口腔微生态在衰老相关稳态失衡及系统性疾病中的作用研究进展^*

Research Advances on the Role of the Oral Microbiota in Age-Related Homeostatic Dysregulation and Systemic Diseases

摘要

微生态在衰老过程中的调控作用日益受到关注。口腔微生态作为人体重要的微生物生态系统，在维持机体健康和参与疾病发生发展中具有独特地位。本文综述了健康和疾病状态下口腔微生态中特定菌属的动态变化，分析了衰老过程中口腔生理性改变对微生态的影响，并详细阐述了衰老相关口腔微生态失衡参与口腔疾病及系统性疾病的作用机制。鉴于口腔微生态与衰老之间的密切互作关系，其在促进健康老龄化中的作用愈发凸显。深入探究口腔微生态的演替规律，不仅有助于解析老年系统性疾病高发的内在机制，也为开发基于微生态重塑的老年健康干预策略及发现新型早期预警标志物提供了重要的理论依据。

Abstract

The regulatory role of the microbiota in the aging process has increasingly attracted attention. As a crucial microbial ecosystem of the human body, the oral microbiota plays a unique role in maintaining host health and contributing to disease development. This review summarizes the dynamic changes in specific oral microbial genera under both healthy and diseased conditions, analyzes the impact of age-related physiological alterations of the oral cavity on the microbiota, and comprehensively elucidates the mechanisms by which age-associated oral microbial dysbiosis participates in oral and systemic diseases. Given the close interplay between the oral microbiota and aging, its significance in promoting healthy aging has become increasingly prominent. Investigating the succession patterns of the oral microbiota not only helps to unravel the mechanisms underlying the high incidence of systemic diseases in the elderly, but also provides a theoretical basis for developing microbiota-based intervention strategies and identifying novel early-biomarkers for healthy aging.

关键词

衰老 / 口腔 / 生态失调 / 疾病 / 健康老龄化 / 综述

Key words

Aging / Oral cavity / Dysbiosis / Disease / Healthy aging / Review

参考文献

[1] Baker J L, Mark Welch J L, Kauffman K M, et al. The oral microbiome: diversity, biogeography and human health[J]. Nat Rev Microbiol, 2024, 22(2): 89-104. DOI: 10.1038/s41579-023-00963-6.

[2] Guo Z L, Cui M W, Dong Y L, et al. The oral microbiome as a regulatory hub for systemic health: a systematic review of mechanistic links and clinical implications[J/OL]. J Oral Microbiol, 2026, 18(1): 2635233. https://doi.org/10.1080/20002297.2026.2635233.

[3] Schmidt T S, Hayward M R, Coelho L P, et al. Extensive transmission of microbes along the gastrointestinal tract[J/OL]. eLife, 2019, 8: e42693. https://doi.org/10.7554/eLife.42693.

[4] Kitamoto S, Nagao-Kitamoto H, Jiao Y, et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis[J]. Cell, 2020, 182(2): 447-462, e14. DOI: 10.1016/j.cell.2020.05.048.

[5] Deng L, Guan G, Cannon R D, et al. Age-related oral microbiota dysbiosis and systemic diseases[J]. Microb Pathog, 2025, 205: 107717. DOI: 10.1016/j.micpath.2025.107717.

[6] Kroemer G, Maier A B, Cuervo A M, et al. From geroscience to precision geromedicine: understanding and managing aging[J]. Cell, 2025, 188(8): 2043-2062. DOI: 10.1016/j.cell.2025.03.011.

[7] López-Otín C, Blasco M A, Partridge L, et al. Hallmarks of aging: an expanding universe[J]. Cell, 2023, 186(2): 243-278. DOI: 10.1016/j.cell.2022.11.001.

[8] Toan N K, Ahn S G. Aging-related metabolic dysfunction in the salivary gland: a review of the literature[J]. Int J Mol Sci, 2021, 22(11): 5835. DOI: 10.3390/ijms22115835.

[9] Lamont R J, Koo H, Hajishengallis G. The oral microbiota: dynamic communities and host interactions[J]. Nat Rev Microbiol, 2018, 16(12): 745-759. DOI: 10.1038/s41579-018-0089-x.

[10] Dominy S S, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer's disease brains: evidence for disease causation and treatment with small-molecule inhibitors[J/OL]. Sci Adv, 2019, 5(1): eaau3333. https://doi.org/10.1126/sciadv.aau3333.

