微生物学报

Strain	Form	Models for validation	Effect	Mechanism	Reference
Lactobacillus plantarum 5BL	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Reduce cellular apoptosis, lead to cytotoxicity, thereby inhibit the proliferation of HPV18	[46]
Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 33323	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Reduce caspase-3 expression and activity, leading to decreased LDH release and upregulate hCG β expression and autophagy	[47]
Lactobacillus gasseri G10+Lactobacillus gasseri H15	Cell-free supernatant	HeLa cells (infected with HPV18)	Anti-inflammatory effects	Produce extracellular polysaccharide, which enables acid bacteria to better adhere to host cells	[48]
Bifidobacterium adolescentis SPM1005-A	Cell-free supernatant	SiHa cells (infected with HPV16)	Inhibition of gene expression	Downregulate the expression of HPV16 E6 and E7 genes at the mRNA and protein levels	[49]
Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Downregulate the expression of CASP3, MMP-2, and MMP-9 while upregulate of the expression of TIMP-1 and TIMP-2	[50]
Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 9857+Lactobacillus jensenii ATCC 25258	Cell-free supernatant	CaSki cells (infected with HPV16)	Antitumor effect and inhibition of gene expression	Downregulate the mRNA levels of HPV16 E6 and E7 oncogenes as well as CDK2 and cyclin A	[51]
Lactobacillus casei SR1+Lactobacillus casei SR2	Cell-free supernatant	HeLa cells (infected with HPV18)	Inhibition of gene expression	Upregulate the expression of BAX, BAD, caspase-3, caspase-8, and caspase-9 genes and downregulate bcl-2 gene	[52]
Lactobacillus delbrueckii DM8909	Cell-free supernatant	U4 cells and HeLa cells (infected with HPV18)	Antitumor effect	Upregulate the expression of E-cadherin	[53]
Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Downregulate the expression of HPV18 E6 gene as well as caspase-3 and ATG14 genes	[54]
Lactobacillus gasseri LGV03	Cell-free supernatant	CaSki cells (infected with HPV16)	Anti-inflammatory effects	Regulate the IRF3 signaling pathway and the NF-κB signaling pathway, while enhance the production of IFN-γ	[55]
Lactobacillus crispatus 2743+Lactobacillus gasseri 3396	Cell-free supernatant	SiHa cells (infected with HPV16)	Antitumor effect	Silence ARHGAP5 expression and reduces the levels of E6 and E7 proteins	[56]
Lactobacillus casei TD-2	Cell-free supernatant	C57BL/6 mice	Antitumor effect	Increase IFN-c, IL-4, and IL-12 level as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumor	[57]
Lactobacillus casei BL23	Cell-free supernatant	TC-1-Challenged Mice	Immune regulation	Increase IL-2 production around the tumor	[58]
Lactobacillus crispatus M247	Cell-free supernatant	Colitis mice	Anti-inflammatory effects and mucosal barrier enhancement	Release hydrogen peroxide which upregulate PPAR-γ and TLR-2, and downregulate TLR-4	[59]
Lactobacillus crispatus M247	Freeze-dried cell-free supernatant	35 females with HPV cervical infection	Mucosal barrier enhancement	Enhance probiotic colonization and encode fibronectin type III domain-containing proteins and N-terminal fibronectin-binding protein A	[60]
Lactobacillus rhamnosus BMX54	Freeze-dried bacteria	117 females with bacterial vaginosis or vaginal inflammation accompanied by HPV infection	Mucosal barrier enhancement	Inhibit colonization of pathogens and improve the vaginal environment	[61]
Lactobacillus crispatus M247	Cell-free supernatant	160 females with HPV cervical infection	Antitumor effect	Release hydrogen peroxide, lactic acid, and bacteriocins to regulate mucosal inflammation and control celluar proliferation/apoptosis	[62]
Lactobacillus casei Shirota	Probiotic drink	54 women with low-grade HPV-infection	Mucosal barrier enhancement and anti-inflammatory effects	Reconstruct vaginal microbiota, directly kill pathogens, compete for host cell receptors, and interfere with the gene expression of pathogens	[63]

