唾液微生物在口腔疾病及全身系统性疾病发生发展与诊断中的作用^*

The Role of Salivary Microbiota in Oral and Systemic Disease Development and Diagnosis

摘要

唾液微生物群在口腔健康与全身疾病中发挥着重要作用，对于疾病发生发展及早期诊断具有重要意义。正常情况下微生物与宿主保持平衡，但当平衡被打破时，可能导致口腔疾病的发生，如龋齿、牙周病和口腔癌等，唾液微生物变化为口腔疾病的早期诊断提供重要信息。此外，口腔微生物群的失调还可能促使病原微生物通过肠道、肺迁移以及菌血症在口腔外异位定植，进而参与全身性疾病如结直肠癌、心血管疾病及自身免疫性疾病的发生和发展。因此，本文基于唾液微生物与口腔疾病及全身疾病的研究进展，总结唾液微生物在疾病发生发展与诊断中的作用，为全身疾病的早期预防及临床诊疗提供新的思路。

Abstract

The salivary microbiome plays a crucial role in both oral health and systemic diseases, offering significant insights into disease development and early diagnosis. Under normal conditions, a balanced relationship exists between the microbiota and the host; however, when this balance is disrupted, it can lead to the onset of oral diseases such as dental caries, periodontal disease, and oral cancer. Changes in the salivary microbiome provide valuable information for the early diagnosis of oral diseases. Moreover, microbial dysbiosis in the oral cavity may promote the translocation of pathogenic microorganisms via the gastrointestinal tract, lungs, or bacteremia, leading to ectopic colonization outside the oral cavity and contributing to the onset and progression of systemic diseases such as colorectal cancer, cardiovascular diseases, and autoimmune disorders. Therefore, this review summarizes the role of the salivary microbiome in disease development and diagnosis, based on recent advancements in research on salivary microbiota, offering new perspectives for the early prevention and clinical management of systemic diseases.

关键词

唾液 / 口腔微生物 / 稳态失衡 / 口腔疾病 / 系统性疾病 / 综述

Key words

Saliva / Oral microbiota / Dysbiosis / Oral diseases / Systemic diseases / Review

参考文献

[1] SHAW L, RIBEIRO A L R, LEVINE A P, et al. The human salivary microbiome is shaped by shared environment rather than genetics: evidence from a large family of closely related individuals. mBio, 2017, 8(5): e01237-17. doi: 10.1128/mBio.01237-17.

[2] HURLEY E, BARRETT M P J, KINIRONS M, et al. Comparison of the salivary and dentinal microbiome of children with severe-early childhood caries to the salivary microbiome of caries-free children. BMC Oral Health, 2019, 19(1): 13. doi: 10.1186/s12903-018-0693-1.

[3] REGUEIRA-IGLESIAS A, SUÁREZ-RODRÍGUEZ B, BLANCO-PINTOS T, et al. The salivary microbiome as a diagnostic biomarker of periodontitis: a 16S multi-batch study before and after the removal of batch effects. Front Cell Infect Microbiol, 2024, 14: 1405699. doi: 10.3389/fcimb.2024.1405699.

[4] HAN Z, HU Y, LIN X, et al. Systematic analyses uncover robust salivary microbial signatures and host-microbiome perturbations in oral squamous cell carcinoma. mSystems, 2025, 10(2): e0124724. doi: 10.1128/msystems.01247-24.

[5] BAO J, LI L, ZHANG Y, et al. Periodontitis may induce gut microbiota dysbiosis via salivary microbiota. Int J Oral Sci, 2022, 14(1): 32. doi: 10.1038/s41368-022-00183-3.

[6] QIAN J, LU J, HUANG Y, et al. Periodontitis salivary microbiota worsens colitis. J Dent Res, 2022, 101(5): 559-568. doi: 10.1177/00220345211049781.

[7] DŽUNKOVÁ M, LIPTÁK R, VLKOVÁ B, et al. Salivary microbiome composition changes after bariatric surgery. Sci Rep, 2020, 10(1): 20086. doi: 10.1038/s41598-020-76991-6.

[8] LU J, ZHANG S, HUANG Y, et al. Periodontitis-related salivary microbiota aggravates Alzheimer's disease via gut-brain axis crosstalk. Gut Microbes, 2022, 14(1): 2126272. doi: 10.1080/19490976.2022.2126272.

