Advertisement

Current Oral Health Reports

, Volume 5, Issue 4, pp 242–249 | Cite as

Saliva – A Promising Tool for Diagnosing Oral Diseases

  • David T. Wu
  • Owen Tao
  • Nathalie Trinh
  • Mohammad A. Javaid
  • Ahad S. Ahmed
  • Robert Durand
  • Simon D. TranEmail author
Epidemiology (M Laine, Section Editor)
  • 64 Downloads
Part of the following topical collections:
  1. Topical Collection on Epidemiology

Abstract

Purpose of Review

This review will present updates on the genome, transcriptome, proteome, metabolome, exosome, and microbiome of saliva and the wide range of biomarkers found within these salivary components. We will explore the effectiveness and potential of salivary diagnostics on specific diseases: dental caries and demineralization diseases, periodontal diseases and peri-implantitis, oral cancers, and Sjögren’s syndrome.

Recent Findings

Recent studies have shown the feasibility of saliva as a diagnostic tool, in addition to the emergence of many novel salivary biomarkers. Unfortunately, many of these studies do not explore further into the outcomes of patient-oriented health and do not demonstrate reliability in diverse patient populations.

Summary

Salivary diagnostics is an emerging field that uses saliva, for its non-invasive, fast, and cost-effective collection properties, as a diagnostic tool. In the near future, we expect that salivary diagnostics will benefit from technological advances and further studies to be used as a routine chair-side test included in a comprehensive diagnostic and risk assessment tool.

