterial community in each generation was determined using Human Oral Microbe Identification by Next-Generation Sequencing (HOMINGS) technology, and analyzed in QIIME. Profiles were steady through the ten generations, as determined by species abundance and prevalence, Spearman's correlation coefficient, and Faith's phylogenetic distance, with slight variation predominantly in low abundance species. Community profiles were distinct between healthy and disease site-derived biofilms as demonstrated by weighted UniFrac distance throughout the ten generations. Differentially abundant species between healthy and disease site-derived biofilms were consistent throughout the generations. CONCLUSIONS Healthy and disease site-derived biofilms can reliably maintain consistent communities through ten generations of in vitro growth. These communities maintain signatures of health and disease and of individual donors despite culture in identical environments. This subgingival oral biofilm growth and perpetuation model may prove useful to studies involving oral infection or cell stimulation, or those measuring microbial interactions, which require the same biofilms over a period of time.
Collapse
Affiliation(s)
- Irina M Velsko
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA
- Research Laboratory for Archaeology and the History of Art, University of Oxford, Oxford, OX1 3QY, UK
- Present Address: Department of Biological Sciences, Clemson University, Clemson, SC, 29634, USA
| | - Luciana M Shaddox
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA.
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA.
| |
Collapse
|
|
26
|
Chukkapalli SS, Easwaran M, Rivera-Kweh MF, Velsko IM, Ambadapadi S, Dai J, Larjava H, Lucas AR, Kesavalu L. Sequential colonization of periodontal pathogens in induction of periodontal disease and atherosclerosis in LDLRnull mice. Pathog Dis 2017; 75:ftx003. [PMID: 28104616 DOI: 10.1093/femspd/ftx003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 01/13/2017] [Indexed: 12/13/2022] Open
Abstract
Periodontal disease (PD) and atherosclerotic vascular disease (ASVD) are both chronic inflammatory diseases with a polymicrobial etiology and have been epidemiologically associated. The purpose is to examine whether periodontal bacteria that infect the periodontium can also infect vascular tissues and enhance pre-existing early aortic atherosclerotic lesions in LDLRnull mice. Mice were orally infected with intermediate bacterial colonizer Fusobacterium nucleatum for the first 12 weeks followed by late bacterial colonizers (Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia) for the remaining 12 weeks mimicking the human oral microbiota ecological colonization. Genomic DNA from all four bacterial was detected in gingival plaque by PCR, consistently demonstrating infection of mouse gingival surfaces. Infected mice had significant levels of IgG and IgM antibodies, alveolar bone resorption, and showed apical migration of junctional epithelium revealing the induction of PD. These results support the ability of oral bacteria to cause PD in mice. Detection of bacterial genomic DNA in systemic organs indicates hematogenous dissemination from the gingival pockets. Bacterial infection did not alter serum lipid fractions or serum amyloid A levels and did not induce aortic atherosclerotic plaque. This is the first study examining the causal role of periodontal bacteria in induction of ASVD in LDLRnull mice.
Collapse
Affiliation(s)
- Sasanka S Chukkapalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610-0424, USA
| | - Meena Easwaran
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610-0424, USA
| | - Mercedes F Rivera-Kweh
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610-0424, USA
| | - Irina M Velsko
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610-0424, USA
| | - Sriram Ambadapadi
- Biodesign Institute, Arizona state University, Tempe, AZ 85287-5001, USA
| | - Jiayin Dai
- Division of Periodontics and Dental Hygiene, University of British Columbia, Vancouver, BCV6T 1Z4, Canada
| | - Hannu Larjava
- Division of Periodontics and Dental Hygiene, University of British Columbia, Vancouver, BCV6T 1Z4, Canada
| | - Alexandra R Lucas
- Biodesign Institute, Arizona state University, Tempe, AZ 85287-5001, USA
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610-0424, USA.,Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610-0424, USA
| |
Collapse
|
|
27
|
Guo SH, Wang HF, Nian ZG, Wang YD, Zeng QY, Zhang G. Immunization with alkyl hydroperoxide reductase subunit C reduces Fusobacterium nucleatum load in the intestinal tract. Sci Rep 2017; 7:10566. [PMID: 28874771 PMCID: PMC5585165 DOI: 10.1038/s41598-017-11127-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/18/2017] [Indexed: 12/19/2022] Open
Abstract
Fusobacterium nucleatum (Fn) is an important tumour-associated bacterium in colorectal cancer (CRC). The antioxidant protein alkyl hydroperoxide reductase subunit C (AhpC) can induce strong antibacterial immune response during various pathogen infections. Our study aimed to evaluate the efficacy of Fn-AhpC as a candidate vaccine. In this work, by western blot analysis, we showed that Fn-AhpC recombinant protein could be recognized specifically by antibodies present in the sera of CRC patients; using the mouse Fn-infection model, we observed that systemic prophylactic immunization with AhpC/alum conferred significant protection against infection in 77.3% of mice. In addition, we measured the anti-AhpC antibody level in the sera of CRC patients and found that there was no obvious increase of anti-AhpC antibodies in the early-stage CRC group. Furthermore, we treated Fn with the sera from both immunized mice and CRC patients and found that sera with high anti-AhpC antibodies titre could inhibit Fn growth. In conclusion, our findings support the use of AhpC as a potential vaccine candidate against inhabitation or infection of Fn in the intestinal tract, which could provide a practical strategy for the prevention of CRC associated with Fn infection.
