口腔微生物组：稳态维持、疾病关联及致病机制^*

The Oral Microbiome: Maintenance of Homeostasis, Disease Associations, and Mechanisms of Pathogenesis

摘要

口腔微生物组是一个复杂且高度结构化的生态系统，由细菌、真菌、病毒等多种微生物构成，与宿主形成密切的共生关系。其在牙齿、黏膜等不同生态位点的组成受年龄、遗传、生活方式等多因素调控，稳定的微生物群落是维持口腔及全身健康的重要屏障。本综述系统探讨了口腔微生物组在健康与疾病状态下的结构与功能，重点分析了菌斑生物膜的形成机制及其在龋病、牙周炎发生发展中的关键作用。龋病主要由产酸、耐酸菌如变形链球菌、乳酸杆菌等主导，伴随微环境酸化与釉质脱矿；牙周炎则与龈下菌斑中“红色复合体”等病原微生物的富集及宿主免疫失调密切相关。此外，口腔微生物的生态失调，特别是核梭杆菌、牙龈卟啉单胞菌等病原体的异常增殖，不仅参与口腔鳞癌的发生发展，亦可通过炎症诱导、免疫抑制及菌群移位等机制，与心血管疾病、糖尿病、类风湿关节炎及胰腺癌等多种全身系统性疾病密切相关。系统揭示口腔微生物组的生态学与致病机制，将为维护口腔微生态稳态、防治口腔及全身相关性疾病提供重要的理论依据。

Abstract

The oral microbiome is a complex and highly structured ecosystem composed of diverse microorganisms, including bacteria, fungi, viruses, and other microbes, which establish an intimate symbiotic relationship with the host. Its composition across distinct ecological niches, such as teeth and mucosa, is modulated by multiple factors, including age, genetics, and lifestyle. A stable microbial community acts as an essential barrier for sustaining oral and systemic health. This review systematically examines the structure and function of the oral microbiome under healthy and diseased conditions, with an emphasis on the formation mechanisms of plaque biofilms and their pivotal roles in the initiation and progression of dental caries and periodontitis. Dental caries is predominantly driven by acidogenic and aciduric bacteria, such as Streptococcus mutans and Lactobacillus spp., accompanied by microenvironmental acidification and enamel demineralization. Periodontitis is closely associated with the enrichment of pathogenic microorganisms, including the "red complex" in subgingival plaque, and host immune dysregulation. Furthermore, ecological dysbiosis of the oral microbiome, particularly the abnormal proliferation of pathogens such asFusobacterium nucleatum and Porphyromonas gingivalis, not only contributes to the development and progression of oral squamous cell carcinoma but also closely correlates with numerous systemic disorders, including cardiovascular diseases, diabetes mellitus, rheumatoid arthritis, and pancreatic cancer, via mechanisms such as inflammatory induction, immunosuppression, and microbial translocation. Systematic elucidation of the ecological characteristics and pathogenic mechanisms of the oral microbiome will provide a critical theoretical foundation for maintaining oral microecological homeostasis and for preventing and treating oral and systemic comorbidities.

关键词

口腔微生物组 / 菌群失调 / 牙周炎 / 龋病 / 综述

Key words

Oral microbiome / Dysbiosis / Periodontitis / Dental caries / 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. Nat Rev Microbiol, 2024, 22(2): 89-104. doi: 10.1038/s41579-023-00963-6.

[2] KLEINSTEIN S E, NELSON K E, FREIRE M. Inflammatory networks linking oral microbiome with systemic health and disease. J Dent Res, 2020, 99(10): 1131-1139. doi: 10.1177/0022034520926126.

[3] RAJASEKARAN J J, KRISHNAMURTHY H K, BOSCO J, et al. Oral microbiome: a review of its impact on oral and systemic health. Microorganisms, 2024, 12(9): 1797. doi: 10.3390/microorganisms12091797.

[4] 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.

[5] SANTONOCITO S, GIUDICE A, POLIZZI A, et al. A cross-talk between diet and the oral microbiome: balance of nutrition on inflammation and immune system's response during periodontitis. Nutrients, 2022, 14(12): 2426. doi: 10.3390/nu14122426.

[6] YU X, DEVINE D A, VERNON J J. Manipulating the diseased oral microbiome: the power of probiotics and prebiotics. J Oral Microbiol, 2024, 16(1): 2307416. doi: 10.1080/20002297.2024.2307416.