Strain	Form	Models for validation	Effect	Mechanism	Reference
Lactobacillus plantarum 5BL	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Reduce cellular apoptosis, lead to cytotoxicity, thereby inhibit the proliferation of HPV18	[46]
Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 33323	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Reduce caspase-3 expression and activity, leading to decreased LDH release and upregulate hCG β expression and autophagy	[47]
Lactobacillus gasseri G10+Lactobacillus gasseri H15	Cell-free supernatant	HeLa cells (infected with HPV18)	Anti-inflammatory effects	Produce extracellular polysaccharide, which enables acid bacteria to better adhere to host cells	[48]
Bifidobacterium adolescentis SPM1005-A	Cell-free supernatant	SiHa cells (infected with HPV16)	Inhibition of gene expression	Downregulate the expression of HPV16 E6 and E7 genes at the mRNA and protein levels	[49]
Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Downregulate the expression of CASP3, MMP-2, and MMP-9 while upregulate of the expression of TIMP-1 and TIMP-2	[50]
Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 9857+Lactobacillus jensenii ATCC 25258	Cell-free supernatant	CaSki cells (infected with HPV16)	Antitumor effect and inhibition of gene expression	Downregulate the mRNA levels of HPV16 E6 and E7 oncogenes as well as CDK2 and cyclin A	[51]
Lactobacillus casei SR1+Lactobacillus casei SR2	Cell-free supernatant	HeLa cells (infected with HPV18)	Inhibition of gene expression	Upregulate the expression of BAX, BAD, caspase-3, caspase-8, and caspase-9 genes and downregulate bcl-2 gene	[52]
Lactobacillus delbrueckii DM8909	Cell-free supernatant	U4 cells and HeLa cells (infected with HPV18)	Antitumor effect	Upregulate the expression of E-cadherin	[53]
Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Downregulate the expression of HPV18 E6 gene as well as caspase-3 and ATG14 genes	[54]
Lactobacillus gasseri LGV03	Cell-free supernatant	CaSki cells (infected with HPV16)	Anti-inflammatory effects	Regulate the IRF3 signaling pathway and the NF-κB signaling pathway, while enhance the production of IFN-γ	[55]
Lactobacillus crispatus 2743+Lactobacillus gasseri 3396	Cell-free supernatant	SiHa cells (infected with HPV16)	Antitumor effect	Silence ARHGAP5 expression and reduces the levels of E6 and E7 proteins	[56]
Lactobacillus casei TD-2	Cell-free supernatant	C57BL/6 mice	Antitumor effect	Increase IFN-c, IL-4, and IL-12 level as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumor	[57]
Lactobacillus casei BL23	Cell-free supernatant	TC-1-Challenged Mice	Immune regulation	Increase IL-2 production around the tumor	[58]
Lactobacillus crispatus M247	Cell-free supernatant	Colitis mice	Anti-inflammatory effects and mucosal barrier enhancement	Release hydrogen peroxide which upregulate PPAR-γ and TLR-2, and downregulate TLR-4	[59]
Lactobacillus crispatus M247	Freeze-dried cell-free supernatant	35 females with HPV cervical infection	Mucosal barrier enhancement	Enhance probiotic colonization and encode fibronectin type III domain-containing proteins and N-terminal fibronectin-binding protein A	[60]
Lactobacillus rhamnosus BMX54	Freeze-dried bacteria	117 females with bacterial vaginosis or vaginal inflammation accompanied by HPV infection	Mucosal barrier enhancement	Inhibit colonization of pathogens and improve the vaginal environment	[61]
Lactobacillus crispatus M247	Cell-free supernatant	160 females with HPV cervical infection	Antitumor effect	Release hydrogen peroxide, lactic acid, and bacteriocins to regulate mucosal inflammation and control celluar proliferation/apoptosis	[62]
Lactobacillus casei Shirota	Probiotic drink	54 women with low-grade HPV-infection	Mucosal barrier enhancement and anti-inflammatory effects	Reconstruct vaginal microbiota, directly kill pathogens, compete for host cell receptors, and interfere with the gene expression of pathogens	[63]