Collapse
Affiliation(s)
- Song-He Guo
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Hai-Fang Wang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Gang Nian
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yi-Dan Wang
- Department of School of Life Science, Sun Yat-sen University, Guangzhou, China
| | - Qiu-Yao Zeng
- Department of Clinical Laboratory Medicine, Sun Yat-sen University cancer center, Guangzhou, China, Guangzhou, China
| | - Ge Zhang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
|
28
|
Wang HF, Li LF, Guo SH, Zeng QY, Ning F, Liu WL, Zhang G. Evaluation of antibody level against Fusobacterium nucleatum in the serological diagnosis of colorectal cancer. Sci Rep 2016; 6:33440. [PMID: 27678333 PMCID: PMC5039407 DOI: 10.1038/srep33440] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 08/24/2016] [Indexed: 12/14/2022] Open
Abstract
Fusobacterium nucleatum (F. nucleatum, Fn) is associated with the colorectal cancer (CRC). Fn-infection could induce significant levels of serum Fn-specific antibodies in human and mice. The objective of this study was to identify Fn-infection that elicit a humoral response in patients with CRC and evaluate the diagnostic performance of serum anti-Fn antibodies. In this work, we showed the mean absorbance value of anti-Fn-IgA and -IgG in the CRC group were significantly higher than those in the benign colon disease group and healthy control group (P < 0.001). The sensitivity and specificity of ELISA for the detection of anti-Fn-IgA were 36.43% and 92.71% based on the optimal cut-off. The combination of anti-Fn-IgA and carcino-embryonic antigen (CEA) was better for diagnosing CRC (Sen: 53.10%, Spe: 96.41%; AUC = 0.848). Furthermore, combining anti-Fn-IgA with CEA and carbohydrate antigen 19-9 (CA19-9) (Sen: 40.00%, Spe: 94.22%; AUC = 0.743) had the better ability to classify CRC patients with stages I-II. These results suggested that Fn-infection elicited high level of serum anti-Fn antibodies in CRC patients, and serum anti-Fn-IgA level may be a potential diagnosing biomarker for CRC. Serum anti-Fn-IgA in combination with CEA and CA19-9 increases the sensitivity of detecting early CRC.
Collapse
Affiliation(s)
- Hai-Fang Wang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lin-Fang Li
- Department of Clinical Laboratory Medicine, Sun Yat-sen University cancer center, Guangzhou, China
| | - Song-He Guo
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qiu-Yao Zeng
- Department of Clinical Laboratory Medicine, Sun Yat-sen University cancer center, Guangzhou, China
| | - Fen Ning
- Guangzhou Institute of Pediatrics, Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wan-Li Liu
- Department of Clinical Laboratory Medicine, Sun Yat-sen University cancer center, Guangzhou, China
| | - Ge Zhang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
29
|
Langbach O, Kristoffersen AK, Abesha-Belay E, Enersen M, Røkke O, Olsen I. Oral, intestinal, and skin bacteria in ventral hernia mesh implants. J Oral Microbiol 2016; 8:31854. [PMID: 27476443 PMCID: PMC4967714 DOI: 10.3402/jom.v8.31854] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 05/29/2016] [Accepted: 06/21/2016] [Indexed: 11/14/2022] Open
Abstract
Background In ventral hernia surgery, mesh implants are used to reduce recurrence. Infection after mesh implantation can be a problem and rates around 6–10% have been reported. Bacterial colonization of mesh implants in patients without clinical signs of infection has not been thoroughly investigated. Molecular techniques have proven effective in demonstrating bacterial diversity in various environments and are able to identify bacteria on a gene-specific level. Objective The purpose of this study was to detect bacterial biofilm in mesh implants, analyze its bacterial diversity, and look for possible resemblance with bacterial biofilm from the periodontal pocket. Methods Thirty patients referred to our hospital for recurrence after former ventral hernia mesh repair, were examined for periodontitis in advance of new surgical hernia repair. Oral examination included periapical radiographs, periodontal probing, and subgingival plaque collection. A piece of mesh (1×1 cm) from the abdominal wall was harvested during the new surgical hernia repair and analyzed for bacteria by PCR and 16S rRNA gene sequencing. From patients with positive PCR mesh samples, subgingival plaque samples were analyzed with the same techniques. Results A great variety of taxa were detected in 20 (66.7%) mesh samples, including typical oral commensals and periodontopathogens, enterics, and skin bacteria. Mesh and periodontal bacteria were further analyzed for similarity in 16S rRNA gene sequences. In 17 sequences, the level of resemblance between mesh and subgingival bacterial colonization was 98–100% suggesting, but not proving, a transfer of oral bacteria to the mesh. Conclusion The results show great bacterial diversity on mesh implants from the anterior abdominal wall including oral commensals and periodontopathogens. Mesh can be reached by bacteria in several ways including hematogenous spread from an oral site. However, other sites such as gut and skin may also serve as sources for the mesh biofilm.