[7] ARAUJO T T, DIONIZIO A, CARVALHO T S, et al. Acquired enamel pellicle and biofilm engineering with a combination of acid-resistant proteins (CaneCPI-5, StN15, and Hemoglobin) for enhanced protection against dental caries - in vivo and in vitro investigations. Clin Oral Investig, 2024, 28(5): 261. doi: 10.1007/s00784-024-05651-0.

[8] MOUSSA D G, KUNG R W, TSE J S, et al. Mechanistic insights into bioengineered antibiofilm enamel pellicles. J Dent Res, 2023, 102(7): 743-751. doi: 10.1177/00220345231162336.

[9] DÍAZ-GARRIDO N, LOZANO C P, KRETH J, et al. Competition and caries on enamel of a dual-species biofilm model with Streptococcus mutans and Streptococcus sanguinis. Appl Environ Microbiol, 2020, 86(21): e01262-20. doi: 10.1128/aem.01262-20.

[10] CHAWHUAVEANG D D, YU O Y, YIN I X, et al. Acquired salivary pellicle and oral diseases: a literature review. J Dent Sci, 2021, 16(1): 523-529. doi: 10.1016/j.jds.2020.10.007.

[11] HAASE E M, KOU Y, SABHARWAL A, et al. Comparative genomics and evolution of the amylase-binding proteins of oral streptococci. BMC Microbiol, 2017, 17(1): 94. doi: 10.1186/s12866-017-1005-7.

[12] JACK A A, DANIELS D E, JEPSON M A, et al. Streptococcus gordonii comCDE (competence) operon modulates biofilm formation with Candida albicans. Microbiology (Reading), 2015, 161(Pt 2): 411-421. doi: 10.1099/mic.0.000010.

[13] HUANG X, PALMER S R, AHN S J, et al. A highly arginolytic Streptococcus species that potently antagonizes Streptococcus mutans. Appl Environ Microbiol, 2016, 82(7): 2187-2201. doi: 10.1128/aem.03887-15.

[14] FORSSTEN S D, BJÖRKLUND M, OUWEHAND A C. Streptococcus mutans, caries and simulation models. Nutrients, 2010, 2(3): 290-298. doi: 10.3390/nu2030290.

[15] XIAO J, HARA A T, KIM D, et al. Biofilm three-dimensional architecture influences in situ pH distribution pattern on the human enamel surface. Int J Oral Sci, 2017, 9(2): 74-79. doi: 10.1038/ijos.2017.8.

[16] ROBERTS W E, MANGUM J E, SCHNEIDER P M. Pathophysiology of demineralization, Part Ⅱ: enamel white spots, cavitated caries, and bone infection. Curr Osteoporos Rep, 2022, 20(1): 106-119. doi: 10.1007/s11914-022-00723-0.

[17] TAKAHASHI N, NYVAD B. The role of bacteria in the caries process: ecological perspectives. J Dent Res, 2011, 90(3): 294-303. doi: 10.1177/0022034510379602.

[18] YANG J, YOSHIDA Y, CISAR J O. Genetic basis of coaggregation receptor polysaccharide biosynthesis in Streptococcus sanguinis and related species. Mol Oral Microbiol, 2014, 29(1): 24-31. doi: 10.1111/omi.12042.

[19] JAKUBOVICS N S, GOODMAN S D, MASHBURN-WARREN L, et al. The dental plaque biofilm matrix. Periodontol 2000, 2021, 86(1): 32-56. doi: 10.1111/prd.12361.

[20] KARYGIANNI L, REN Z, KOO H, et al. Biofilm matrixome: extracellular components in structured microbial communities. Trends Microbiol, 2020, 28(8): 668-681. doi: 10.1016/j.tim.2020.03.016.

[21] FLEMMING H C, Van HULLEBUSCH E D, NEU T R, et al. The biofilm matrix: multitasking in a shared space. Nat Rev Microbiol, 2023, 21(2): 70-86. doi: 10.1038/s41579-022-00791-0.

[22] RIBEIRO A A, PASTER B J. Dental caries and their microbiomes in children: what do we do now? J Oral Microbiol, 2023, 15(1): 2198433. doi: 10.1080/20002297.2023.2198433.

[23] MA X, LIN X, ZHONG T, et al. Evaluation of the efficacy of casein phosphopeptide-amorphous calcium phosphate on remineralization of white spot lesions in vitro and clinical research: a systematic review and meta-analysis. BMC Oral Health, 2019, 19(1): 295. doi: 10.1186/s12903-019-0977-0.

