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Table of Contents
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 73-78

The Pathogenicity of Actinomyces naeslundii is associated with polymicrobial interactions: A systematic review

1 Department of Basic Medical Sciences, Kulliyyah of Nursing, International Islamic University Malaysia, Kuantan Campus; Cluster for Cancer Research Initiative IIUM (COCRII), International Islamic University of Malaysia, Pahang, Malaysia
2 Cluster for Cancer Research Initiative IIUM (COCRII); Department of Fundamental Dental and Medical Sciences, Kulliyyah of Dentistry, International Islamic University Malaysia, Kuantan Campus, Pahang, Malaysia
3 Cluster for Cancer Research Initiative IIUM (COCRII); Department of Paediatric Dentistry and Dental Public Health, Kulliyyah of Dentistry, International Islamic University Malaysia, Kuantan Campus, Pahang, Malaysia

Date of Submission14-Jul-2020
Date of Decision20-Aug-2020
Date of Acceptance16-Sep-2020
Date of Web Publication17-Oct-2020

Correspondence Address:
Noratikah Othman
Department of Basic Medical Sciences, Kulliyah of Nursing, International Islamic University Malaysia, Kuantan Campus, 25200 Kuantan, Pahang
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/SDJ.SDJ_31_20

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The aim of this systematic review was to demonstrate how the oral pathogenicity of Actinomyces naeslundii is associated with its interactions with other microbes in the oral microbiome. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P) 2015 protocol was used for this review. Articles published between January 2010 and February 2020 were searched in the PubMed, Web of Science, Science Direct, and Scopus databases. Articles included in the final analysis mainly discuss the symbiotic relationship of A. naeslundii with other oral microbes. The findings show that A. naeslundii is not directly involved in oral pathogenesis; instead, initial tooth surface colonization is promoted by polymicrobial interactions in the oral microbiome in which A. naeslundii participates.

Keywords: Actinomyces naeslundii, biofilm, oral diseases, polymicrobial interactions

How to cite this article:
Rismayuddin NA, Kamaluddin WN, Arzmi MH, Ismail AF, Aidid EM, Othman N. The Pathogenicity of Actinomyces naeslundii is associated with polymicrobial interactions: A systematic review. Sci Dent J 2020;4:73-8

How to cite this URL:
Rismayuddin NA, Kamaluddin WN, Arzmi MH, Ismail AF, Aidid EM, Othman N. The Pathogenicity of Actinomyces naeslundii is associated with polymicrobial interactions: A systematic review. Sci Dent J [serial online] 2020 [cited 2021 Jan 24];4:73-8. Available from: https://www.scidentj.com/text.asp?2020/4/3/73/298441

  Background Top

According to the World Dental Federation, healthy oral cavity is a state of being free from chronic mouth and facial pain, oral infection and sores, periodontal diseases, tooth decay, tooth loss, and other diseases and disorder that limit an individual's capacity in biting, chewing, smiling, and psychosocial well-being.[1] At least 3.58 billion people worldwide suffer from diseases in the oral cavity. The most common condition is caries in the permanent teeth of adults.[2] Caries affects an estimated 2.4 billion adults worldwide, while caries in primary teeth affects over 486 million children. An increase in oral diseases worldwide has caused concerns among health-care practitioners. Various factors contribute to this increase and are mostly related to improper oral care.[3] The World Health Survey (2002–2004) indicated that the demand for oral health care in third-world countries is beyond the capacity of their health-care systems.[4] Moreover, oral diseases are more prevalent among low-income and poverty-stricken populations.[5]

A balanced oral microbiome is important in sustaining an optimal environment in the oral cavity. However, under certain conditions in which the oral environment is imbalanced (a phenomenon known as dysbiosis), oral diseases such as caries can occur.[6] Common bacteria in the human oral microbiome include Candida albicans and Streptococcus, Lactobacillus, Actinomyces, and Enterococcus spp. Microbial coaggregation also occurs among secondary bacterial colonizers, such as Bacteroides, Campylobacter, Capnocytophaga, Fusobacterium, Gemella, Granulicatella, Haemophilus, Neisseria, and Veillonella.[7]

Actinomyces species are Gram-positive anaerobic bacteria that reside in the oral cavity. These bacteria contribute to various diseases, such as actinomycosis, caused by Actinomyces israelii. Even though studies have shown the relationship between Actinomyces israelli and oral disease, the role of A. naeslundii in oral pathogenesis, including periodontal diseases, remains unclear.[8],[9],[10]A. naeslundii can attach to the acquired salivary pellicle on the exposed surface of teeth and hence is frequently isolated at the basal layer of dental plaque.[11] The bacterium can adhere to different surfaces of the oral cavity due to the fimbriae it has. There are two bacterial fimbriae found on the surface of the bacterium: The type 1 fimbriae used for adhesion-receptor binding to adhere to the tooth surface and collagen, while type 2 fimbriae bind to β-linked galactose and galactosamine appendages on epithelial and bacterial surfaces.[12]

Polymicrobial interactions are defined as interactions of microorganisms of different species. Such interactions can occur in planktonic and biofilm forms.[13],[14] This review aimed to determine the role of polymicrobial interactions of Actinomyces naeslundii with other oral microbes in inducing oral pathogenesis. The hypothesis of the study is that polymicrobial interactions induce the pathogenicity of A. naeslundii in the oral cavity.