Collapse
Affiliation(s)
- Odd Langbach
- Department of Gastroenterologic Surgery, Akershus University Hospital, University of Oslo, Lørenskog, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway;
| | | | - Emnet Abesha-Belay
- Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Morten Enersen
- Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Ola Røkke
- Department of Gastroenterologic Surgery, Akershus University Hospital, University of Oslo, Lørenskog, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ingar Olsen
- Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| |
Collapse
|
|
30
|
Cui D, Li H, Lei L, Chen C, Yan F. Nonsurgical periodontal treatment reduced aortic inflammation in ApoE(-/-) mice with periodontitis. SPRINGERPLUS 2016; 5:940. [PMID: 27386384 PMCID: PMC4929118 DOI: 10.1186/s40064-016-2637-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 06/21/2016] [Indexed: 01/07/2023]
Abstract
Background Although the correlation between periodontal infection and atherosclerotic lesions has been well recognized, whether and how the nonsurgical periodontal treatment (NSPT) can improve the vascular inflammation has not been investigated clearly. Methods Thirty-two apolipoprotein E−/− (apoE−/−) mice were randomly divided into four groups: (1) Con group: no treatment, blank control group; (2) Lig group: ligature-induced-periodontitis group; (3) Lig-N group: ligatures were removed on the 7th day; (4) Lig-SRP group: ligatures were removed on the 7th day, and scaling and root planing (SRP) were performed on the 9th day. All the animals were euthanized on the 30th day. Alveolar bone loss (ABL) was assessed under microcomputed tomography. Systemic inflammatory status and lipid contents in the plasma were detected. Expression of several surrogate markers for vascular inflammation was evaluated by immunohistology and quantitative real time PCR. Results NSPT reduced ABL, improved lipid profile, and inhibited systemic inflammation with reduced plasma interleukin-6 (IL-6) level in apoE−/− mice; in addition, reduced inflammation in arterial wall was observed in NSPT treated mice, showing less vascular cell adhesion molecule-1 expression and less macrophage adhesion; furthermore, NSPT improved elastic fiber fragmentation disorder in the aortic wall, thus preserved elasticity of aortic artery. Conclusion Ligature-induced periodontitis can lead to inflammatory response in the vascular wall and NSPT has beneficial effect on the early stage of atherosclerosis process in the articular wall by reducing systemic inflammation and improving lipid profile.
