The Emerging Role of Extracellular Vesicles Derived from Oral Bacteria in Periodontal Disease Progression and Systemic Inflammation

Abstract

Extracellular vesicles derived from oral bacteria have recently been identified as central players in oral and systemic intercellular communication. These nanoscale particles are produced by commensal and pathogenic bacteria and carry a broad range of protein, lipid, and nucleic- acid biomolecules that can substantially affect host immune responses and surrounding/microbial response. Bacterial EVs have been shown to be involved in the pathogenesis of periodontal disease by destroying gingival tissue, affecting cytokine production transcription, and enhancing a chronic inflammatory response from the host’s innate immune system through activation of the patients’ pattern recognition receptor s, specifically TLRs. In addition, oral bacterial EVs can reach the bloodstream and induce systemic inflammation, providing a potential connection between periodontitis and other conditions such as atherosclerotic cardiovascular disease, diabetes, and rheumatoid arthritis. Consequently, a comprehensive understanding of oral and systemic health concepts is required to reach the full extent of these areas. It is evident that due to recent molecular research, omics technology application, and several developments in the field of nanomedicine, bacterial EVs have shown both clinical and research potential. However, the increased options for isolating EVs have led to questions surrounding potential heterogeneity and the absence of standard tests, among others. Thus, since oral bacterial EVs are re-studied to serve as biomarkers and help develop new periodontal and systemic anti-inflammatory therapies, the trends in future work will consider their newly developed research priorities.

Keywords:

Extracellular vesicles, Oral bacteria, Periodontal disease, Inflammation, Toll-like receptors, Biomarkers

References

Hasturk H, Schulte F, Martins M, Sherzai H, Floros C, Cugini M, et al. Safety and preliminary efficacy of a novel host-modulatory therapy for reducing gingival inflammation. Front Immunol (2021) 12:704163. doi: 10.3389/fimmu.2021.704163

Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol (2003) 74(3):391–401. doi: 10.1902/jop.2003.74.3.391

Collaborators GBDOD, Bernabe E, Marcenes W, Hernandez CR, Bailey J, Abreu LG, et al. Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: A systematic analysis for the global burden of disease 2017 study. J Dent Res (2020) 99(4):362–73. doi: 10.1177/0022034520908533

Peres MA, Macpherson LMD, Weyant RJ, Daly B, Venturelli R, Mathur MR, et al. Oral diseases: a global public health challenge. Lancet. (2019) 394(10194):249–60. doi: 10.1016/S0140-6736(19)31146-8

Chapple IL. Time to take periodontitis seriously. BMJ (2014) 348:g2645. doi: 10.1136/bmj.g2645

Yamamoto M, Aizawa R. Maintaining a protective state for human periodontal tissue. Periodontol 2000. (2021) 86(1):142–56. doi: 10.1111/prd.12367

Moutsopoulos NM, Konkel JE. Tissue-specific immunity at the oral mucosal barrier. Trends Immunol (2018) 39(4):276–87. doi: 10.1016/j.it.2017.08.005

Van Dyke TE. The management of inflammation in periodontal disease. J Periodontol (2008) 79(8 Suppl):1601–8. doi: 10.1902/jop.2008.080173

Okada H, Murakami S. Cytokine expression in periodontal health and disease. Crit Rev Oral Biol Med (1998) 9(3):248–66. doi: 10.1177/10454411980090030101

Page RC, Offenbacher S, Schroeder HE, Seymour GJ, Kornman KS. Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontol 2000. (1997) 14:216–48. doi: 10.1111/j.1600-0757.1997.tb00199.x

Hajishengallis E, Hajishengallis G. Neutrophil homeostasis and periodontal health in children and adults. J Dent Res (2014) 93(3):231–7. doi: 10.1177/ 0022034513507956

Chakravarti A, Raquil MA, Tessier P, Poubelle PE. Surface RANKL of toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood. (2009) 114(8):1633–44. doi: 10.1182/blood-2008-09-178301

Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol (2008) 79(8 Suppl):1585–91. doi: 10.1902/jop.2008.080183

Lamont RJ, Koo H, Hajishengallis G. The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol (2018) 16(12):745–59. doi: 10.1038/s41579-018-0089-x