  Materials and Methods Top


This review used the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P) 2015 protocol, intended primarily for meta-analyses and systematic reviews.[15]

Formulation of the review question

The P atient population or problem, Intervention or exposure, C omparison of interventions or exposures, and O utcome of interest (PICO) model was used to formulate the review question.[16] As suggested by Higgins and Green, this formulation was used as a model for developing review questions and search terms in the Cochrane Handbook for Systematic Review for Interventions.[17] The question formulated for this review was, “What are the role of polymicrobial interaction between A. naeslundii and oral microbiome in inducing oral pathogenesis?”

Article search

Articles published from January 2010 to February 2020 were searched in four electronic databases (PubMed, Web of Science, Scopus, and Science Direct). Boolean search was applied to optimize the article search. The main search keywords used were (A. naeslundii) AND (oral cavity) AND (oral disease OR oral diseases) AND (oral microbiome OR oral microbiota OR oral microflora). The same search strategy was employed in all databases.

Eligibility criteria

Study that discussed the polymicrobial interactions between A. naeslundii and other microbes in the oral microbiome were included in this review. The inclusion criteria based on the PICO framework where P: Polymicrobial interaction, I: A. naeslundii, C: Interactions with other microbes in the oral microbiome O: A. naeslundii pathogenicity. Studies that did not focus on the PICO framework were excluded as they did not meet the review selection criteria. Gray literature, case reports, letters, conference abstracts, and reviews were also excluded.

Study selection

The articles that have potential for inclusion in this review were done independently by four authors (AFI, EMA, NAO, and MHA). The selected articles were reviewed by two authors to determine their eligibility (NAR, WNF). The titles and abstracts of the selected articles were screened to identify the studies that met the inclusion criteria. After this process, full-text assessment of the selected articles was performed to exclude the ones that did not meet the inclusion criteria. The PRISMA-P protocol flow diagram for the selection of studies is shown in [Figure 1].
Figure 1: The Preferred Reporting Items for Systematic Reviews (PRISMA-P) 2015 protocol

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Risk of bias assessment

To ensure transparency of the systematic review results, the included studies were evaluated for risk of bias. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Randomized Controlled Trials was used by two authors (NAR and WNF) to determine the quality and transparency of the study's methods. This evaluation determines the degree to which a study minimizes the risk of bias in its design, performance, and analysis.[18] Most included studies were of high quality, as indicated by the low risk of bias.

  Results Top

Search results and excluded studies

The initial database search resulted in 5448 papers. Three additional articles that are highly relevant to the review study were handpicked based on the inclusion criteria. The articles were retrieved from FEMS Immunology and Medical Microbiology, The Journal of Translational Medicine and Proceedings of The National Academy of Sciences of the United States of America. The addition of the articles was agreed among the authors and the consensus was achieved. The articles were identified for the duplicates, resulted in the inclusion of 4645 articles. The remaining articles were narrowed based on their titles and abstracts resulting to the total of 17 potentially relevant articles. After assessing the full text, 11 articles were excluded due to the absence of data on the interaction of A. naeslundii with the oral microbiome in oral pathogenesis. Another three articles were excluded due to the absence of discussion on the association of A. naeslundii with the oral microbiome, oral pathogenesis, and polymicrobial interactions of A. naeslundii. The articles were further evaluated, and a total of three articles were selected for the final analysis. Kappa score among the authors showed a high level of agreement (K > 0.90).

Characteristics of the included studies

All included studies investigated the polymicrobial interactions of A. naeslundii with other members of the oral microbiome. All three were published in the last 10 years. The countries where the studies were conducted were also identified. The included studies usedin vitro experiments using members of oral microbiome.[14],[19],[20] The characteristics of the included studies are reported in [Table 1] and the symbiotic relationship of A. naeslundii with other members of oral microbiome is summarized in [Table 2].
Table 1: Overview of the selected studies

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Table 2: Oral microorganism that develop symbiotic relationships with Actinomyces naeslundii

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Risk of bias assessment

The quality of the included studies was evaluated using the JBI Critical Appraisal Tools. The assessment revealed that methods for the determination of the studies' sample sizes were not reported. Nevertheless, the overall quality score for the included studies was “high.” The results of the risk of bias assessment are reported in [Table 3].
Table 3: Assessment of the risk of bias associated with the included studies using the Joanna Briggs institute appraisal tools

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  Discussion Top

The polymicrobial interactions of A. naeslundii identified in the included studies are associated with cytokine expression and biofilm formation.