Keywords

Saliva Diagnostics Salivaomics Dental caries Periodontal disease Oral cancer 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Chojnowska S, Baran T, Wilinska I, Sienicka P, Cabaj-Wiater I, Knas M. Human saliva as a diagnostic material. Adv Med Sci. 2018;63(1):185–91.  https://doi.org/10.1016/j.advms.2017.11.002.CrossRefPubMedGoogle Scholar
  2. 2.
    Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DT. Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev. 2013;26(4):781–91.  https://doi.org/10.1128/CMR.00021-13.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Trindade F, Oppenheim FG, Helmerhorst EJ, Amado F, Gomes PS, Vitorino R. Uncovering the molecular networks in periodontitis. Proteomics Clin Appl. 2014;8(9–10):748–61.  https://doi.org/10.1002/prca.201400028.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zhang CZ, Cheng XQ, Li JY, Zhang P, Yi P, Xu X, et al. Saliva in the diagnosis of diseases. Int J Oral Sci. 2016;8(3):133–7.  https://doi.org/10.1038/ijos.2016.38.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hassona Y, Scully C. Salivary changes in oral mucosal diseases. Periodontol 2000. 2016;70(1):111–27.  https://doi.org/10.1111/prd.12102.CrossRefPubMedGoogle Scholar
  6. 6.
    •• Zhang Y, Sun J, Lin CC, Abemayor E, Wang MB, Wong DT. The emerging landscape of salivary diagnostics. Periodontology 2000. 2016;70(1):38–52.  https://doi.org/10.1111/prd.12099 This review paper describes recent developments in salivary diagnostics in oral disease and systemic diseases using comprehensive salivaomics approaches. CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang A, Sun H, Wang P, Wang X. Salivary proteomics in biomedical research. Clin Chim Acta. 2013;415:261–5.  https://doi.org/10.1016/j.cca.2012.11.001.CrossRefPubMedGoogle Scholar
  8. 8.
    Devi DS. Salivary biomarkers - a review. J Pharm Sci Res. 2013;5(10):210–2.Google Scholar
  9. 9.
    Schafer CA, Schafer JJ, Yakob M, Lima P, Camargo P, Wong DT. Saliva diagnostics: utilizing oral fluids to determine health status. Monogr Oral Sci. 2014;24:88–98.  https://doi.org/10.1159/000358791.CrossRefPubMedGoogle Scholar
  10. 10.
    • Korte DL, Kinney J. Personalized medicine: an update of salivary biomarkers for periodontal diseases. Periodontology 2000. 2016;70(1):26–37.  https://doi.org/10.1111/prd.12103 This review paper describes recent advances in salivary diagnostics for periodontal disease and provides a summary of potential salivary biomarkers. CrossRefPubMedGoogle Scholar
  11. 11.
    Malon RSP, Sadir S, Balakrishnan M, Córcoles EP. Saliva-Based Biosensors: Noninvasive Monitoring Tool for Clinical Diagnostics. Biomed Res Int. 2014;2014:20.  https://doi.org/10.1155/2014/962903.CrossRefGoogle Scholar
  12. 12.
    Wang X, Kaczor-Urbanowicz KE, Wong DTW. Salivary Biomarkers in Cancer Detection. Med Oncol. 2017;34(1):7.  https://doi.org/10.1007/s12032-016-0863-4.CrossRefPubMedGoogle Scholar
  13. 13.
    Wong DT. Salivary extracellular noncoding RNA: emerging biomarkers for molecular diagnostics. Clin Ther. 2015;37(3):540–51.  https://doi.org/10.1016/j.clinthera.2015.02.017.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Spielmann N, Ilsley D, Gu J, Lea K, Brockman J, Heater S, et al. The human salivary RNA transcriptome revealed by massively parallel sequencing. Clin Chem. 2012;58(9):1314–21.  https://doi.org/10.1373/clinchem.2011.176941.CrossRefPubMedGoogle Scholar
  15. 15.
    Bahn JH, Zhang Q, Li F, Chan TM, Lin X, Kim Y, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem. 2015;61(1):221–30.  https://doi.org/10.1373/clinchem.2014.230433.CrossRefPubMedGoogle Scholar
  16. 16.
    Yoshizawa JM, Wong DT. Salivary microRNAs and oral cancer detection. Methods Mol Biol. 2013;936:313–24.  https://doi.org/10.1007/978-1-62703-083-0_24.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Saikumar J, Ramachandran K, Vaidya VS. Noninvasive micromarkers. Clin Chem. 2014;60(9):1158–73.  https://doi.org/10.1373/clinchem.2013.216044.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Salazar MG, Jehmlich N, Murr A, Dhople VM, Holtfreter B, Hammer E, et al. Identification of periodontitis associated changes in the proteome of whole human saliva by mass spectrometric analysis. J Clin Periodontol. 2013;40(9):825–32.  https://doi.org/10.1111/jcpe.12130.CrossRefPubMedGoogle Scholar