[9] 郑欣, 徐欣, 周学东, 等. 新型冠状病毒感染中味觉障碍及防治. 四川大学学报(医学版), 2023, 54(2): 334-341. doi: 10.12182/20230260306.

[10] ZHENG X, XU X, ZHOU X D, et al. Dysgeusia in COVID-19 and its prevention and treatment. J Sichuan Univ (Med Sci), 2023, 54(2): 334-341. doi: 10.12182/20230260306.

[11] 李玉姣, 程小刚, 钱飞, 等. 健康成人口腔微生物组成及功能的宏基因组学研究. 口腔疾病防治, 2022, 30(8): 533-541. doi: 10.12016/j.issn.2096-1456.2022.08.001.

[12] LI Y J, CHENG X G, QIAN F, et al. Metagenomic study of the composition and function of the oral microbiome in healthy adults. J Prev Treat Stomatol Dis, 2022, 30(8): 533-541. doi: 10.12016/j.issn.2096-1456.2022.08.001.

[13] SEDGHI L, DIMASSA V, HARRINGTON A, et al. The oral microbiome: role of key organisms and complex networks in oral health and disease. Periodontol 2000, 2021, 87(1): 107-131. doi: 10.1111/prd.12393.

[14] BAKER J L, MARK WELCH J L, KAUFFMAN K M, et al. The oral microbiome: diversity, biogeography and human health. Nat Rev Microbiol, 2024, 22(2): 89-104. doi: 10.1038/s41579-023-00963-6.

[15] MARK WELCH J L, DEWHIRST F E, BORISY G G. Biogeography of the oral microbiome: the site-specialist hypothesis. Annu Rev Microbiol, 2019, 73: 335-358. doi: 10.1146/annurev-micro-090817-062503.

[16] EREN A M, BORISY G G, HUSE S M, et al. Oligotyping analysis of the human oral microbiome. Proc Natl Acad Sci U S A, 2014, 111(28): E2875-E2884. doi: 10.1073/pnas.1409644111.

[17] SCHWARTZ J L, PEÑA N, KAWAR N, et al. Old age and other factors associated with salivary microbiome variation. BMC Oral Health, 2021, 21(1): 490. doi: 10.1186/s12903-021-01828-1.

[18] HANSEN T H, KERN T, BAK E G, et al. Impact of a vegan diet on the human salivary microbiota. Sci Rep, 2018, 8(1): 5847. doi: 10.1038/s41598-018-24207-3.

[19] WU J, PETERS B A, DOMINIANNI C, et al. Cigarette smoking and the oral microbiome in a large study of American adults. ISME J, 2016, 10(10): 2435-2446. doi: 10.1038/ismej.2016.37.

[20] FAN X, PETERS B A, JACOBS E J, et al. Drinking alcohol is associated with variation in the human oral microbiome in a large study of American adults. Microbiome, 2018, 6(1): 59. doi: 10.1186/s40168-018-0448-x.

[21] LIU T, WU M H, HU P H, et al. Relationship between masticatory dysfunction and salivary microbiota. J Oral Rehabil, 2025, 52(7): 991-1000. doi: 10.1111/joor.13963.

[22] GAZDECK R K, FRUSCIONE S R, ADAMI G R, et al. Diversity of the oral microbiome between dentate and edentulous individuals. Oral Dis, 2019, 25(3): 911-918. doi: 10.1111/odi.13039.

[23] 郑欣, 程磊, 周学东. 龋病研究的前沿与进展. 中华口腔医学杂志, 2024, 59(1): 14-22. doi: 10.3760/cma.j.cn112144-20231010-00187.

[24] ZHENG X, CHENG L, ZHOU X D. Frontiers and advances in caries research. Chin J Stomatol, 2024, 59(1): 14-22. doi: 10.3760/cma.j.cn112144-20231010-00187.

[25] BELSTRØM D, FIEHN N E, NIELSEN C H, et al. Altered bacterial profiles in saliva from adults with caries lesions: a case-cohort study. Caries Res, 2014, 48(5): 368-375. doi: 10.1159/000357502.

[26] ZHANG Y, HUANG S, JIA S, et al. The predictive power of saliva electrolytes exceeds that of saliva microbiomes in diagnosing early childhood caries. J Oral Microbiol, 2021, 13(1): 1921486. doi: 10.1080/20002297.2021.1921486.

