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Mesa, F.; Magan-Fernandez, A.; , .; Benavides-Reyes, C.; Nibali, L.; Mainas, G.; Rizzo, M. Dysbiosis of the Subgingival Microbiome. Encyclopedia. Available online: https://encyclopedia.pub/entry/22290 (accessed on 20 July 2025).
Mesa F, Magan-Fernandez A,  , Benavides-Reyes C, Nibali L, Mainas G, et al. Dysbiosis of the Subgingival Microbiome. Encyclopedia. Available at: https://encyclopedia.pub/entry/22290. Accessed July 20, 2025.
Mesa, Francisco, Antonio Magan-Fernandez,  , Cristina Benavides-Reyes, Luigi Nibali, Giuseppe Mainas, Manfredi Rizzo. "Dysbiosis of the Subgingival Microbiome" Encyclopedia, https://encyclopedia.pub/entry/22290 (accessed July 20, 2025).
Mesa, F., Magan-Fernandez, A., , ., Benavides-Reyes, C., Nibali, L., Mainas, G., & Rizzo, M. (2022, April 26). Dysbiosis of the Subgingival Microbiome. In Encyclopedia. https://encyclopedia.pub/entry/22290
Mesa, Francisco, et al. "Dysbiosis of the Subgingival Microbiome." Encyclopedia. Web. 26 April, 2022.
Dysbiosis of the Subgingival Microbiome
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This entry is adapted from the peer-reviewed paper 10.3390/medicina58040546

Human microbiomes are polymicrobial structures, and the different microenvironments that harbour them are regulated by environmental factors, complicated inter-microbial communication signals, and hosts’ immune responses. A collective functioning of these microbial communities leads to symbiosis or eubiosis with the host. However, when they are broken due to the dominance of specific species, it leads to dysbiosis and the onset of pathological processes or diseases. In the oral microbiome, extrinsic factors such as diet, tobacco, stress, and antibiotics, as well as intrinsic factors such as poor dental hygiene, cytokines, microRNAs, and diabetes, will have an effect on the microbiota-host immunity axis, promoting the loss of microbial diversity of the symbiotic subgingival biofilm, and favouring the predominance of a certain disease-initiating dysbiotic flora.