益生菌对人类乳头瘤病毒感染的治疗作用及其机制研究进展

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王崇岳 ¹^,² , 吴毓薇 ³ , 谢新强 ² , 李滢 ²^,^* , 吴清平 ²^,^*

微生物学报 | 综述 2025,65(2): 437-452

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微生物学报 | 综述 2025, 65(2): 437-452

益生菌对人类乳头瘤病毒感染的治疗作用及其机制研究进展

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王崇岳¹^,², 吴毓薇³, 谢新强², 李滢²^,^*, 吴清平²^,^*

作者信息

1 陕西科技大学食品科学与工程学院，陕西西安

2 广东省科学院微生物研究所，华南应用微生物国家重点实验室，广东省微生物安全与健康重点实验室，国家卫健委微生物食品营养与安全科技创新平台，广东广州

3 广东科环生物科技有限公司，广东广州

Research progress in the therapeutic effects and mechanisms of probiotics in HPV infection

Chongyue WANG¹^,², Yuwei WU³, Xinqiang XIE², Ying LI²^,^*, Qingping WU²^,^*

Affiliations

1 School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi, China

2 State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Safety and Health, National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China

3 Guangdong Kehuan Biotechnology Co. , Ltd. , Guangzhou, Guangdong, China

出版时间: 2025-02-04 doi: 10.13343/j.cnki.wsxb.20240472

文章导航

摘要

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人类乳头瘤病毒(human papillomavirus, HPV)感染是全球重大的健康挑战，与宫颈癌等疾病密切相关。目前暂无有效的HPV治疗手段，因此需要开发新型的抗病毒生物制剂以减少HPV感染的危害。最近多项研究揭示了HPV感染与人体微生物组之间的复杂关系，提示HPV感染会破坏微生物组的平衡，导致菌群失调，继而引起机体免疫功能的障碍。近年来，研究发现口服或外用特定的益生菌菌株可降低患者HPV滴度、预防病毒感染相关癌症，是具有开发价值的新型抗HPV制剂。本文从HPV的分子生物学特征出发，系统阐述了HPV感染的致病机制，并从抑制病毒复制、免疫调控、增强黏膜屏障功能及重塑微生态4个角度总结现有抗HPV益生菌的作用机制，为抗HPV益生菌的高效选育及机制解析提供理论参考。

关键词

人类乳头瘤病毒 / 免疫逃逸 / 微生物组 / 益生菌 / 抗病毒机制

Abstract

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Human papillomavirus (HPV) infection is a major global health challenge closely related to diseases such as cervical cancer. At present, there is no effective treatment for HPV, and thus it is essential to develop new antiviral biological agents to reduce the harm of HPV infection. Recent studies have revealed a complex relationship between HPV infection and the human microbiome, suggesting that HPV infection can disrupt the balance of the microbiome and cause immune dysfunction in the body. In recent years, studies have found that oral or topical use of specific probiotic strains can reduce HPV titers in patients and prevent viral infection-related cancers, demonstrating probiotics as a new class of anti-HPV preparations with a development value. From the molecular biological characteristics of HPV, this article systematically summarizes the pathogenic mechanism of HPV infection and explains the antiviral mechanisms of probiotics from four perspectives: inhibiting virus replication, regulating immune responses, enhancing the mucosal barrier function, and reshaping the human microbiome. This review aims to provide theoretical references for the efficient breeding and mechanism analysis of anti-HPV probiotics.

Key words

human papillomavirus / immune escape / microbiome / probiotics / antiviral mechanism

引用本文

王崇岳, 吴毓薇, 谢新强, 李滢, 吴清平. 益生菌对人类乳头瘤病毒感染的治疗作用及其机制研究进展. 微生物学报, 2025 , 65 (2) : 437 -452 . DOI: 10.13343/j.cnki.wsxb.20240472

Chongyue WANG, Yuwei WU, Xinqiang XIE, Ying LI, Qingping WU. Research progress in the therapeutic effects and mechanisms of probiotics in HPV infection[J]. Acta Microbiologica Sinica, 2025 , 65 (2) : 437 -452 . DOI: 10.13343/j.cnki.wsxb.20240472