Hajishengallis G. New developments in neutrophil biology and periodontitis. Periodontol 2000. (2020) 82(1):78–92. doi: 10.1111/prd.12313

Pan W, Wang Q, Chen Q. The cytokine network involved in the host immune response to periodontitis. Int J Oral Sci (2019) 11(3):30. doi: 10.1038/s41368-019-0064-z

Kinane DF. Causation and pathogenesis of periodontal disease. Periodontol 2000 (2001) 25:8–20. doi: 10.1034/j.1600-0757.2001.22250102.x

American Academy of periodontology task force report on the update to the 1999 classification of periodontal diseases and conditions. J Periodontol (2015) 86 (7):835–8. doi: 10.1902/jop.2015.157001

Haffajee AD, Socransky SS, Goodson JM. Clinical parameters as predictors of destructive periodontal disease activity. J Clin Periodontol (1983) 10(3):257–65. doi: 10.1111/j.1600-051x.1983.tb01274.x

Renvert S, Persson GR. A systematic review on the use of residual probing depth, bleeding on probing and furcation status following initial periodontal therapy to predict further attachment and tooth loss. J Clin Periodontol (2002) 29 Suppl 3:82–9. doi: 10.1034/j.1600-051x.29.s-3.2.x

Chapple IL. Periodontal disease diagnosis: current status and future developments. J Dent. (1997) 25(1):3–15. doi: 10.1016/s0300-5712(95)00118-2

Marini L, Tonetti MS, Nibali L, Rojas MA, Aimetti M, Cairo F, et al. The staging and grading system in defining periodontitis cases: consistency and accuracy amongst periodontal experts, general dentists and undergraduate students. J Clin Periodontol (2021) 48(2):205–15. doi: 10.1111/jcpe.13406

Han P, Bartold PM, Ivanovski S. The emerging role of small extracellular vesicles in saliva and gingival crevicular fluid as diagnostics for periodontitis. J Periodontal Res (2022) 57(1):219–31. doi: 10.1111/jre.12950

Armitage GC. The complete periodontal examination. Periodontol 2000 (2004) 34:22–33. doi: 10.1046/j.0906-6713.2002.003422.x

Khattri S, Kumbargere Nagraj S, Arora A, Eachempati P, Kusum CK, Bhat KG, et al. Adjunctive systemic antimicrobials for the non-surgical treatment of periodontitis. Cochrane Database Syst Rev (2020) 11(11):CD012568. doi: 10.1002/ 14651858.CD012568.pub2.

Cobb CM. Clinical significance of non-surgical periodontal therapy: an evidence-based perspective of scaling and root planing. J Clin Periodontol (2002) 29 (Suppl 2):6–16. doi: 10.1034/j.1600-051X.29.s2.2.x

Graziani F, Karapetsa D, Alonso B, Herrera D. Nonsurgical and surgical treatment of periodontitis: how many options for one disease? Periodontol 2000 (2017) 75(1):152–88. doi: 10.1111/prd.12201.

Liu J, Ruan J, Weir MD, Ren K, Schneider A, Wang P, et al. Periodontal boneLigament-Cementum regeneration via scaffolds and stem cells. Cells (2019) 8(6):537. doi: 10.3390/cells8060537

Wang HL, Greenwell H. Surgical periodontal therapy. Periodontol 2000 (2001) 25:89–99. doi: 10.1034/j.1600-0757.2001.22250107.x

Han J, Menicanin D, Gronthos S, Bartold PM. Stem cells, tissue engineering and periodontal regeneration. Aust Dent J (2014) 59 Suppl 1:117–30. doi: 10.1111/ adj.12100

Ding T, Kang W, Li J, Yu L, Ge S. An in situ tissue engineering scaffold with growth factors combining angiogenesis and osteoimmunomodulatory functions for advanced periodontal bone regeneration. J Nanobiotechnology. (2021) 19(1):247. doi: 10.1186/s12951-021-00992-4

Zhuang Y, Cheng M, Li M, Cui J, Huang J, Zhang C, et al. Small extracellular vesicles derived from hypoxic mesenchymal stem cells promote vascularized bone regeneration through the miR-210-3p/EFNA3/PI3K pathway. Acta Biomater. (2022) 15 (150):150:413–426. doi: 10.1016/j.actbio.2022.07.015