[24] KIM H E, LIU Y, DHALL A, et al. Synergism of Streptococcus mutans and Candida albicans reinforces biofilm maturation and acidogenicity in saliva: an in vitro study. Front Cell Infect Microbiol, 2020, 10: 623980. doi: 10.3389/fcimb.2020.623980.

[25] IKEBE K, IMAZATO S, IZUTANI N, et al. Association of salivary Streptococcus mutans levels determined by rapid detection system using monoclonal antibodies with prevalence of root surface caries. Am J Dent, 2008, 21(5): 283-287.

[26] MANTZOURANI M, FENLON M, BEIGHTON D. Association between bifidobacteriaceae and the clinical severity of root caries lesions. Oral Microbiol Immunol, 2009, 24(1): 32-37. doi: 10.1111/j.1399-302X.2008.00470.x.

[27] XIONG K, ZHU H, LI Y, et al. The arginine biosynthesis pathway of Candida albicans regulates its cross-kingdom interaction with actinomyces viscosus to promote root caries. Microbiol Spectr, 2022, 10(4): e0078222. doi: 10.1128/spectrum.00782-22.

[28] PARIS S, BITTER K, KROIS J, et al. Seven-year-efficacy of proximal caries infiltration - randomized clinical trial. J Dent, 2020, 93: 103277. doi: 10.1016/j.jdent.2020.103277.

[29] VALM A M. The structure of dental plaque microbial communities in the transition from health to dental caries and periodontal disease. J Mol Biol, 2019, 431(16): 2957-2969. doi: 10.1016/j.jmb.2019.05.016.

[30] LIMA K C, COELHO L T, PINHEIRO I V, et al. Microbiota of dentinal caries as assessed by reverse-capture checkerboard analysis. Caries Res, 2011, 45(1): 21-30. doi: 10.1159/000322299.

[31] KURIBAYASHI M, KITASAKO Y, MATIN K, et al. Intraoral pH measurement of carious lesions with qPCR of cariogenic bacteria to differentiate caries activity. J Dent, 2012, 40(3): 222-228. doi: 10.1016/j.jdent.2011.12.013.

[32] TAKAHASHI N, NYVAD B. Ecological hypothesis of dentin and root caries. Caries Res, 2016, 50(4): 422-431. doi: 10.1159/000447309.

[33] ZHANG H, XIA M, ZHANG B, et al. Sucrose selectively regulates Streptococcus mutans polysaccharide by GcrR. Environ Microbiol, 2022, 24(3): 1395-1410. doi: 10.1111/1462-2920.15887.

[34] ZHANG Q, MA Q, WANG Y, et al. Molecular mechanisms of inhibiting glucosyltransferases for biofilm formation in Streptococcus mutans. Int J Oral Sci, 2021, 13(1): 30. doi: 10.1038/s41368-021-00137-1.

[35] DENG Y, YANG Y, ZHANG B, et al. The vicK gene of Streptococcus mutans mediates its cariogenicity via exopolysaccharides metabolism. Int J Oral Sci, 2021, 13(1): 45. doi: 10.1038/s41368-021-00149-x.

[36] HOLGERSON P L, VESTMAN N R, CLAESSON R, et al. Oral microbial profile discriminates breast-fed from formula-fed infants. J Pediatr Gastroenterol Nutr, 2013, 56(2): 127-136. doi: 10.1097/MPG.0b013e31826f2bc6.

[37] BADET C, THEBAUD N B. Ecology of lactobacilli in the oral cavity: a review of literature. Open Microbiol J, 2008, 2: 38-48. doi: 10.2174/1874285800802010038.

[38] MIRA A, SIMON-SORO A, CURTIS M A. Role of microbial communities in the pathogenesis of periodontal diseases and caries. J Clin Periodontol, 2017, 44(Suppl 18): S23-S38. doi: 10.1111/jcpe.12671.

[39] BELIBASAKIS G N, BELSTRØM D, EICK S, et al. Periodontal microbiology and microbial etiology of periodontal diseases: Historical concepts and contemporary perspectives. Periodontol 2000, 2023, 00: 1-17. doi: 10.1111/prd.12473.

[40] CHEN T, MARSH P D, Al-HEBSHI N N. SMDI: an index for measuring subgingival microbial dysbiosis. J Dent Res, 2022, 101(3): 331-338. doi: 10.1177/00220345211035775.