正文

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人类乳头瘤病毒(human papillomavirus, HPV)是一种DNA病毒，隶属于乳头多瘤空泡病毒科，是一种嗜上皮性病毒^[1]。HPV主要感染人体皮肤和黏膜组织的上皮细胞，主要通过性接触传播，可引起皮肤、生殖道炎症，甚至诱发癌症^[2]。据统计，在美国每年约有1 400万新发的HPV感染病例，因此，HPV对全人类的健康构成了重大挑战，也给全球医疗系统带来了巨大负担^[3]。HPV感染危害严重，但尚无特效药物清除，因此增强自身免疫力和接种疫苗成为HPV预防与治疗的主要手段^[4]。为研发防控药物，研究者需要深入探究HPV的致病机制，寻找筛选靶点。

HPV的致病机制包括病毒感染、免疫逃逸、持续感染、细胞病变与基因整合等多个环节^[5]。若在感染早期无法得到有效清除，HPV将整合至宿主基因组中，激活细胞癌基因的表达，最终引起癌变^[6]。Virgin^[7]研究发现，HPV感染的迁延不愈除了与宿主免疫状态密切相关外，还与宿主的微生态密切相关，在女性患者中，HPV感染会引起阴道微生态失衡，继而加重阴道黏膜的炎症反应，从而加速癌变进程。因此，加强宿主机体免疫监视、维持宿主微生态平衡对于防治HPV感染具有重要意义。

益生菌是一类定殖在人体内，对机体健康产生促进作用的活性微生物。益生菌作为一种一般认为安全(generally recognized as safe, GRAS)的食品资源，可被添加至发酵食品、乳制品、果蔬制品等食品中，应用范围广阔^[8]。目前研究发现，应用益生菌治疗可以降低HPV感染患者阴道黏膜的病毒滴度、减轻黏膜炎症、增强机体免疫功能，并恢复阴道微生态平衡^[9]。因此，益生菌作为拮抗HPV感染的新型生物制剂，具有广阔的开发潜能。

本文在归纳HPV病毒的分子生物学特征的基础上，解析了HPV感染过程及其病理机制，并据此提出了防控HPV感染的关键调控靶点。根据这些潜在的抗感染靶点，系统总结了目前已知具有抗HPV作用的益生菌菌株，并且梳理归纳这些功能菌株的抗病毒机制，以期为高效拮抗HPV感染的益生菌资源精准选育提供理论依据。

1 HPV的分子生物学特征

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HPV是一种具有环形双链结构的小型非包膜DNA病毒，隶属于乳头多瘤空泡病毒科乳头瘤病毒属。1983年，澳大利亚病毒学家Frazer教授团队首次在一名宫颈癌患者的癌组织样品中发现HPV病毒的存在，此后人们开始认识到许多生殖道及皮肤的疾病，尤其是癌症均与该病毒的感染密切相关^[10]。HPV基因组长度约 8 kb，含有8-9个开放阅读框(open reading frame, ORF)^[11]。电镜分析指出，HPV病毒颗粒大小约为60 nm，由无包膜的二十面体衣壳蛋白内包裹双链DNA形成^[12]。其中，HPV的DNA主要由早期区、晚期区与上游调控区3个功能区域组成：早期区基因编码了HPV病毒复制周期所有必需基因，在细胞转化中起重要作用；晚期区基因主要编码病毒颗粒外壳成分，包括主要外壳蛋白L1和次要外壳蛋白L2；上游调控区则又被称为长控制区，含有病毒复制起点和转录因子结合点的非编码区，具有调控HPV DNA复制的功能^[13]。

根据HPV主要外壳蛋白L1核苷酸序列的差异，HPV可被分为不同亚型。流行病学调查指出，目前已有200多个HPV亚型在临床样本中被鉴定出来^[14]。同时，大规模的跟踪调查研究指出，不同亚型的HPV感染所致的临床症状与预后存在较大差异^[15]。根据感染后的致癌风险，HPV可被分为高危型和低危型，其中，常见的高危型包括HPV 16和HPV 18，而常见的低危型则包括HPV 6和HPV 11^[16]。