Nyman S, Lindhe J, Karring T, Rylander H. New attachment following surgical treatment of human periodontal disease. J ClinPeriodontol (1982) 9(4):290–6. doi: 10.1111/j.1600-051x.1982.tb02095.x

Larsson L, Decker AM, Nibali L, Pilipchuk SP, Berglundh T, Giannobile WV. Regenerative medicine for periodontal and peri-implant diseases. J Dent Res (2016) 95 (3):255–66. doi: 10.1177/0022034515618887

Chen FM, Zhang J, Zhang M, An Y, Chen F, Wu ZF. A review on endogenous regenerative technology in periodontal regenerative medicine. Biomaterials. (2010) 31 (31):7892–927. doi: 10.1016/j.biomaterials.2010.07.019

Nibali L, Koidou VP, Nieri M, Barbato L, Pagliaro U, Cairo F. Regenerative surgery versus access flap for the treatment of intra-bony periodontal defects: A systematic review and meta-analysis. J Clin Periodontol (2020)

Suppl 22:320–51. doi: 10.1111/jcpe.13237 37. Sculean A, Nikolidakis D, Nikou G, Ivanovic A, Chapple IL, Stavropoulos A. Biomaterials for promoting periodontal regeneration in human intrabony defects: a systematic review. Periodontol 2000. (2015) 68(1):182–216. doi: 10.1111/prd.12086

QinY, SunR, WuC, WangL, ZhangC.Exosome: Anovelapproachtostimulate bone regeneration through regulation of osteogenesis and angiogenesis. Int J Mol Sci (2016) 17(5):712. doi: 10.3390/ijms17050712.

Schuh C, Cuenca J, Alcayaga-Miranda F, Khoury M. Exosomes on the border of species and kingdom intercommunication. Transl Res (2019) 210:80–98. doi: 10.1016/ j.trsl.2019.03.008

Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells (2019) 8(7):727. doi: 10.3390/cells8070727.

Zhang X, Zhang H, Gu J, Zhang J, Shi H, Qian H, et al. Engineered extracellular vesicles for cancer therapy. Adv Mater (2021) 33(14):e2005709. doi: 10.1002/ adma.202005709

Waldenstrom A, Ronquist G. Role of exosomes in myocardial remodeling. Circ Res (2014) 114(2):315–24. doi: 10.1161/CIRCRESAHA.114.300584

Al-Karawi, A. S., Kadhim, A. S., Mohammed, A. A., Alajeeli, F., & Lippi, G. (2024). The Impact of Spirulina Supplementation on Iraqi Obese Females: A Cohort Study. Al-Mustansiriyah Journal of Science, 35(4), 24-30.‏

Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. (2013) 113(1):1–11. doi: 10.1007/s11060-013-1084-8

Aherkar, V. V., Mohammed, A. A., Al-Shimary, A. A., Kshirsagar, V., Shendage, R., Ubale, P. A., ... & Ovhal, R. M. (2025). Photocatalytic dye degradation efficacy and antimicrobial potency of zinc oxide nanoparticles synthesized via sol-gel method. Next Materials, 9, 100972.‏

Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. (2018) 7(1):1535750. doi: 10.1080/ 20013078.2018.1535750

Hussein, A. F., Khamees, H. H., Mohammed, A. A., Hussein, S. A. M., Ahmed, M. A., Saad, A., & Raoof, M. In-Silico Study Of Destabilizing Alzheimer’s Aβ42 Protofibrils With Curcumin.‏

Walker S, Busatto S, Pham A, Tian M, Suh A, Carson K, et al. Extracellular vesicle-based drug delivery systems for cancer treatment. Theranostics. (2019) 9 (26):8001–17. doi: 10.7150/thno.37097

Huang CC, Kang M, Narayanan R, DiPietro LA, Cooper LF, Gajendrareddy P, et al. Evaluating the endocytosis and lineage-specification properties of mesenchymal stem cell derived extracellular vesicles for targeted therapeutic applications. Front Pharmacol (2020) 11:163. doi: 10.3389/fphar.2020.00163