[41] ABUSLEME L, HOARE A, HONG B Y, et al. Microbial signatures of health, gingivitis, and periodontitis. Periodontol 2000, 2021, 86(1): 57-78. doi: 10.1111/prd.12362.

[42] SPRAGGE F, BAKKEREN E, JAHN M T, et al. Microbiome diversity protects against pathogens by nutrient blocking. Science, 2023, 382(6676): eadj3502. doi: 10.1126/science.adj3502.

[43] HOU K, WU Z X, CHEN X Y, et al. Microbiota in health and diseases. Signal Transduct Target Ther, 2022, 7(1): 135. doi: 10.1038/s41392-022-00974-4.

[44] SU Y, XU M Y, CUI Y, et al. Bacterial quorum sensing orchestrates longitudinal interactions to shape microbiota assembly. Microbiome, 2023, 11(1): 241. doi: 10.1186/s40168-023-01699-4.

[45] De GOFFAU M C, JALLOW A T, SANYANG C, et al. Gut microbiomes from Gambian infants reveal the development of a non-industrialized Prevotella-based trophic network. Nat Microbiol, 2022, 7(1): 132-144. doi: 10.1038/s41564-021-01023-6.

[46] DURAN-PINEDO A E, SOLBIATI J, TELES F, et al. Subgingival host-microbiome metatranscriptomic changes following scaling and root planing in grade Ⅱ/Ⅲ periodontitis. J Clin Periodontol, 2023, 50(3): 316-330. doi: 10.1111/jcpe.13737.

[47] SISK-HACKWORTH L, ORTIZ-VELEZ A, REED M B, et al. Compositional data analysis of periodontal disease microbial communities. Front Microbiol, 2021, 12: 617949. doi: 10.3389/fmicb.2021.617949.

[48] SCANNAPIECO F A, DONGARI-BAGTZOGLOU A. Dysbiosis revisited: Understanding the role of the oral microbiome in the pathogenesis of gingivitis and periodontitis: a critical assessment. J Periodontol, 2021, 92(8): 1071-1078. doi: 10.1002/jper.21-0120.

[49] LACHNIT T, ULRICH L, WILLMER F M, et al. Nutrition-induced changes in the microbiota can cause dysbiosis and disease development. mBio, 2025, 16(4): e0384324. doi: 10.1128/mbio.03843-24.

[50] LI X, LIU Y, YANG X, et al. The oral microbiota: community composition, influencing factors, pathogenesis, and interventions. Front Microbiol, 2022, 13: 895537. doi: 10.3389/fmicb.2022.895537.

[51] LU J, WANG Y, WU J, et al. Linking microbial communities to rheumatoid arthritis: focus on gut, oral microbiome and their extracellular vesicles. Front Immunol, 2025, 16: 1503474. doi: 10.3389/fimmu.2025.1503474.

[52] FAN X, ALEKSEYENKO A V, WU J, et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut, 2018, 67(1): 120-127. doi: 10.1136/gutjnl-2016-312580.

[53] OLSEN I, LAMBRIS J D, HAJISHENGALLIS G. Porphyromonas gingivalis disturbs host-commensal homeostasis by changing complement function. J Oral Microbiol, 2017, 9(1): 1340085. doi: 10.1080/20002297.2017.1340085.

[54] BLASCO-BAQUE V, GARIDOU L, POMIÉ C, et al. Periodontitis induced by Porphyromonas gingivalis drives periodontal microbiota dysbiosis and insulin resistance via an impaired adaptive immune response. Gut, 2017, 66(5): 872-885. doi: 10.1136/gutjnl-2015-309897.

[55] ZHANG S, JIAO Y, LIU S, et al. Effects of Porphyromonas gingivalis outer membrane vesicles (OMVs) on macrophages in periodontitis. Oral Dis, 2025, 31(7): 1973-1981. doi: 10.1111/odi.15264.

[56] ANGABO S, PANDI K, DAVID K, et al. CD47 and thrombospondin-1 contribute to immune evasion by Porphyromonas gingivalis. Proc Natl Acad Sci U S A, 2024, 121(47): e2405534121. doi: 10.1073/pnas.2405534121.

[57] XU W, ZHOU W, WANG H, et al. Roles of Porphyromonas gingivalis and its virulence factors in periodontitis. Adv Protein Chem Struct Biol, 2020, 120: 45-84. doi: 10.1016/bs.apcsb.2019.12.001.