periodontitis dysbiosis

1. Introduction: Dysbiosis of the Subgingival Microbiome

Human microbiomes are polymicrobial structures, and the different microenvironments that harbour them are regulated by environmental factors, complicated inter-microbial communication signals, and hosts’ immune responses. A collective functioning of these microbial communities leads to symbiosis or eubiosis with the host. However, when they are broken due to the dominance of specific species, it leads to dysbiosis and the onset of pathological processes or diseases [1]. In the oral microbiome, extrinsic factors such as diet, tobacco, stress, and antibiotics, as well as intrinsic factors such as poor dental hygiene, cytokines, microRNAs, and diabetes, will have an effect on the microbiota-host immunity axis, promoting the loss of microbial diversity of the symbiotic subgingival biofilm, and favouring the predominance of a certain disease-initiating dysbiotic flora. It has been now accepted that periodontitis is caused by an imbalance in the subgingival microbial composition and function (dysbiosis) rather than an infectious process caused by specific periodontopathogenic species [2]. Therefore, the microbiota associated with a state of health is considered more varied and stable over time; whereas the microbiota associated with disease is dominated by ‘specialist’ microorganisms that have metabolic functions and high virulence potential that are adapted to and promote the persistence of a disease state [3][4].
The subgingival microenvironment is characterized by being exposed to the gingival crevicular fluid and to low oxygen pressures when it comes to gingival pockets (patients with periodontitis). This fact favours the accessibility and/or colonization of specific microbial communities (strict anaerobes) that could cause a homeostatic imbalance in the hosts (dysbiotic biofilm) and induce a destructive inflammatory process, affecting the hosts’ immune systems (ecological plaque hypothesis). These characteristics support the evidence that, in patients with periodontitis, the gingival microbiome becomes less diverse and this diversity is also lower in the gastrointestinal tract [5], probably due to the additional nutrients provided by tissue damage (destruction of bones and connective and epithelial tissue) and the physical conditions of deeper and deeper closed spaces (periodontal pockets) [1]. This periodontal dysbiotic biofilm seems to interact with inflammation, as recently proposed by the inflammation-mediated polymicrobial-emergence and dysbiotic-exacerbation (IMPEDE) model, considering inflammation as the main agent, shifting the microbial environment and contributing to disease progression [6]. Anti-inflammatory treatments have not only inhibited periodontitis in mice, rats, and rabbits, but they have also decreased the periodontal bacterial load and reversed dysbiosis [7]. Finally, transcriptomic analyses of the biofilm associated with periodontitis have revealed high expression of genes related to proteolytic enzymes, genes related to peptide transport and iron acquisition, and genes for the synthesis of lipopolysaccharides, all of them demonstrating the clear pro-inflammatory potential of this biofilm [8].
These perturbations in the subgingival microbiome leading to periodontitis have been found in both young and elderly cohorts of periodontal patients [9], but periodontal treatment and hygiene measures have also shown to have an effect in reverting this perturbation. An example of how dental hygiene can influence the disruption of interdental biofilm through the use of interdental brushes has been recently demonstrated by Bourgeois et al. in a clinical trial. They assessed 100 interproximal spaces in 25 healthy young individuals, comparing spaces sanitized using interproximal brushes with others without cleaning. These authors demonstrated, at different times, using rtPCR, that a decrease in red complex bacteria (Socransky) (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) and orange complex bacteria (Fusobacterium nucleatum, Prevotella intermedia, Prevotella nigrescens, Parvimonas micra, Eubacterium nodatum, and Campylobacter rectus) is considered a high and moderate risk for periodontitis according to conventional models based on bacterial cultures. A symbiotic favourable microbiota was re-established (yellow, blue, and purple Socransky bacterial complexes), and, clinically, inflammation in interdental sites decreased after three months, when compared to the initial state [10]. This same improvement in microbiological factors was observed even in in the absence of professional periodontal treatment, in patients trained to perform a proper subgingival root brushing [11].