[11] Schenkein H A, Loos B G. Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases[J]. J Clin Periodontol, 2013, 40(Suppl 14): S51-S69. DOI: 10.1111/jcpe.12060.

[12] Zhang P, Wang Q, Nie L, et al. Hyperglycemia-induced inflamm-aging accelerates gingival senescence via NLRC4 phosphorylation[J]. J Biol Chem, 2019, 294(49): 18807-18819. DOI: 10.1074/jbc.RA119.010648.

[13] Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities[J]. Nat Rev Immunol, 2021, 21(7): 426-440. DOI: 10.1038/s41577-020-00488-6.

[14] Singh H, Torralba M G, Moncera K J, et al. Gastro-intestinal and oral microbiome signatures associated with healthy aging[J]. GeroScience, 2019, 41(6): 907-921. DOI: 10.1007/s11357-019-00098-8.

[15] Carbone E, Fabrizi E, Rivabene R, et al. Human oral microbiome in aging: a systematic review[J]. Mech Ageing Dev, 2025, 226: 112080. DOI: 10.1016/j.mad.2025.112080.

[16] Liu S, Wang Y, Zhao L, et al. Microbiome succession with increasing age in three oral sites[J]. Aging (Albany NY), 2020, 12(9): 7874-7907. DOI: 10.18632/aging.103108.

[17] Xu X, He J, Xue J, et al. Oral cavity contains distinct niches with dynamic microbial communities[J]. Environ Microbiol, 2015, 17(3): 699-710. DOI: 10.1111/1462-2920.12502.

[18] Ji Y, Sun H, Wang Y, et al. Characterizing the oral and gastrointestinal microbiome associated with healthy aging: insights from long-lived populations in northeastern China[J]. GeroScience, 2024, 47(2): 2275-2292. DOI: 10.1007/s11357-024-01419-2.

[19] Declercq V, Wright R J, Nearing J T, et al. Oral microbial signatures associated with age and frailty in Canadian adults[J/OL]. Sci Rep, 2024, 14: 9685. https://doi.org/10.1038/s41598-024-60409-8.

[20] Percival R S, Challacombe S J, Marsh P D . Age-related microbiological changes in the salivary and plaque microflora of healthy adults[J]. J Med Microbiol, 1991, 35(1): 5-11. DOI: 10.1099/00222615-35-1-5.

[21] Spatafora G, Li Y, He X, et al. The evolving microbiome of dental caries[J/OL]. Microorganisms, 2024, 12(1): 121. https://doi.org/10.3390/microorganisms12010121.

[22] Akata K, Noguchi S, Kawanami T, et al. Microbiology of aspiration pneumonia[J]. J UOEH, 2019, 41(2): 185-195. DOI: 10.7888/juoeh.41.185.

[23] Santacroce L, Passarelli P C, Azzolino D, et al. Oral microbiota in human health and disease: a perspective[J]. Exp Biol Med, 2023, 248(15): 1288-1301. DOI: 10.1177/15353702231187645.

[24] Silva D N de A, Casarin M, Monajemzadeh S, et al. The microbiome in periodontitis and diabetes[J/OL]. Front Oral Health, 2022, 3: 859209. https://doi.org/10.3389/froh.2022.859209.

[25] Deo P N, Deshmukh R. Oral microbiome: unveiling the fundamentals[J]. J Oral Maxillofac Pathol, 2019, 23(1): 122-128. DOI: 10.4103/jomfp.JOMFP_304_18.

[26] Li X, Liu Y, Yang X, et al. The oral microbiota: community composition, influencing factors, pathogenesis, and interventions[J/OL]. Front Microbiol, 2022, 13: 895537. https://doi.org/10.3389/fmicb.2022.895537.

[27] Prodan A, Brand H S, Ligtenberg A J M, et al. Interindividual variation, correlations, and sex-related differences in the salivary biochemistry of young healthy adults[J]. Eur J Oral Sci, 2015, 123(3): 149-157. DOI: 10.1111/eos.12182.

[28] Kazarina A, Kuzmicka J, Bortkevica S, et al. Oral microbiome variations related to ageing: possible implications beyond oral health[J]. Arch Microbiol, 2023, 205(4): 116. DOI: 10.1007/s00203-023-03464-5.

[29] Sarafidou K, Alexakou E, Talioti E, et al. The oral microbiome in older adults: a state-of-the-art review[J/OL]. Arch Gerontol Geriatr Plus, 2024, 1(4): 100061. https://doi.org/10.1016/j.aggp.2024.100061.