[58] ZHANG Z, LIU D, LIU S, et al. The role of Porphyromonas gingivalis outer membrane vesicles in periodontal disease and related systemic diseases. Front Cell Infect Microbiol, 2020, 10: 585917. doi: 10.3389/fcimb.2020.585917.

[59] MEI F, XIE M, HUANG X, et al. Porphyromonas gingivalis and its systemic impact: current status. Pathogens, 2020, 9(11): 944. doi: 10.3390/pathogens9110944.

[60] KRUEGER E, BROWN A C. Aggregatibacter actinomycetemcomitans leukotoxin: from mechanism to targeted anti-toxin therapeutics. Mol Oral Microbiol, 2020, 35(3): 85-105. doi: 10.1111/omi.12284.

[61] VEGA B A, SCHOBER L T, KIM T, et al. Aggregatibacter actinomycetemcomitans Leukotoxin (LtxA) requires death receptor Fas, in addition to LFA-1, to trigger cell death in T lymphocytes. Infect Immun, 2019, 87(8): e00309-19. doi: 10.1128/iai.00309-19.

[62] VEGA B A, BELINKA B A, Jr., KACHLANY S C. Aggregatibacter actinomycetemcomitans Leukotoxin (LtxA; Leukothera(®)): mechanisms of action and therapeutic applications. Toxins (Basel), 2019, 11(9): 489. doi: 10.3390/toxins11090489.

[63] HÖGLUND ÅBERG C, KWAMIN F, CLAESSON R, et al. Progression of attachment loss is strongly associated with presence of the JP2 genotype of Aggregatibacter actinomycetemcomitans: a prospective cohort study of a young adolescent population. J Clin Periodontol, 2014, 41(3): 232-241. doi: 10.1111/jcpe.12209.

[64] HAUBEK D, ENNIBI O K, POULSEN K, et al. Risk of aggressive periodontitis in adolescent carriers of the JP2 clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans in Morocco: a prospective longitudinal cohort study. Lancet, 2008, 371(9608): 237-242. doi: 10.1016/s0140-6736(08)60135-x.

[65] PARK D H, PARK O J, YOO Y J, et al. Microbiota association and profiling of gingival sulci and root canals of teeth with primary or secondary/persistent endodontic infections. J Endod, 2024, 50(8): 1124-1133. doi: 10.1016/j.joen.2024.04.016.

[66] ADELFIO M, CALLEN G E, DIAZ A R, et al. Underscoring long-term host-microbiome interactions in a physiologically relevant gingival tissue model. NPJ Biofilms Microbiomes, 2025, 11(1): 9. doi: 10.1038/s41522-024-00641-2.

[67] FANG P, KONYALI D, FISCHER E, et al. Effects of cigarette-derived compounds on the spread of antimicrobial resistance in artificial human lung sputum medium, simulated environmental media, and wastewater. Environ Health Perspect, 2025, 133(3/4): 47003. doi: 10.1289/ehp14704.

[68] APATZIDOU D A. The role of cigarette smoking in periodontal disease and treatment outcomes of dental implant therapy. Periodontol 2000, 2022, 90(1): 45-61. doi: 10.1111/prd.12449.

[69] BUDUNELI N. Environmental factors and periodontal microbiome. Periodontol 2000, 2021, 85(1): 112-125. doi: 10.1111/prd.12355.

[70] WUERSCHING S N, KOHL L, HICKEL R, et al. Assessing the marginal seal of bioactive restorative materials in class Ⅱ cavities with a bacterial penetration model. Dent Mater, 2025, 41(5): 553-560. doi: 10.1016/j.dental.2025.03.003.

[71] YUAN C, WANG X, GAO X, et al. Effects of surface properties of polymer-based restorative materials on early adhesion of Streptococcus mutans in vitro. J Dent, 2016, 54: 33-40. doi: 10.1016/j.jdent.2016.07.010.

[72] MORADI J, BERGGREEN E, BUNÆS D F, et al. Microbiome composition and metabolic pathways in shallow and deep periodontal pockets. Sci Rep, 2025, 15(1): 12926. doi: 10.1038/s41598-025-97531-0.

[73] CRISPINO A, VARRICCHIO S, ESPOSITO A, et al. The oral microbiome and its role in oral squamous cell carcinoma: a systematic review of microbial alterations and potential biomarkers. Pathologica, 2024, 116(6): 338-357. doi: 10.32074/1591-951x-n867.