  19. 19.
    Elashoff D, Zhou H, Reiss J, Wang J, Xiao H, Henson B, et al. Prevalidation of salivary biomarkers for Oral Cancer detection. Cancer epidemiology biomarkers &amp. Prevention. 2012;21(4):664–72.  https://doi.org/10.1158/1055-9965.CrossRefGoogle Scholar
  20. 20.
    Rai B, Kaur J, Jacobs R, Anand SC. Adenosine deaminase in saliva as a diagnostic marker of squamous cell carcinoma of tongue. Clin Oral Investig. 2011;15(3):347–9.  https://doi.org/10.1007/s00784-010-0404-z.CrossRefPubMedGoogle Scholar
  21. 21.
    • Kaczor-Urbanowicz KE, Martin Carreras-Presas C, Aro K, Tu M, Garcia-Godoy F, Wong DTW. Saliva diagnostics – Current views and directions. Exp Biol Med. 2017;242(5):459–72.  https://doi.org/10.1177/1535370216681550 This review paper provides a description of current main diagnostic applications of saliva, and provide a highlight on the emerging, newly developing technologies and tools for cancer screening, detection and monitoring. CrossRefGoogle Scholar
  22. 22.
    Sweet SP, Denbury AN, Challacombe SJ. Salivary calprotectin levels are raised in patients with oral candidiasis or Sjogren's syndrome but decreased by HIV infection. Oral Microbiol Immunol. 2001;16(2):119–23.CrossRefGoogle Scholar
  23. 23.
    Amado FM, Ferreira RP, Vitorino R. One decade of salivary proteomics: current approaches and outstanding challenges. Clin Biochem. 2013;46(6):506–17.  https://doi.org/10.1016/j.clinbiochem.2012.10.024.CrossRefPubMedGoogle Scholar
  24. 24.
    Washio J, Takahashi N. Metabolomic Studies of Oral Biofilm, Oral Cancer, and Beyond. Int J Mol Sci. 2016;17(6):870.  https://doi.org/10.3390/ijms17060870.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nonaka T, Wong DTW. Saliva-Exosomics in Cancer: molecular characterization of Cancer-derived exosomes in saliva. Enzymes. 2017;42:125–51.  https://doi.org/10.1016/bs.enz.2017.08.002.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang Y, Wang X, Li H, Ni C, Du Z, Yan F. Human oral microbiota and its modulation for oral health. Biomed Pharmacother. 2018;99:883–93.  https://doi.org/10.1016/j.biopha.2018.01.146.CrossRefPubMedGoogle Scholar
  27. 27.
    Yamashita Y, Takeshita T. The oral microbiome and human health. J Oral Sci. 2017;59(2):201–6.  https://doi.org/10.2334/josnusd.16-0856.CrossRefPubMedGoogle Scholar
  28. 28.
    • Gao X, Jiang S, Koh D, Hsu CY. Salivary biomarkers for dental caries. Periodontology 2000. 2016;70(1):128–41.  https://doi.org/10.1111/prd.12100 This review paper describes recent advances in salivary diagnostics for dental caries and provides a summary of potential salivary biomarkers. CrossRefPubMedGoogle Scholar
  29. 29.
    Guo L, Shi W. Salivary biomarkers for caries risk assessment. J Calif Dent Assoc. 2013;41(2):107–18.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Hajishengallis E, Parsaei Y, Klein MI, Koo H. Advances in the microbial etiology and pathogenesis of early childhood caries. Mol Oral Microbiol. 2017;32(1):24–34.  https://doi.org/10.1111/omi.12152.CrossRefPubMedGoogle Scholar
  31. 31.
    Martins C, Buczynski AK, Maia LC, Siqueira WL, Castro GF. Salivary proteins as a biomarker for dental caries--a systematic review. J Dent. 2013;41(1):2–8.  https://doi.org/10.1016/j.jdent.2012.10.015.CrossRefPubMedGoogle Scholar
  32. 32.
    Vukosavljevic D, Custodio W, Buzalaf MA, Hara AT, Siqueira WL. Acquired pellicle as a modulator for dental erosion. Arch Oral Biol. 2014;59(6):631–8.  https://doi.org/10.1016/j.archoralbio.2014.02.002.CrossRefPubMedGoogle Scholar
  33. 33.
    Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 2012;91(10):914–20.  https://doi.org/10.1177/0022034512457373.CrossRefPubMedGoogle Scholar
  34. 34.
    Guncu GN, Yilmaz D, Kononen E, Gursoy UK. Salivary antimicrobial peptides in early detection of periodontitis. Front Cell Infect Microbiol. 2015;5:99.  https://doi.org/10.3389/fcimb.2015.00099.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Heikkinen AM, Nwhator SO, Rathnayake N, Mantyla P, Vatanen P, Sorsa T. Pilot study on Oral health status as assessed by an active matrix Metalloproteinase-8 chairside Mouthrinse test in adolescents. J Periodontol. 2016;87(1):36–40.  https://doi.org/10.1902/jop.2015.150377.CrossRefPubMedGoogle Scholar