[30] Elsayed R, Elashiry M, Liu Y, et al. Microbially-induced exosomes from dendritic cells promote paracrine immune senescence: novel mechanism of bone degenerative disease in mice[J]. Aging Dis, 2023, 14(1): 136-151. DOI: 10.14336/AD.2022.0623.

[31] Elsayed R, Elashiry M, Liu Y, et al. Porphyromonas gingivalis provokes exosome secretion and paracrine immune senescence in bystander dendritic cells[J/OL]. Front Cell Infect Microbiol, 2021, 11: 669989. https://doi.org/10.3389/fcimb.2021.669989.

[32] 徐欣, 何金枝, 周学东. 口腔微生物群落在口腔与全身疾病预警中的作用[J]. 华西口腔医学杂志, 2015, 33(6): 555-560. DOI: 10.7518/hxkq.2015.06.001.

[33] Xu X, He J Z, Zhou X D. Oral microbiota: a promising predictor of human oral and systemic diseases[J]. West China J Stomatol, 2015, 33(6): 555-560. DOI: 10.7518/hxkq.2015.06.001.

[34] 李雅卓, 陈雨晴, 陈帅, 等. 衰老背景下口腔微生态失调与功能减退在阿尔茨海默病进程中的作用[J]. 四川大学学报(医学版), 2026, 57(1): 56-64. DOI: 10.12182/20260160510.

[35] Li Y Z, Chen Y Q, Chen S, et al. Aging-Associated Oral Microbiota Dysbiosis and Hypofunction: Their Role in Alzheimer's Disease Pathogenesis[J]. J Sichuan Univ (Med Sci), 2026, 57(1): 56-64. DOI: 10.12182/20260160510.

[36] Yue Z, Li C, Yan F, et al. The oral microbiome in aging: a window into health and longevity[J/OL]. J Oral Microbiol, 2025, 17(1): 2589648. https://doi.org/10.1080/20002297.2025.2589648.

[37] Wang Z, Saxena A, Yan W, et al. The impact of aging on neutrophil functions and the contribution to periodontitis[J]. Int J Oral Sci, 2025, 17: 10. DOI: 10.1038/s41368-024-00332-w.

[38] Takeuchi H, Nakamura E, Yamaga S, et al. Porphyromonas gingivalis infection induces lipopolysaccharide and peptidoglycan penetration through gingival epithelium[J/OL]. Front Oral Health, 2022, 3: 845002. https://doi.org/10.3389/froh.2022.845002.

[39] Ren Y, Chen M, Wang Z, et al. Oral microbiota in aging and diseases[J]. Life Med, 2024, 3(3): lnae024. DOI: 10.1093/lifemedi/lnae024.

[40] Yu L X, Wang X, Feng X P, et al. The relationship between different types of caries and periodontal disease severity in middle-aged and elderly people: findings from the 4th national oral health survey of China[J/OL]. BMC Oral Health, 2021, 21(1): 229. https://doi.org/10.1186/s12903-021-01585-1.

[41] Okuyama K, Yanamoto S. Saliva in balancing oral and systemic health, oral cancer, and beyond: a narrative review[J/OL]. Cancers, 2024, 16(24): 4276. https://doi.org/10.3390/cancers16244276.

[42] Altarawneh S, Bencharit S, Mendoza L, et al. Clinical and histological findings of denture stomatitis as related to intraoral colonization patterns of C. albicans, salivary flow, and dry mouth[J/OL]. J Prosthodont, 2013, 22(1): 13-22. https://doi.org/10.1111/j.1532-849X.2012.00906.x.

[43] Visentin D, Gobin I, Maglica Ž. Periodontal pathogens and their links to neuroinflammation and neurodegeneration[J/OL]. Microorganisms, 2023, 11(7): 1832. https://doi.org/10.3390/microorganisms11071832.

[44] Li Y, Guo R, Oduro P K, et al. The relationship between Porphyromonas gingivalis and rheumatoid arthritis: a meta-analysis[J/OL]. Front Cell Infect Microbiol, 2022, 12: 956417. https://doi.org/10.3389/fcimb.2022.956417.

[45] Shoemark D K, Allen S J. The microbiome and disease: reviewing the links between the oral microbiome, aging, and Alzheimer's disease[J]. J Alzheimers Dis, 2014, 43(3): 725-738. DOI: 10.3233/JAD-141170.

[46] Zeng F, Liu Y, Huang W, et al. Receptor for advanced glycation end products up-regulation in cerebral endothelial cells mediates cerebrovascular-related amyloid β accumulation after Porphyromonas gingivalis infection[J/OL]. J Neurochem, 2021, 158(3): 724-736. https://doi.org/10.1111/jnc.15096.

