阴道微生物组及其代谢产物对HPV感染及宫颈病变的影响及作用机制

doi:10.12280/gjfckx.20251498

摘要/Abstract

摘要：

宫颈癌作为全球女性第四大恶性肿瘤，其发病与高危型人乳头瘤病毒（high-risk human papilloma virus，HR-HPV）持续感染密切相关。阴道微生物组（vaginal microbiome，VMB）及其代谢产物是影响HR-HPV感染结局与宫颈病变进展的关键因素。健康状态下，乳杆菌主导的VMB通过分泌乳酸维持阴道酸性环境、释放过氧化氢（H₂O₂）及细菌素，抑制HPV吸附与复制，同时调节固有免疫与适应性免疫促进病毒清除。而VMB紊乱会通过激活核因子κB（nuclear factor-κB，NF-κB）诱发慢性炎症、破坏阴道上皮屏障，加速病变进展。乳酸、短链脂肪酸等代谢产物通过调控免疫细胞功能、炎症通路参与病理进程。当前基于VMB的干预策略中，益生菌补充与中药等可有效恢复微生态平衡、增强免疫应答，提升HPV清除率。

关键词: 微生物群, 阴道, 乳头状瘤病毒科, 肿瘤病毒感染, 宫颈疾病, 免疫调节

Abstract:

Cervical cancer, the fourth most common malignant tumor among women globally, is closely associated with persistent infection by high-risk human papilloma virus (HR-HPV). The vaginal microbiome (VMB) and its metabolites are key factors influencing the outcome of HR-HPV infection and the progression of cervical lesions. Under healthy conditions, a Lactobacillus-dominant VMB maintains an acidic vaginal environment through the secretion of lactic acid, releases hydrogen peroxide (H₂O₂) and bacteriocins to inhibit HPV adsorption and replication, and simultaneously regulates innate and adaptive immunity to promote viral clearance. Conversely, VMB dysbiosis can induce chronic inflammation by activating nuclear factor-κB (NF-κB), damage the vaginal epithelial barrier, and accelerate lesion progression. Metabolites such as lactic acid and short-chain fatty acids are involved in the pathological process by modulating immune cell function and inflammatory pathways. In current VMB-based intervention strategies, approaches such as probiotic supplementation and traditional Chinese medicine can effectively restore microbial balance, enhance immune responses, and improve the rate of HPV clearance.

Key words: Microbiota, Vagina, Papillomaviridae, Tumor virus infections, Uterine cervical diseases, Immunomodulation

刘栋, 郭洁, 宋殿荣. 阴道微生物组及其代谢产物对HPV感染及宫颈病变的影响及作用机制[J]. 国际妇产科学杂志, 2026, 53(3): 341-346.

LIU Dong, GUO Jie, SONG Dian-rong. Impact and Mechanisms of the Vaginal Microbiome and Its Metabolites on HPV Infection and Cervical Lesions[J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 341-346.