  36. 36.
    • Zhang L, Li X, Yan H, Huang L. Salivary matrix metalloproteinase (MMP-8) as a biomarker for periodontitis: A PRISMA-compliant systematic review and meta-analysis. Medicine. 2018;97(3):e9642.  https://doi.org/10.1097/md.0000000000009642 This meta-analysis show that MMP-8 is a promising biomarker for periodontitis. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    de Lima CL, Acevedo AC, Grisi DC, Taba M Jr, Guerra E, De Luca Canto G. Host-derived salivary biomarkers in diagnosing periodontal disease: systematic review and meta-analysis. J Clin Periodontol. 2016;43(6):492–502.  https://doi.org/10.1111/jcpe.12538.CrossRefPubMedGoogle Scholar
  38. 38.
    Zhang P, Fan Y, Li Q, Chen J, Zhou W, Luo Y, et al. Macrophage activating factor: a potential biomarker of periodontal health status. Arch Oral Biol. 2016;70:94–9.  https://doi.org/10.1016/j.archoralbio.2016.06.010.CrossRefPubMedGoogle Scholar
  39. 39.
    Song B, Zhang YL, Chen LJ, Zhou T, Huang WK, Zhou X, et al. The role of toll-like receptors in periodontitis. Oral Dis. 2017;23(2):168–80.  https://doi.org/10.1111/odi.12468.CrossRefPubMedGoogle Scholar
  40. 40.
    Kinney JS, Morelli T, Braun T, Ramseier CA, Herr AE, Sugai JV, et al. Saliva/pathogen biomarker signatures and periodontal disease progression. J Dent Res. 2011;90(6):752–8.  https://doi.org/10.1177/0022034511399908.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lee A, Ghaname CB, Braun TM, Sugai JV, Teles RP, Loesche WJ, et al. Bacterial and salivary biomarkers predict the gingival inflammatory profile. J Periodontol. 2012;83(1):79–89.  https://doi.org/10.1902/jop.2011.110060.CrossRefPubMedGoogle Scholar
  42. 42.
    Saygun I, Nizam N, Keskiner I, Bal V, Kubar A, Acikel C, et al. Salivary infectious agents and periodontal disease status. J Periodontal Res. 2011;46(2):235–9.  https://doi.org/10.1111/j.1600-0765.2010.01335.x.CrossRefPubMedGoogle Scholar
  43. 43.
    Song GG, Choi SJ, Ji JD, Lee YH. Association between tumor necrosis factor-alpha promoter −308 a/G, −238 a/G, interleukin-6 -174 G/C and −572 G/C polymorphisms and periodontal disease: a meta-analysis. Mol Biol Rep. 2013;40(8):5191–203.  https://doi.org/10.1007/s11033-013-2621-4.CrossRefPubMedGoogle Scholar
  44. 44.
    Coli P, Christiaens V, Sennerby L, Bruyn H. Reliability of periodontal diagnostic tools for monitoring peri-implant health and disease. Periodontol 2000. 2017;73(1):203–17.  https://doi.org/10.1111/prd.12162.CrossRefPubMedGoogle Scholar
  45. 45.
    Carcuac O, Abrahamsson I, Albouy JP, Linder E, Larsson L, Berglundh T. Experimental periodontitis and peri-implantitis in dogs. Clin Oral Implants Res. 2013;24(4):363–71.  https://doi.org/10.1111/clr.12067.CrossRefPubMedGoogle Scholar
  46. 46.
    Emecen-Huja P, Hasan I, Miller CS. Biologic markers of failing implants. Dent Clin N Am. 2015;59(1):179–94.  https://doi.org/10.1016/j.cden.2014.08.007.CrossRefPubMedGoogle Scholar
  47. 47.
    Ji S, Choi Y. Point-of-care diagnosis of periodontitis using saliva: technically feasible but still a challenge. Front Cell Infect Microbiol. 2015;5:65.  https://doi.org/10.3389/fcimb.2015.00065.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Liu D, Zhao X, Zeng X, Dan H, Chen Q. Non-invasive techniques for detection and diagnosis of Oral potentially malignant disorders. Tohoku J Exp Med. 2016;238(2):165–77.CrossRefGoogle Scholar
  49. 49.
    Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JL, Lingen MW, et al. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2015;5:CD010276.  https://doi.org/10.1002/14651858.CrossRefGoogle Scholar
  50. 50.
    Stuani VT, Rubira CM, Sant'Ana AC, Santos PS. Salivary biomarkers as tools for oral squamous cell carcinoma diagnosis: a systematic review. Head Neck. 2017;39(4):797–811.  https://doi.org/10.1002/hed.24650.CrossRefPubMedGoogle Scholar
  51. 51.
    Panta P, Venna VR. Salivary RNA signatures in Oral Cancer detection. Anal Cell Pathol. 2014;2014:7–7.  https://doi.org/10.1155/2014/450629.CrossRefGoogle Scholar
  52. 52.
    Fabryova H, Celec P. On the origin and diagnostic use of salivary RNA. Oral Dis. 2014;20(2):146–52.  https://doi.org/10.1111/odi.12098.CrossRefPubMedGoogle Scholar