[27] TENG F, YANG F, HUANG S, et al. Prediction of early childhood caries via spatial-temporal variations of oral microbiota. Cell Host Microbe, 2015, 18(3): 296-306. doi: 10.1016/j.chom.2015.08.005.

[28] MAZUREL D, BRANDT B W, BOOMSMA M, et al. Streptococcus mutans and caries: a systematic review and meta-analysis. J Dent Res, 2025, 104(6): 594-603. doi: 10.1177/00220345241303880.

[29] HEMADI A S, HUANG R, ZHOU Y, et al. Salivary proteins and microbiota as biomarkers for early childhood caries risk assessment. Int J Oral Sci, 2017, 9(11): e1. doi: 10.1038/ijos.2017.35.

[30] 王思维, 郑黎薇, 周媛. 唾液标志物预测低龄儿童龋研究进展. 中国医药导报, 2024, 21(6): 54-57. doi: 10.20047/j.issn1673-7210.2024.06.12.

[31] WANG S W, ZHENG L W, ZHOU Y. Research progress of salivary biomarkers in predicting early childhood caries. China Med Her, 2024, 21(6): 54-57. doi: 10.20047/j.issn1673-7210.2024.06.12.

[32] FOROUGHI M, TORABINEJAD M, ANGELOV N, et al. Bridging oral and systemic health: exploring pathogenesis, biomarkers, and diagnostic innovations in periodontal disease. Infection, 2025, 53(6): 2277-2302. doi: 10.1007/s15010-025-02568-y.

[33] KINANE D F, STATHOPOULOU P G, PAPAPANOU P N. Periodontal diseases. Nat Rev Dis Primers, 2017, 3: 17038. doi: 10.1038/nrdp.2017.38.

[34] HAJISHENGALLIS G, LAMONT R J. Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol Oral Microbiol, 2012, 27(6): 409-419. doi: 10.1111/j.2041-1014.2012.00663.x.

[35] DASHPER S G, SEERS C A, TAN K H, et al. Virulence factors of the oral spirochete Treponema denticola . J Dent Res, 2011, 90(6): 691-703. doi: 10.1177/0022034510385242.

[36] CASTELLARIN M, WARREN R L, FREEMAN J D, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res, 2012, 22(2): 299-306. doi: 10.1101/gr.126516.111.

[37] LUNDMARK A, HU Y O O, HUSS M, et al. Identification of salivary microbiota and its association with host inflammatory mediators in periodontitis. Front Cell Infect Microbiol, 2019, 9: 216. doi: 10.3389/fcimb.2019.00216.

[38] HARIRIAN H, ANDRUKHOV O, BERTL K, et al. Microbial analysis of subgingival plaque samples compared to that of whole saliva in patients with periodontitis. J Periodontol, 2014, 85(6): 819-828. doi: 10.1902/jop.2013.130306.

[39] SAYGUN I, NIZAM N, KESKINER I, et al. Salivary infectious agents and periodontal disease status. J Periodontal Res, 2011, 46(2): 235-239. doi: 10.1111/j.1600-0765.2010.01335.x.

[40] DAMGAARD C, DANIELSEN A K, ENEVOLD C, et al. Porphyromonas gingivalis in saliva associates with chronic and aggressive periodontitis. J Oral Microbiol, 2019, 11(1): 1653123. doi: 10.1080/20002297.2019.1653123.

[41] TAN Y, WANG Z, XU M, et al. Oral squamous cell carcinomas: state of the field and emerging directions. Int J Oral Sci, 2023, 15(1): 44. doi: 10.1038/s41368-023-00249-w.

[42] 龚涛, 郑欣, 周学东. 唾液肿瘤标志物的研究进展. 四川大学学报(医学版), 2023, 54(3): 462-468. doi: 10.12182/20230560112.

[43] GONG T, ZHENG X, ZHOU X D. Research progress on salivary tumor biomarkers. J Sichuan Univ (Med Sci), 2023, 54(3): 462-468. doi: 10.12182/20230560112.

[44] SUN J, TANG Q, YU S, et al. F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production. EBioMedicine, 2023, 88: 104444. doi: 10.1016/j.ebiom.2023.104444.

[45] HISHIDA M, NOMOTO K, HASHIMOTO K, et al. Identification of non-invasive diagnostic markers for oral squamous cell carcinoma through salivary microbiome and gene expression analysis. Int J Mol Sci, 2025, 26(16): 8104. doi: 10.3390/ijms26168104.