Collapse
Affiliation(s)
- Di Cui
- Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhong Yang Road, Nanjing, 210008 Jiangsu People's Republic of China
| | - Houxuan Li
- Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhong Yang Road, Nanjing, 210008 Jiangsu People's Republic of China
| | - Lang Lei
- Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhong Yang Road, Nanjing, 210008 Jiangsu People's Republic of China
| | - Changxing Chen
- Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhong Yang Road, Nanjing, 210008 Jiangsu People's Republic of China
| | - Fuhua Yan
- Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhong Yang Road, Nanjing, 210008 Jiangsu People's Republic of China
| |
Collapse
|
|
31
|
Audirac-Chalifour A, Torres-Poveda K, Bahena-Román M, Téllez-Sosa J, Martínez-Barnetche J, Cortina-Ceballos B, López-Estrada G, Delgado-Romero K, Burguete-García AI, Cantú D, García-Carrancá A, Madrid-Marina V. Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study. PLoS One 2016; 11:e0153274. [PMID: 27115350 PMCID: PMC4846060 DOI: 10.1371/journal.pone.0153274] [Citation(s) in RCA: 264] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 03/25/2016] [Indexed: 12/27/2022] Open
Abstract
Cervical cancer (CC) is caused by high-risk human papillomavirus persistence due to the immunosuppressive tumor microenvironment mediated by cytokines. Vaginal microbiota determines the presence of certain cytokines locally. We assessed the association between cervical microbiota diversity and the histopathological diagnosis of each stage of CC, and we evaluated mRNA cervical expression levels of IL-4, IL-6, IL-10, TGF-β1, TNF-α and IFN-γ across the histopathological diagnosis and specific bacterial clusters. We determined the cervical microbiota by high throughput sequencing of 16S rDNA amplicons and classified it in community state types (CST). Mean difference analyses between alpha-diversity and histopathological diagnosis were carried out, as well as a β-diversity analysis within the histological diagnosis. Cervical cytokine mRNA expression was analyzed across the CSTs and the histopathological diagnoses. We found a significant difference in microbiota's diversity in NCL-HPV negative women vs those with squamous intraepithelial lesions (SIL) and CC(p = 0.006, p = 0.036).When β-diversity was evaluated, the CC samples showed the highest variation within groups (p<0.0006) and the largest distance compared to NCL-HPV negative ones (p<0.00001). The predominant bacteria in women with normal cytology were L. crispatus and L. iners, whereas for SIL, it was Sneathia spp. and for CC, Fusobacterium spp. We found higher median cervical levels of IL-4 and TGF-β1 mRNA in the CST dominated by Fusobacterium spp. These results suggest that the cervical microbiota may be implicated in cervical cancer pathology. Further cohort studies are needed to validate these findings.
Collapse
Affiliation(s)
- Astride Audirac-Chalifour
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | - Kirvis Torres-Poveda
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | - Margarita Bahena-Román
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | - Juan Téllez-Sosa
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | - Jesús Martínez-Barnetche
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | - Bernardo Cortina-Ceballos
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | | | - Karina Delgado-Romero
- Centro de Atención para la Salud de la Mujer (CAPASAM) (Center for Women’s Health), Health Services of the State of Morelos, Cuernavaca, Mexico
| | - Ana I. Burguete-García
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| | - David Cantú
- Division of Clinical Research, Instituto Nacional de Cancerología (INCan), SS, Mexico City, Mexico
| | | | - Vicente Madrid-Marina
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP) (Chronic Infectious Diseases and Cancer Division, Center for Research on Infectious Diseases, National Institute of Public Health), Cuernavaca, Morelos, Mexico
| |
Collapse
|
|
32
|
Bui FQ, Johnson L, Roberts J, Hung SC, Lee J, Atanasova KR, Huang PR, Yilmaz Ö, Ojcius DM. Fusobacterium nucleatum infection of gingival epithelial cells leads to NLRP3 inflammasome-dependent secretion of IL-1β and the danger signals ASC and HMGB1. Cell Microbiol 2016; 18:970-81. [PMID: 26687842 DOI: 10.1111/cmi.12560] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 12/13/2015] [Accepted: 12/15/2015] [Indexed: 12/14/2022]
Abstract
Fusobacterium nucleatum is an invasive anaerobic bacterium that is associated with periodontal disease. Previous studies have focused on virulence factors produced by F. nucleatum, but early recognition of the pathogen by the immune system remains poorly understood. Although an inflammasome in gingival epithelial cells (GECs) can be stimulated by danger-associated molecular patterns (DAMPs) (also known as danger signals) such as ATP, inflammasome activation by this periodontal pathogen has yet to be described in these cells. This study therefore examines the effects of F. nucleatum infection on pro-inflammatory cytokine expression and inflammasome activation in GECs. Our results indicate that infection induces translocation of NF-κB into the nucleus, resulting in cytokine gene expression. In addition, infection activates the NLRP3 inflammasome, which in turn activates caspase-1 and stimulates secretion of mature IL-1β. Unlike other pathogens studied until now, F. nucleatum activates the inflammasome in GECs in the absence of exogenous DAMPs such as ATP. Finally, infection promotes release of other DAMPs that mediate inflammation, such as high-mobility group box 1 protein and apoptosis-associated speck-like protein, with a similar time-course as caspase-1 activation. Thus, F. nucleatum expresses the pathogen-associated molecular patterns necessary to activate NF-κB and also provides an endogenous DAMP to stimulate the inflammasome and further amplify inflammation through secretion of secondary DAMPs.