The profile of the cytokines and chemokines released by the oral surface mucosa was identified using a novel multi-species model.[20] The cytokines were responsible for the inflammation in the gum tissues.[20] To imitate the oral environment, the biofilms that include A. naeslundii were developed on rigid gas-permeable lenses (RGPL). RGPL is a model that is used to evaluate host cell response toward mono- or polymicrobial biofilms through the identification of the regulated genes. The expressed product is associated with inflammation, adaptive and innate immunity.[20] Cytokines are small proteins that are involved in cell signaling, which mediate and regulate the immune response.[21] The increase production of cytokines induced by A. naeslundii in polymicrobial interactions may contribute to the oral inflammation which linked to oral pathogenesis.

From the study, cytokines production was induced by mono- and polymicrobial biofilms. The polymicrobial biofilms of A. naeslundii, Streptococcus sanguinis, and Fusobacterium nucleatum were found to expressed interleukin-6 (IL-6) from OKF4 cells higher that in mono-species biofilm. OKF4 cell is an immortalized epithelial cell line cultured to form a confluent monolayer.[22] The cytokine molecule IL-6 has important functions in the division and development of various cells that involved in inflammation.[23] The polymicrobial biofilms also showed increased levels of IL-8 and fractalkine in basal epithelial cells.[20] IL-8 or also known as CXCL8 induces inflammation and neutrophil-mediated tissue damage.[24] The expression of IL-6 and IL-8 at high levels has been previously linked to oral carcinogenesis.[25] Thus, these findings supported the hypothesis of the present study that the pathogenicity of A. naeslundii is induced by polymicrobial interactions.

The interaction of the A. naeslundii with oral microbiome was determined through biofilm formation. The symbiotic relationship of A. naeslundii with other oral microbiomes was evaluated in patients with peri-implant mucositis (PM).[19] A longitudinal study was done by observing patients receiving preventive maintenance therapy (PMT) and without PMT. PMT is a clinical treatment and assessment procedure that is performed during routine dental visits to sustain the long-term condition of peri-implant tissues.[26] A significant increase in the isolated frequency of F. nucleatum and a decrease in A. naeslundii was observed in those patients. Fusobacteria required A. naeslundii for biofilm growth and improved the initial colonization of streptococci in two-species biofilms.[27] This is likely due to the characteristic production of catalase in A. naeslundii, which inactivates the hydrogen peroxide necessary for anaerobic fusobacterial growth.[27] In addition, A. naeslundii was also identified as the primary bacterium which resides in the biofilm and is associated in co-adhesion with other oral colonisers, including F. nucleatum. Primary and secondary colonizers grow gradually in line with the growth of biofilm biomass and thickness, eventually becoming persistent in the oral cavity.[28] This is in accordance to the previous study that A. naeslundii provide foundation for the biofilm development.[29],[30]

In addition, the role of polymicrobial interactions between A. naeslundii with C. albicans and Streptococcus mutans was also reported.[14] Mono-species and polymicrobial biofilms were developed in different growth media; ASM and RPMI-1640, which induced the formation of yeast and hyphal forms, respectively. This study illustrated the role of polymicrobial interactions governed by the morphology of the yeast and the microorganisms incorporated in the biofilms. The symbiotic interaction shown in the study can be linked to the ability of these microorganisms to co-aggregate, which eventually leads to the increase of microbial biomass in polymicrobial biofilm consortiums.[31] The study showed that different strains of C. albicans produced biofilms with different biomass and metabolic activities when co-cultured with A. naeslundii. The biomass was significantly increased when A. naeslundii and clinical strains of C. albicans were co-cultured together. Furthermore, all the C. albicans strains showed increased metabolic activity when co-cultured for biofilm production with A. naeslundii. Thus, the results suggest that symbiotic interactions between A. naeslundii and other microorganisms may be responsible for the high colonization rate in the mouth cavity. However, depending on the microbial interactions present, C. albicans metabolic activity decreased in tri-species biofilms. The previous study suggested that microbial interactions of bacteria are dependent on various factors such as competition of nutrient and production of quorum sensing molecules such as farnesol.[32] This outcome indicates the essential role that polymicrobial interactions play in the development of oral disease and supports the hypothesis posited that interactions with other oral microbes induce pathogenicity in A. naeslundii.

This review has an important limitation. The lack of extensive research into the pathogenic role of A. naeslundii and the scarce relevant literature made it difficult to ascertain the pathogenic role of the polymicrobial interactions of A. naeslundii with other members of the oral microbiome. Within this limitation, this is to the best of our knowledge, the first systematic review to explore the role of the polymicrobial interactions of A. naeslundii in the oral microbiome.

  Conclusion Top

The outcomes of this systematic review revealed that A. naeslundii isolated from the oral cavity is able to co-adhere with other oral bacteria, subsequently inducing its colonization to the tooth surface. In conclusion, A. naeslundii pathogenicity is induced by polymicrobial interactions.

Financial support and sponsorship

Ministry of Higher Education, Malaysia (FRGS/1/2018/SKK11UIAM/03/1), and International Islamic University Malaysia (P-RIGS18-036-0036) for the funding.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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