[46] MÄKINEN A I, PAPPALARDO V Y, BUIJS M J, et al. Salivary microbiome profiles of oral cancer patients analyzed before and after treatment. Microbiome, 2023, 11(1): 171. doi: 10.1186/s40168-023-01613-y.

[47] ABDELBARY M M H, HATTING M, BOTT A, et al. The oral-gut axis: salivary and fecal microbiome dysbiosis in patients with inflammatory bowel disease. Front Cell Infect Microbiol, 2022, 12: 1010853. doi: 10.3389/fcimb.2022.1010853.

[48] MOTTAWEA W, CHIANG C K, MÜHLBAUER M, et al. Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease. Nat Commun, 2016, 7: 13419. doi: 10.1038/ncomms13419.

[49] LI Q, LUO W, XIAO L, et al. Microbial manipulators: Fusobacterium nucleatum modulates the tumor immune microenvironment in colorectal cancer. J Oral Microbiol, 2025, 17(1): 2544169. doi: 10.1080/20002297.2025.2544169.

[50] ZHENG X, GONG T, LUO W, et al. Fusobacterium nucleatum extracellular vesicles are enriched in colorectal cancer and facilitate bacterial adhesion. Sci Adv, 2024, 10(38): eado0016. doi: 10.1126/sciadv.ado0016.

[51] LI R, LI J, ZHOU X. Lung microbiome: new insights into the pathogenesis of respiratory diseases. Signal Transduct Target Ther, 2024, 9(1): 19. doi: 10.1038/s41392-023-01722-y.

[52] GARMENDIA J, CEBOLLERO-RIVAS P. Environmental exposures, the oral-lung axis and respiratory health: the airway microbiome goes on stage for the personalized management of human lung function. Microb Biotechnol, 2024, 17(6): e14506. doi: 10.1111/1751-7915.14506.

[53] KELLY N, WINNING L, IRWIN C, et al. Periodontal status and chronic obstructive pulmonary disease (COPD) exacerbations: a systematic review. BMC Oral Health, 2021, 21(1): 425. doi: 10.1186/s12903-021-01757-z.

[54] ZHOU M, LIU Y, YIN X, et al. The role of oral microbiota in lung carcinogenesis through the oral-lung axis: a comprehensive review of mechanisms and therapeutic potential. Discov Oncol, 2025, 16(1): 1651. doi: 10.1007/s12672-025-03440-z.

[55] FIGUERO E, SÁNCHEZ-BELTRÁN M, CUESTA-FRECHOSO S, et al. Detection of periodontal bacteria in atheromatous plaque by nested polymerase chain reaction. J Periodontol, 2011, 82(10): 1469-1477. doi: 10.1902/jop.2011.100719.

[56] EMERY D C, CERAJEWSKA T L, SEONG J, et al. Comparison of blood bacterial communities in periodontal health and periodontal disease. Front Cell Infect Microbiol, 2020, 10: 577485. doi: 10.3389/fcimb.2020.577485.

[57] DEL GIUDICE C, VAIA E, LICCARDO D, et al. Infective endocarditis: a focus on oral microbiota. Microorganisms, 2021, 9(6): 1218. doi: 10.3390/microorganisms9061218.

[58] CHAPPLE I L C, HIRSCHFELD J, COCKWELL P, et al. Interplay between periodontitis and chronic kidney disease. Nat Rev Nephrol, 2025, 21(4): 226-240. doi: 10.1038/s41581-024-00910-5.

[59] SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33. doi: 10.3322/caac.21708.

[60] LU J, WEI W, ZHENG D. Fusobacterium nucleatum in colorectal cancer: ally mechanism and targeted therapy strategies. Research (Wash D C), 2025, 8: 0640. doi: 10.34133/research.0640.

[61] GUO H, YANG R, CHENG W, et al. An update of salivary biomarkers for the diagnosis of Alzheimer's disease. Int J Mol Sci, 2025, 26(5): 2059. doi: 10.3390/ijms26052059.

[62] ROZENBLUM G, AIT-AISSA K, ZAHRAN G, et al. Unraveling the oral microbiome's role in Alzheimer's disease: from pathophysiology to therapeutic potential. Alzheimers Dement, 2025, 21(12): e71011. doi: 10.1002/alz.71011.

[63] GUO H, LI B, YAO H, et al. Profiling the oral microbiomes in patients with Alzheimer's disease. Oral Dis, 2023, 29(3): 1341-1355. doi: 10.1111/odi.14110.