  53. 53.
    Gualtero DF, Suarez CA. Biomarkers in saliva for the detection of oral squamous cell carcinoma and their potential use for early diagnosis: a systematic review. Acta Odontol Scand. 2016;74(3):170–7.  https://doi.org/10.3109/00016357.2015.1110249.CrossRefPubMedGoogle Scholar
  54. 54.
    Walsh T, Liu JL, Brocklehurst P, Glenny AM, Lingen M, Kerr AR, et al. Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults. Cochrane Database Syst Rev. 2013;21(11):CD010173.  https://doi.org/10.1002/14651858.CD010173.CrossRefGoogle Scholar
  55. 55.
    Nagadia R, Pandit P, Coman WB, Cooper-White J, Punyadeera C. miRNAs in head and neck cancer revisited. Cell Oncol (Dordr). 2013;36(1):1–7.  https://doi.org/10.1007/s13402-012-0122-4.CrossRefGoogle Scholar
  56. 56.
    Principe S, Hui AB, Bruce J, Sinha A, Liu FF, Kislinger T. Tumor-derived exosomes and microvesicles in head and neck cancer: implications for tumor biology and biomarker discovery. Proteomics. 2013;13(10–11):1608–23.  https://doi.org/10.1002/pmic.201200533.CrossRefPubMedGoogle Scholar
  57. 57.
    Juodzbalys G, Kasradze D, Cicciu M, Sudeikis A, Banys L, Galindo-Moreno P, et al. Modern molecular biomarkers of head and neck cancer. Part I. epigenetic diagnostics and prognostics: systematic review. Cancer Biomark. 2016;17(4):487–502.  https://doi.org/10.3233/CBM-160666.CrossRefPubMedGoogle Scholar
  58. 58.
    Normando AGC, Rocha CL, de Toledo IP, de Souza Figueiredo PT, Dos Reis PED, De Luca CG, et al. Biomarkers in the assessment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis. Support Care Cancer. 2017;25(9):2969–88.  https://doi.org/10.1007/s00520-017-3783-8.CrossRefPubMedGoogle Scholar
  59. 59.
    Beckman KA, Luchs J, Milner MS, Ambrus JL Jr. The potential role for early biomarker testing as part of a modern, multidisciplinary approach to Sjogren's syndrome diagnosis. Adv Ther. 2017;34(4):799–812.  https://doi.org/10.1007/s12325-017-0501-3.CrossRefPubMedGoogle Scholar
  60. 60.
    Chen W, Cao H, Lin J, Olsen N, Zheng SG. Biomarkers for primary Sjögren’s syndrome. Genomics Proteomics Bioinformatics. 2015;13(4):219–23.  https://doi.org/10.1016/j.gpb.2015.06.002.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Katsiougiannis S, Wong DT. The proteomics of saliva in Sjogren's syndrome. Rheum Dis Clin N Am. 2016;42(3):449–56.  https://doi.org/10.1016/j.rdc.2016.03.004.CrossRefGoogle Scholar
  62. 62.
    Baldini C, Cecchettini A, Gallo A, Bombardieri S. Updates on Sjogren's syndrome: from proteomics to protein biomarkers. Expert Rev Proteomics. 2017;14(6):491–8.  https://doi.org/10.1080/14789450.2017.1333904.CrossRefPubMedGoogle Scholar
  63. 63.
    Pagano G, Castello G, Pallardo FV. Sjogren's syndrome-associated oxidative stress and mitochondrial dysfunction: prospects for chemoprevention trials. Free Radic Res. 2013;47(2):71–3.  https://doi.org/10.3109/10715762.2012.748904.CrossRefPubMedGoogle Scholar
  64. 64.
    Novy BB. Saliva and biofilm-based diagnostics: a critical review of the literature concerning sialochemistry. J Evid Based Dent Pract. 2014;14(Suppl):27–32.  https://doi.org/10.1016/j.jebdp.2014.04.004.CrossRefPubMedGoogle Scholar
  65. 65.
    Khan RS, Khurshid Z, Yahya Ibrahim Asiri F. Advancing Point-of-Care (PoC) Testing Using Human Saliva as Liquid Biopsy. Diagnostics (Basel). 2017:7(3). doi:  https://doi.org/10.3390/diagnostics7030039 CrossRefGoogle Scholar
  66. 66.
    Tasoulas J, Patsouris E, Giaginis C, Theocharis S. Salivaomics for oral diseases biomarkers detection. Expert Rev Mol Diagn. 2016;16(3):285–95.  https://doi.org/10.1586/14737159.2016.1133296.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • David T. Wu
    • 1
  • Owen Tao
    • 1
  • Nathalie Trinh
    • 1
  • Mohammad A. Javaid
    • 2
  • Ahad S. Ahmed
    • 3
  • Robert Durand
    • 4
  • Simon D. Tran
    • 1
    Email author
  1. 1.Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of DentistryMcGill UniversityMontrealCanada
  2. 2.Graduate Periodontics, School of Dentistry, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada
  3. 3.Henry M. Goldman School of Dental MedicineBoston UniversityBostonUSA
  4. 4.Division of Periodontics, Faculty of DentistryUniversité de MontréalMontrealCanada

Personalised recommendations