However, there is another scientific trend that questions: (a) the role of subgingival dysbiosis in periodontitis, i.e., the determining role of age and the hyper-responsiveness of neutrophils in late forms of periodontitis in sensitive adults; (b) the positive experimental response in oral health with anti-aging therapies [12]; (c) the change that occurs in the oral microbiota due to dysregulated immunity [13].

2. Fusobacterium Nucleatum

One of the most representative pathogenic species of the subgingival dysbiotic biofilm is Fusobacterium nucleatum (Fn). The pathogenic species of the genus Fusobacterium spp. include F. nucleatum, F. necrophorum, F. canifelinum, F.gonidiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. russii, F. ulcerans, and F. varium, the first two species being the most pathogenic [14].
Fn is an anaerobic, invasive, and pro-inflammatory bacterium, mainly linked to periodontitis but also associated with odontogenic abscesses and other oropharyngeal diseases such as Lemierre’s syndrome [15]. It is rare in the faecal microbiome and, until recently, never described in colon adenocarcinomas. With an activity similar to Porphyromonas gingivalis, it causes a stimulation of IL-8 (pro-inflammatory cytokine) ten times longer than that caused by E. coli. It expresses numerous adhesins, such as RadD, by which it binds to the SpaP adhesin of Streptococcus mutans and Candida albicans in coaggregation and organization phenomena of the oral biofilm [16][17]. However, three characteristics make Fn a particularly pathogenic bacterium. Fn adhesin A (FadA), expressed on the surface, makes epithelial and endothelial cells adhere and invade, binding to E-cadherin (transmembrane adhesion glycoprotein, responsible for cell-cell union) [18]. Vascular endothelial-cadherin, a protein responsible for cell-cell junction at the endothelial level, was determined as the endothelial receptor for FadA. FadA co-localized with cadherin on endothelial cells caused the relocation of cadherin away from the cell-cell junctions [19]. As a result, endothelial permeability was increased by loss of the intercellular union, allowing the bacteria to cross the endothelium. This crossing mechanism may explain why the organism is able to disseminate systemically to colonize different body sites [20]. FadA is unique to Fn and exists in two forms, namely, non-secreted pre-FadA, bound to the inner surface of the bacterial membrane, and secreted mature mFadA (125 aa protein) that is expressed on the bacterial surface. Together, mFadA and pre-FadA form a high molecular weight complex, necessary for attaching and invading host cells [21]. Lectin-type Fap-2 molecules exhibit a high affinity to bind to polysaccharides that express tumours (d-galactose-β (1–3)-N-acetyl-d-galactosamine (Gal-GalNAc) [22] and exhibit the ability to block the action of immune cells. Finally, the universal autoinducer molecule (AI-2) mediates the intergenetic signalling of multiple species in bacterial communities, determining the microbial quorum sensing and intervening in the formation and maturation of oral biofilm. AI-2 of Fn regulates which microbial and/or periodontopathogenic species are inhibited or mature in the biofilm [23]. Most of the microbiome bacteria coexist in a state of symbiosis (eubiosis), but pathogenic bacteria cause states of dysbiosis or pathogenic alteration of the microbiome. Bacterial dysbiosis is linked to different diseases, such as ulcerative colitis, Crohn’s disease, and colorectal cancer [24].
To summarize, Fn is an anaerobic, invasive, and pro-inflammatory bacterium and is one of the most representative pathogenic species of the subgingival microbial environment. It is mainly linked to periodontitis and other infections, and their main pathogenicity mechanisms are the expression of FadA, the expression of Lectin-type Fap-2 molecules, and the AI-2 molecule that mediates its quorum sensing. These capabilities confer the ability to this species to invade host cells, bind to tumoral cells, and shift the local microbiome.