参考文献 38

[1]	Singh D, Vignat J, Lorenzoni V, et al. Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative[J]. Lancet Glob Health, 2023, 11(2):e197-e206. doi: 10.1016/S2214-109X(22)00501-0.
[2]	Guan P, Howell-Jones R, Li N, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer[J]. Int J Cancer, 2012, 131(10):2349-2359. doi: 10.1002/ijc.27485. pmid: 22323075
[3]	Qing X, Xie M, Liu P, et al. Correlation between dysbiosis of vaginal microecology and endometriosis: A systematic review and meta-analysis[J]. PLoS One, 2024, 19(7):e0306780. doi: 10.1371/journal.pone.0306780.
[4]	Dong B, Huang Y, Cai H, et al. Prevotella as the hub of the cervicovaginal microbiota affects the occurrence of persistent human papillomavirus infection and cervical lesions in women of childbearing age via host NF-κB/C-myc[J]. J Med Virol, 2022, 94(11):5519-5534. doi: 10.1002/jmv.28001.
[5]	Schellekens H, Schmidt L, Morré SA, et al. Vaginal Microbiota and Local Immunity in HPV-Induced High-Grade Cervical Dysplasia: A Narrative Review[J]. Int J Mol Sci, 2025, 26(9):3954. doi: 10.3390/ijms26093954.
[6]	France MT, Ma B, Gajer P, et al. VALENCIA: a nearest centroid classification method for vaginal microbial communities based on composition[J]. Microbiome, 2020, 8(1):166. doi: 10.1186/s40168-020-00934-6. pmid: 33228810
[7]	Leon-Gomez P, Romero VI. Human papillomavirus, vaginal microbiota and metagenomics: the interplay between development and progression of cervical cancer[J]. Front Microbiol, 2024, 15:1515258. doi: 10.3389/fmicb.2024.1515258.
[8]	Shen J, Sun H, Chu J, et al. Cervicovaginal microbiota: a promising direction for prevention and treatment in cervical cancer[J]. Infect Agent Cancer, 2024, 19(1):13. doi: 10.1186/s13027-024-00573-8.
[9]	Liu Y, Zhao X, Wu F, et al. Effectiveness of vaginal probiotics Lactobacillus crispatus chen-01 in women with high-risk HPV infection: a prospective controlled pilot study[J]. Aging(Albany NY), 2024, 16(14):11446-11459. doi: 10.18632/aging.206032.
[10]	Di Paola M, Sani C, Clemente AM, et al. Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection[J]. Sci Rep, 2017, 7(1):10200. doi: 10.1038/s41598-017-09842-6. pmid: 28860468
[11]	Thomas M, Pim D, Banks L. The role of the E6-p53 interaction in the molecular pathogenesis of HPV[J]. Oncogene, 1999, 18(53):7690-7700. doi: 10.1038/sj.onc.1202953. pmid: 10618709
[12]	Peng Q, Wang L, Zuo L, et al. HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor[J]. Cancer Gene Ther, 2024, 31(1):9-17. doi: 10.1038/s41417-023-00682-3. pmid: 38102462
[13]	Wang Y, Wang T, Yan D, et al. Vaginal microbial profile of cervical cancer patients receiving chemoradiotherapy: the potential involvement of Lactobacillus iners in recurrence[J]. J Transl Med, 2024, 22(1):575. doi: 10.1186/s12967-024-05332-2. pmid: 38886729
[14]	Bai B, Tuerxun G, Tuerdi A, et al. Analysis of vaginal flora diversity and study on the role of Porphyromonas asaccharolytica in promoting IL-1β in regulating cervical cancer[J]. Sci Rep, 2024, 14(1):21731. doi: 10.1038/s41598-024-73146-9. pmid: 39289490
[15]	Zeng M, Li X, Jiao X, et al. Roles of vaginal flora in human papillomavirus infection, virus persistence and clearance[J]. Front Cell Infect Microbiol, 2022, 12:1036869. doi: 10.3389/fcimb.2022.1036869.
[16]	Pawar K, Aranha C. Lactobacilli metabolites restore E-cadherin and suppress MMP9 in cervical cancer cells[J]. Curr Res Toxicol, 2022, 3:100088. doi: 10.1016/j.crtox.2022.100088.
[17]	Xu H, Zhang S, Zhang B, et al. Vaginal colonization of Lactobacilli: Mechanism and function[J]. Microb Pathog, 2025, 198:107141. doi: 10.1016/j.micpath.2024.107141.
[18]	Borgogna JC, Shardell MD, Santori EK, et al. The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis[J]. BJOG, 2020, 127(2):182-192. doi: 10.1111/1471-0528.15981.
[19]	Tong LC, Wang Y, Wang ZB, et al. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress[J]. Front Pharmacol, 2016, 7:253. doi: 10.3389/fphar.2016.00253.