[47] Li R, Wang J, Xiong W, et al. The oral-brain axis: can periodontal pathogens trigger the onset and progression of Alzheimer's disease?[J/OL]. Front Microbiol, 2024, 15: 1358179. https://doi.org/10.3389/fmicb.2024.1358179.

[48] Habashneh R A, Khader Y S, Alhumouz M K, et al. The association between inflammatory bowel disease and periodontitis among Jordanians: a case-control study[J]. J Periodontal Res, 2012, 47(3): 293-298. DOI: 10.1111/j.1600-0765.2011.01431.x.

[49] Gualtero D F, Lafaurie G I, Buitrago D M, et al. Oral microbiome mediated inflammation, a potential inductor of vascular diseases: a comprehensive review[J/OL]. Front Cardiovasc Med, 2023, 10: 1250263. https://doi.org/10.3389/fcvm.2023.1250263.

[50] Sreedevi M, Ramesh A, Dwarakanath C. Periodontal status in smokers and nonsmokers: a clinical, microbiological, and histopathological study[J/OL]. Int J Dent, 2012, 2012: 571590. https://doi.org/10.1155/2012/571590.

[51] Huang X, Xie M, Lu X, et al. The roles of periodontal bacteria in atherosclerosis[J/OL]. Int J Mol Sci, 2023, 24(16): 12861. https://doi.org/10.3390/ijms241612861.

[52] Kwun J S, Kang S H, Lee H J, et al. Comparison of thrombus, gut, and oral microbiomes in Korean patients with ST-elevation myocardial infarction: a case-control study[J/OL]. Exp Mol Med, 2020, 52(12): 2069-2079. https://doi.org/10.1038/s12276-020-00543-1.

[53] Adil N A, Omo-Erigbe C, Yadav H, et al. The oral-gut microbiome-brain axis in cognition[J/OL]. Microorganisms, 2025, 13(4): 814. https://doi.org/10.3390/microorganisms13040814.

[54] Iwauchi M, Horigome A, Ishikawa K, et al. Relationship between oral and gut microbiota in elderly people[J/OL]. Immun Inflamm Dis, 2019, 7(3): 229-236. https://doi.org/10.1002/iid3.266.

[55] Tan X, Wang Y, Gong T. The interplay between oral microbiota, gut microbiota and systematic diseases[J/OL]. J Oral Microbiol, 2023, 15(1): 2213112. https://doi.org/10.1080/20002297.2023.2213112.

[56] Tanwar H, Gnanasekaran J M, Allison D, et al. Unraveling the link between periodontitis and inflammatory bowel disease: challenges and outlook[J/OL]. ArXiv, 2023, 2308.10907v1. https://doi.org/10.48550/arXiv.2308.10907.

[57] Yao C, Lan D, Li X, et al. Porphyromonas gingivalis is a risk factor for the development of nonalcoholic fatty liver disease via ferroptosis[J]. Microbes Infect, 2023, 25(1/2): 105040. DOI: 10.1016/j.micinf.2022.105040.

[58] Serhal L, Lwin M N, Holroyd C, et al. Rheumatoid arthritis in the elderly: characteristics and treatment considerations[J]. Autoimmun Rev, 2020, 19(6): 102528. DOI: 10.1016/j.autrev.2020.102528.

[59] Hitchon C A, Chandad F, Ferucci E D, et al. Antibodies to Porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives[J]. J Rheumatol, 2010, 37(6): 1105-1112. DOI: 10.3899/jrheum.091323.

[60] Zhao Y, Li Z, Su L, et al. Characterization and regulation of osteoclast precursors following chronic Porphyromonas gingivalis infection[J]. J Leukoc Biol, 2020, 108(4): 1037-1050. DOI: 10.1002/jlb.1hi0620-230r.

[61] Teng F, Yang F, Huang S, et al. Prediction of early childhood caries via spatial-temporal variations of oral microbiota[J]. Cell Host Microbe, 2015, 18(3): 296-306. DOI: 10.1016/j.chom.2015.08.005.

[62] Song H Y, Li Y. Can eradication rate of gastric Helicobacter pylori be improved by killing oral Helicobacter pylori?[J/OL]. World J Gastroenterol, 2013, 19(39): 6645-6650. https://doi.org/10.3748/wjg.v19.i39.6645.

基金资助

*国家自然科学基金(32470108)