References

  1. Lamont, R.J.; Koo, H.; Hajishengallis, G. The oral microbiota: Dynamic communities and host interactions. Nat. Rev. Microbiol. 2018, 16, 745–759.
  2. Curtis, M.A.; Diaz, P.I.; Van Dyke, T.E. The role of the microbiota in periodontal disease. Periodontology 2000 2020, 83, 14–25.
  3. Dabdoub, S.M.; Ganesan, S.M.; Kumar, P.S. Comparative metagenomics reveals taxonomically idiosyncratic yet functionally congruent communities in periodontitis. Sci. Rep. 2016, 6, 38993.
  4. Tamashiro, R.; Strange, L.; Schnackenberg, K.; Santos, J.; Gadalla, H.; Zhao, L.; Li, E.C.; Hill, E.; Hill, B.; Sidhu, G.; et al. Stability of healthy subgingival microbiome across space and time. Sci. Rep. 2021, 11, 23987.
  5. Byrd, K.M.; Gulati, A.S. The “Gum-Gut” Axis in Inflammatory Bowel Diseases: A Hypothesis-Driven Review of Associations and Advances. Front. Immunol. 2021, 12, 620124.
  6. Van Dyke, T.E.; Bartold, P.M.; Reynolds, E.C. The Nexus Between Periodontal Inflammation and Dysbiosis. Front. Immunol. 2020, 11, 511.
  7. Lee, C.T.; Teles, R.; Kantarci, A.; Chen, T.; McCafferty, J.; Starr, J.R.; Brito, L.C.; Paster, B.J.; Van Dyke, T.E. Resolvin E1 Reverses Experimental Periodontitis and Dysbiosis. J. Immunol. 2016, 197, 2796–2806.
  8. Duran-Pinedo, A.E.; Chen, T.; Teles, R.; Starr, J.R.; Wang, X.; Krishnan, K.; Frias-Lopez, J. Community-wide transcriptome of the oral microbiome in subjects with and without periodontitis. ISME J. 2014, 8, 1659–1672.
  9. Papapanou, P.N.; Park, H.; Cheng, B.; Kokaras, A.; Paster, B.; Burkett, S.; Watson, C.W.; Annavajhala, M.K.; Uhlemann, A.C.; Noble, J.M. Subgingival microbiome and clinical periodontal status in an elderly cohort: The WHICAP ancillary study of oral health. J. Periodontol. 2020, 91 (Suppl. 1), S56–S67.
  10. Bourgeois, D.; Bravo, M.; Llodra, J.C.; Inquimbert, C.; Viennot, S.; Dussart, C.; Carrouel, F. Calibrated interdental brushing for the prevention of periodontal pathogens infection in young adults—A randomized controlled clinical trial. Sci. Rep. 2019, 9, 15127.
  11. Page, L.R.; Rams, T.E. Subgingival root brushing in deep human periodontal pockets. J. Int. Acad. Periodontol. 2013, 15, 55–63.
  12. An, J.Y.; Kerns, K.A.; Ouellette, A.; Robinson, L.; Morris, H.D.; Kaczorowski, C.; Park, S.I.; Mekvanich, T.; Kang, A.; McLean, J.S.; et al. Rapamycin rejuvenates oral health in aging mice. eLife 2020, 9, e54318.
  13. Tiffany, C.R.; Baumler, A.J. Dysbiosis: From fiction to function. Am. J. Physiol. Gastrointest Liver Physiol. 2019, 317, G602–G608.
  14. Goldberg, E.A.; Venkat-Ramani, T.; Hewit, M.; Bonilla, H.F. Epidemiology and clinical outcomes of patients with Fusobacterium bacteraemia. Epidemiol. Infect. 2013, 141, 325–329.
  15. Abbas, M.; Constantin, M.I.; Narendra, A. Pylephlebitis Caused by Fusobacterium nucleatum in a Septuagenarian Healthy Caucasian Male: Atypical Presentation of Lemierre’s Syndrome. Case Rep. Infect. Dis. 2022, 2022, 5160408.
  16. Guo, L.; Shokeen, B.; He, X.; Shi, W.; Lux, R. Streptococcus mutans SpaP binds to RadD of Fusobacterium nucleatum ssp. polymorphum. Mol. Oral Microbiol. 2017, 32, 355–364.
  17. Wu, T.; Cen, L.; Kaplan, C.; Zhou, X.; Lux, R.; Shi, W.; He, X. Cellular Components Mediating Coadherence of Candida albicans and Fusobacterium nucleatum. J. Dent. Res. 2015, 94, 1432–1438.
  18. Li, D.H.; Li, Z.P.; Yan, Z.; Zhou, G.Z.; Ren, R.R.; Zhao, H.J.; Zhang, N.N.; Li, J.F.; Peng, L.H.; Yang, Y.S. Fecal Fusobacterium nucleatum harbored virulence gene fadA are associated with ulcerative colitis and clinical outcomes. Microb. Pathog. 2021, 157, 104964.
  19. Zhou, Z.; Wang, Y.; Ji, R.; Zhang, D.; Ma, C.; Ma, W.; Ma, Y.; Jiang, X.; Du, K.; Zhang, R.; et al. Vanillin Derivatives Reverse Fusobacterium nucleatum-Induced Proliferation and Migration of Colorectal Cancer Through E-Cadherin/beta-Catenin Pathway. Front. Pharmacol. 2022, 13, 841918.
  20. Fardini, Y.; Wang, X.; Temoin, S.; Nithianantham, S.; Lee, D.; Shoham, M.; Han, Y.W. Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity. Mol. Microbiol. 2011, 82, 1468–1480.
  21. Xu, M.; Yamada, M.; Li, M.; Liu, H.; Chen, S.G.; Han, Y.W. FadA from Fusobacterium nucleatum utilizes both secreted and nonsecreted forms for functional oligomerization for attachment and invasion of host cells. J. Biol. Chem. 2007, 282, 25000–25009.
  22. Abed, J.; Emgard, J.E.; Zamir, G.; Faroja, M.; Almogy, G.; Grenov, A.; Sol, A.; Naor, R.; Pikarsky, E.; Atlan, K.A.; et al. Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. Cell Host Microbe 2016, 20, 215–225.
  23. Bashir, A.; Miskeen, A.Y.; Bhat, A.; Fazili, K.M.; Ganai, B.A. Fusobacterium nucleatum: An emerging bug in colorectal tumorigenesis. Eur J. Cancer Prev. 2015, 24, 373–385.
  24. Han, Y.W. Fusobacterium nucleatum: A commensal-turned pathogen. Curr. Opin. Microbiol. 2015, 23, 141–147.
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Subjects: Pathology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Francisco Mesa
,
Antonio Magan-Fernandez
,
,
Cristina Benavides-Reyes
,
Luigi Nibali
,
Giuseppe Mainas
,
MANFREDI RIZZO
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Update Date: 05 May 2022
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