Collapse
Affiliation(s)
- Fiona Q Bui
- Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, 95343, USA
| | - Larry Johnson
- Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, 95343, USA.,Immunobiology Program, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941, Brazil
| | - JoAnn Roberts
- Department of Periodontology and Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Shu-Chen Hung
- Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, 95343, USA
| | - Jungnam Lee
- Department of Periodontology and Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Kalina Rosenova Atanasova
- Department of Periodontology and Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Pei-Rong Huang
- Center for Molecular and Clinical Immunology, Chang Gung University, Gueishan, Taoyuan 333, Taiwan
| | - Özlem Yilmaz
- Department of Periodontology and Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32610, USA
| | - David M Ojcius
- Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, 95343, USA
| |
Collapse
|
|
33
|
Chukkapalli SS, Velsko IM, Rivera-Kweh MF, Zheng D, Lucas AR, Kesavalu L. Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice. PLoS One 2015; 10:e0143291. [PMID: 26619277 PMCID: PMC4664240 DOI: 10.1371/journal.pone.0143291] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 11/02/2015] [Indexed: 12/17/2022] Open
Abstract
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoEnull mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.
Collapse
Affiliation(s)
- Sasanka S. Chukkapalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Irina M. Velsko
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Mercedes F. Rivera-Kweh
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
| | - Donghang Zheng
- Division of Cardiovascular Medicine, Department of Medicine, Gainesville, Florida, United States of America
| | - Alexandra R. Lucas
- Division of Cardiovascular Medicine, Department of Medicine, Gainesville, Florida, United States of America
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
| |
Collapse
|
|
34
|
Nayar G, Gauna A, Chukkapalli S, Velsko I, Kesavalu L, Cha S. Polymicrobial infection alter inflammatory microRNA in rat salivary glands during periodontal disease. Anaerobe 2015; 38:70-75. [PMID: 26481834 DOI: 10.1016/j.anaerobe.2015.10.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/08/2015] [Accepted: 10/10/2015] [Indexed: 12/11/2022]
Abstract
Periodontal disease initiated by subgingival pathogens is linked with diminished secretion of saliva, and implies pathogenic bacteria dissemination to or affects secondary sites such as the salivary glands. MicroRNAs activated in response to bacteria may modulate immune responses against pathogens. Therefore, Sprague-Dawley rats were infected by oral lavage consisting of polymicrobial inocula, namely Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, or sham-infected for 12 weeks (n = 6). We quantified inflammatory miRNA expression levels of miRNA-132, miR-146a, and miR-155 at secondary sites to the primary infection of the gingiva, including submandibular salivary glands, lacrimal glands, and pancreas. The presence of bacteria was detected in situ at secondary sites. Infected rat gingiva showed increased relative expression of miR-155. In contrast, miRNA-155 expression was decreased in submandibular salivary glands, along with positive identification of P. gingivalis in 2/6 and T. denticola in 1/6 rat salivary glands. Furthermore, miRNA-132 and miRNA-146a were significantly decreased in the pancreas of infected rats. This study is the first to show primary periodontal infections can alter miRNA profiles in secondary sites such as the salivary gland and pancreas. Whether these alterations contribute to pathologies of salivary glands in Sjögren's syndrome or of pancreas in diabetes warrants further investigation.
Collapse
Affiliation(s)
- Gautam Nayar
- Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA
| | - Adrienne Gauna
- Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA
| | - Sasanka Chukkapalli
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA
| | - Irina Velsko
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA
| | - Lakshmyya Kesavalu
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA; Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA.
| | - Seunghee Cha
- Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL, 32610, USA
| |
Collapse
|
|
35
|
Periodontal pathogens invade gingiva and aortic adventitia and elicit inflammasome activation in αvβ6 integrin-deficient mice. Infect Immun 2015; 83:4582-93. [PMID: 26371120 DOI: 10.1128/iai.01077-15] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 09/04/2015] [Indexed: 12/21/2022] Open
Abstract
The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6(-/-) mouse model to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobially infected Itgβ6(-/-) mice demonstrate greater susceptibility to gingival colonization/infection, with severe gingival inflammation, apical migration of the junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of the gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Levels of atherosclerosis risk factors, including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation, were significantly altered by polybacterial infection, demonstrating an enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific Toll-like receptor (TLR) and nucleotide-binding domain- and leucine-rich-repeat-containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of the aorta demonstrated larger atherosclerotic plaques in Itgβ6(-/-) mice than in wild-type (WT) mice but no significant difference in atherosclerotic plaque size between mice with polybacterial infection and mice with sham infection. Fluorescence in situ hybridization demonstrated active invasion of the aortic adventitial layer by P. gingivalis. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly increases local aortic oxidative stress. These results are the first to demonstrate the mechanism of the host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens.
Collapse
|