[74] SARKAR P, MALIK S, LAHA S, et al. Dysbiosis of oral microbiota during oral squamous cell carcinoma development. Front Oncol, 2021, 11: 614448. doi: 10.3389/fonc.2021.614448.

[75] ZHU W, SHEN W, WANG J, et al. Capnocytophaga gingivalis is a potential tumor promotor in oral cancer. Oral Dis, 2024, 30(2): 353-362. doi: 10.1111/odi.14376.

[76] LU X, HU S, ZHANG Z, et al. A pH-sensitive CuHP composite hydrogel featuring antibacterial, antioxidant and osteogenic properties for treating diabetic periodontitis. Regen Biomater, 2025, 12: rbaf065. doi: 10.1093/rb/rbaf065.

[77] DREWES J L, WHITE J R, DEJEA C M, et al. Erratum: author correction: high-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia. NPJ Biofilms Microbiomes, 2019, 5(1): 2. doi: 10.1038/s41522-018-0078-x.

[78] BRENNAN C A, GARRETT W S. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat Rev Microbiol, 2019, 17(3): 156-166. doi: 10.1038/s41579-018-0129-6.

[79] ZELLER G, TAP J, VOIGT A Y, et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol, 2014, 10(11): 766. doi: 10.15252/msb.20145645.

[80] YAMAMURA K, IZUMI D, KANDIMALLA R, et al. Intratumoral fusobacterium nucleatum levels predict therapeutic response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma. Clin Cancer Res, 2019, 25(20): 6170-6179. doi: 10.1158/1078-0432.Ccr-19-0318.

[81] GAO S, LI S, MA Z, et al. Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer. Infect Agent Cancer, 2016, 11: 3. doi: 10.1186/s13027-016-0049-x.

[82] ZANZONI A, SPINELLI L, BRAHAM S, et al. Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins. Microbiome, 2017, 5(1): 89. doi: 10.1186/s40168-017-0307-1.

[83] MANSON MCGUIRE A, COCHRANE K, GRIGGS A D, et al. Evolution of invasion in a diverse set of Fusobacterium species. mBio, 2014, 5(6): e01864. doi: 10.1128/mBio.01864-14.

[84] MYSAK J, PODZIMEK S, SOMMEROVA P, et al. Porphyromonas gingivalis: major periodontopathic pathogen overview. J Immunol Res, 2014, 2014: 476068. doi: 10.1155/2014/476068.

[85] WOO B H, KIM D J, CHOI J I, et al. Oral cancer cells sustainedly infected with Porphyromonas gingivalis exhibit resistance to Taxol and have higher metastatic potential. Oncotarget, 2017, 8(29): 46981-46992. doi: 10.18632/oncotarget.16550.

[86] KATZ J, ONATE M D, PAULEY K M, et al. Presence of Porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci, 2011, 3(4): 209-215. doi: 10.4248/ijos11075.

[87] RELVAS M, MENDES-FRIAS A, GONÇALVES M, et al. Salivary IL-1β, IL-6, and IL-10 are key biomarkers of periodontitis severity. Int J Mol Sci, 2024, 25(15): 8401. doi: 10.3390/ijms25158401.

[88] HU Z, MURAKAMI T, TAMURA H, et al. Neutrophil extracellular traps induce IL-1β production by macrophages in combination with lipopolysaccharide. Int J Mol Med, 2017, 39(3): 549-558. doi: 10.3892/ijmm.2017.2870.

[89] CHENG R, WU Z, LI M, et al. Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review. Int J Oral Sci, 2020, 12(1): 2. doi: 10.1038/s41368-019-0068-8.

[90] GASMI BENAHMED A, KUMAR MUJAWDIYA P, NOOR S, et al. Porphyromonas gingivalis in the development of periodontitis: impact on dysbiosis and inflammation. Arch Razi Inst, 2022, 77(5): 1539-1551. doi: 10.22092/ari.2021.356596.1875.

[91] WANG B, DENG J, DONATI V, et al. The roles and interactions of Porphyromonas gingivalis and Fusobacterium nucleatum in oral and gastrointestinal carcinogenesis: a narrative review. Pathogens, 2024, 13(1): 93. doi: 10.3390/pathogens13010093.

[92] XU G, JIANG Y, SUN C, et al. Role of oral bacteria in mediating gemcitabine resistance in pancreatic cancer. Biomolecules, 2025, 15(7): 1018. doi: 10.3390/biom15071018.

基金资助

*国家重点研发计划(2022YFC2405900)

国家重点研发计划(2022YFC2405902)