[64] SANTIAGO J A, POTASHKIN J A. The impact of disease comorbidities in Alzheimer's disease. Front Aging Neurosci, 2021, 13: 631770. doi: 10.3389/fnagi.2021.631770.

[65] CHIANG G C, MAO X, KANG G, et al. Relationships among cortical glutathione levels, brain amyloidosis, and memory in healthy older adults investigated in vivo with 1H-MRS and Pittsburgh compound-B PET. AJNR Am J Neuroradiol, 2017, 38(6): 1130-1137. doi: 10.3174/ajnr.A5143.

[66] KOEPSELL H. Glucose transporters in brain in health and disease. Pflugers Arch, 2020, 472(9): 1299-1343. doi: 10.1007/s00424-020-02441-x.

[67] FANG H, LIN J, QIU Y, et al. Epidemiology and pathogenesis of the link between rheumatoid arthritis and periodontitis. J Zhejiang Univ Sci B, 2025, 26(5): 448-460. doi: 10.1631/jzus.B2300519.

[68] ERIKSSON K, LUNDMARK A, DELGADO L F, et al. Salivary microbiota and host-inflammatory responses in periodontitis affected individuals with and without rheumatoid arthritis. Front Cell Infect Microbiol, 2022, 12: 841139. doi: 10.3389/fcimb.2022.841139.

[69] 徐玉, 陈园园, 朱斐然, 等. 检测牙龈卟啉单胞菌胶体金试纸条的制备与应用. 北京口腔医学, 2024, 32(4): 261-265. doi: 10.20049/j.bjkqyx.1006-673X.2024.04.007.

[70] XU Y, CHEN Y Y, ZHU F R, et al. Preparation and application of colloidal gold test strip for detection of Porphyromonas gingivalis . Beijing J Stomatol, 2024, 32(4): 261-265. doi: 10.20049/j.bjkqyx.1006-673X.2024.04.007.

[71] 项益榛, 沈一鸣. 一种快速检测唾液中针对头颈部肿瘤标志物的试纸: CN120779035A.

[72] BECKER K, PAN D, WHITLEY C B. Real-time quantitative polymerase chain reaction to assess gene transfer. Hum Gene Ther, 1999, 10(15): 2559-2566. doi: 10.1089/10430349950016898.

[73] 孙同正. 基于荧光定量PCR检测龋病相关病原菌及风险评估模型构建. 青岛: 青岛大学, 2018.

[74] SUN T Z. Detection of caries-related pathogens based on fluorescent quantitative PCR and construction of risk assessment model. Qingdao: Qingdao University, 2018.

[75] BEDARF J R, BERAZA N, KHAZNEH H, et al. Much ado about nothing? Off-target amplification can lead to false-positive bacterial brain microbiome detection in healthy and Parkinson's disease individuals. Microbiome, 2021, 9(1): 75. doi: 10.1186/s40168-021-01012-1.

[76] KNIGHT R, VRBANAC A, TAYLOR B C, et al. Best practices for analysing microbiomes. Nat Rev Microbiol, 2018, 16(7): 410-422. doi: 10.1038/s41579-018-0029-9.

[77] JIANG Y, LIU J, ZHANG Y, et al. High-resolution microbiome analysis of host-rich samples using 2bRAD-M without host depletion. NPJ Biofilms Microbiomes, 2025, 11(1): 223. doi: 10.1038/s41522-025-00851-2.

[78] HERRERA G, ZOUIOUICH S, DIAZ-MAYORAL N, et al. Comparison of oral collection methods for 16S rRNA gene and shotgun metagenomic sequencing. Microbiol Spectr, 2025: e0180625. doi: 10.1128/spectrum.01806-25.

[79] YANO Y, HUA X, WAN Y, et al. Comparison of oral microbiota collected using multiple methods and recommendations for new epidemiologic studies. mSystems, 2020, 5(4): e00156-20. doi: 10.1128/mSystems.00156-20.

[80] VOGTMANN E, CHEN J, KIBRIYA M G, et al. Comparison of oral collection methods for studies of microbiota. Cancer Epidemiol Biomarkers Prev, 2019, 28(1): 137-143. doi: 10.1158/1055-9965.EPI-18-0312.

基金资助

*国家自然科学基金(32270120)

国家自然科学基金(32470110)

四川省自然科学基金(2026NSFSC0672)