[20]	Liu Y, Zhou Q, Ye F, et al. Gut microbiota-derived short-chain fatty acids promote prostate cancer progression via inducing cancer cell autophagy and M2 macrophage polarization[J]. Neoplasia, 2023, 43:100928. doi: 10.1016/j.neo.2023.100928.
[21]	He N, Chen K, Yu S, et al. Stachyose Exerts Anticolitis Efficacy by Re-balancing Treg/Th17 and Activating the Butyrate-Derived PPARγ Signaling Pathway[J]. J Agric Food Chem, 2024, 72(21):12171-12183. doi: 10.1021/acs.jafc.4c01387.
[22]	Krüger H, Bauer G. Lactobacilli enhance reactive oxygen species-dependent apoptosis-inducing signaling[J]. Redox Biol, 2017, 11:715-724. doi: 10.1016/j.redox.2017.01.015. pmid: 28193594
[23]	Incognito GG, Ronsini C, Palmara V, et al. The Interplay Between Cervicovaginal Microbiota Diversity, Lactobacillus Profiles and Human Papillomavirus in Cervical Cancer: A Systematic Review[J]. Healthcare(Basel), 2025, 13(6):599. doi: 10.3390/healthcare13060599.
[24]	Supriya Y, Sivamalar S, Nallusamy D, et al. Application of probiotics in cervical cancer infections to enhance the immune response[J]. Microb Pathog, 2024, 193:106764. doi: 10.1016/j.micpath.2024.106764.
[25]	Gao Q, Fan T, Luo S, et al. Lactobacillus gasseri LGV03 isolated from the cervico-vagina of HPV-cleared women modulates epithelial innate immune responses and suppresses the growth of HPV-positive human cervical cancer cells[J]. Transl Oncol, 2023, 35:101714. doi: 10.1016/j.tranon.2023.101714.
[26]	Singh N, Thangaraju M, Prasad PD, et al. Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases[J]. J Biol Chem, 2010, 285(36):27601-27608. doi: 10.1074/jbc.M110.102947. pmid: 20601425
[27]	Nastasi C, Fredholm S, Willerslev-Olsen A, et al. Butyrate and propionate inhibit antigen-specific CD8+ T cell activation by suppressing IL-12 production by antigen-presenting cells[J]. Sci Rep, 2017, 7(1):14516. doi: 10.1038/s41598-017-15099-w.
[28]	Yan S, Wan G. Tumor-associated macrophages in immunotherapy[J]. FEBS J, 2021, 288(21):6174-6186. doi: 10.1111/febs.15726. pmid: 33492779
[29]	Zhang Q, Zhao Q, Li T, et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity[J]. Cell Metab, 2023, 35(6):943-960.e9. doi: 10.1016/j.cmet.2023.04.015.
[30]	Fong W, Li Q, Ji F, et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis[J]. Gut, 2023, 72(12):2272-2285. doi: 10.1136/gutjnl-2023-329543. pmid: 37770127
[31]	Dinesh DC, Tamilarasan S, Rajaram K, et al. Antiviral Drug Targets of Single-Stranded RNA Viruses Causing Chronic Human Diseases[J]. Curr Drug Targets, 2020, 21(2):105-124. doi: 10.2174/1389450119666190920153247. pmid: 31538891
[32]	Fracella M, Oliveto G, Sorrentino L, et al. Common Microbial Genital Infections and Their Impact on the Innate Immune Response to HPV in Cervical Cells[J]. Pathogens, 2022, 11(11):1361. doi: 10.3390/pathogens11111361.
[33]	Cruz-Gregorio A, Aranda-Rivera AK. Redox-sensitive signalling pathways regulated by human papillomavirus in HPV-related cancers[J]. Rev Med Virol, 2021, 31(6):e2230. doi: 10.1002/rmv.2230. pmid: 33709497
[34]	Zhang Z, Zheng K, Zhang Z, et al. Lactobacillus gasseri LGV03-derived indole-3-lactic acid ameliorates immune response by activating aryl hydrocarbon receptor[J]. Microb Cell Fact, 2025, 24(1):34. doi: 10.1186/s12934-025-02662-8. pmid: 39885499
[35]	Palma E, Recine N, Domenici L, et al. Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection[J]. BMC Infect Dis, 2018, 18(1):13. doi: 10.1186/s12879-017-2938-z. pmid: 29304768
[36]	He N, Song L, Lu Z, et al. Clinical efficacy analysis of the Chinese medicine Paiteling applied to human papillomavirus infection: A retrospective study[J]. PLoS One, 2024, 19(12):e0315376. doi: 10.1371/journal.pone.0315376.
[37]	Li X, Ning L, Zhao H, et al. Jiawei Ermiao Granules (JWEMGs) clear persistent HR-HPV infection though improving vaginal microecology[J]. J Ethnopharmacol, 2025, 341:119342. doi: 10.1016/j.jep.2025.119342.
[38]	Dang YP, Yuan XY, Tian R, et al. Curcumin improves the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cells via the NF-κB-p53-caspase-3 pathway[J]. Exp Ther Med, 2015, 9(4):1470-1476. doi: 10.3892/etm.2015.2240. pmid: 25780454