HPV的感染周期始于其主要外壳蛋白L1与宿主皮肤或黏膜鳞状上皮细胞表面硫酸肝素蛋白多糖受体(heparan sulfate proteoglycan, HSPG)的结合。结合后，病毒通过受体介导的多步内吞作用进入细胞，并在核内体和溶酶体的作用下实现脱衣壳^[17]。脱去外壳蛋白L1后，HPV的次要外壳蛋白L2进一步通过转运到达反式高尔基网络，在核膜破裂的前期进入细胞核并整合进入宿主基因组。进入细胞核后，HPV将开始其生命周期，包括建立、维持和扩增3个阶段^[18]。在建立阶段，HPV DNA以附加体(episome)形式存在，在此阶段病毒基因表达受到严格控制；在维持阶段，病毒在宿主细胞的S期(DNA合成期)进行复制，并伴随有丝分裂进入子代宿主细胞；而在扩增阶段，HPV病毒可以激活宿主DNA的复制，并促进病毒外壳蛋白的表达，促使更多病毒被组装为完整的HPV病毒颗粒，进而侵染感染部位周边的其他宿主细胞^[18] (图1)。目前，HPV与宿主基因整合的机制尚待完全解析，但有研究指出，HPV病毒整合进入宿主基因组的过程与其引发的肿瘤预后密切相关^[19]。

2 HPV的致病机制

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在进入病毒复制周期后，HPV起初以低载量复制，随后进一步感染皮肤黏膜底层的干细胞群，通过整合至干细胞基因组，HPV随着细胞转录与合成过程产生子代病毒^[19]。HPV病毒感染会导致宿主的皮肤黏膜损伤甚至肿瘤诱发，而病毒的致病作用与其逃避宿主免疫清除、形成持续感染、诱导黏膜细胞损伤、引发肿瘤突变以及破坏黏膜微生态平衡密切相关。

2.1 HPV的持续感染

del Pino等^[20]研究指出，HPV的持续感染与其通过多种机制逃避宿主免疫应答的生物学特性密切相关。病原体的识别、免疫信号的传递以及免疫杀伤的执行是宿主清除外源性病原体的3个重要环节^[21]。在病原体识别阶段，免疫系统中的抗原递呈细胞(antigen-presenting cells, APC)通过识别外源生物的主要组织相容性复合物(major histocompatibility complex, MHC)从而区分自我与非我，在识别到携带非我信号的病原微生物后，APC将启动免疫清除机制，实现外源生物的清除^[22]。通常情况下，病毒感染细胞后，会导致宿主细胞异常表达MHC，进而被免疫细胞识别并清除。不同于其他病原微生物，HPV病毒侵入宿主后，其合成的致癌蛋白E5和E7会降低受感染细胞表面MHC I类分子的表达^[23]，进而阻断免疫细胞的抗原呈递，导致细胞毒性T淋巴细胞(cytotoxic lymphocyte, CTL)和自然杀伤细胞(natural killer cell, NK)的激活受到抑制^[24]。此外，HPV感染后还将刺激细胞产生免疫抑制因子，如白细胞介素-10 (interleukin-10, IL-10)和转化生长因子-β (transforming growth factor-β, TGF-β)。这些免疫抑制因子的产生会进一步抑制CTL与NK细胞的激活，从而减少免疫细胞对病毒及其感染细胞的清除作用^[25]。同时，HPV感染也会诱导负性免疫调节细胞的功能异常，如抑制性T细胞活化和调节性T细胞(regulatory T cells, Treg)数量的增加，这些异常进一步削弱了宿主免疫系统对HPV病毒的清除能力，最终导致HPV的持续感染^[26]。

2.2 HPV的黏膜损伤作用

HPV是一类以皮肤黏膜为感染靶器官的病毒，病毒感染后会引起黏膜完整性受损、分泌功能异常以及局部炎症反应，导致黏膜病变。研究指出，HPV病毒侵入宿主细胞后，其合成的致癌蛋白E6和E7能够与宿主细胞中的视网膜母细胞瘤肿瘤(retinoblastoma, Rb)抑制基因(p105-RB)编码的产物结合成复合物，引起宿主细胞的异常增殖，从而破坏黏膜的完整性^[27]。此外，HPV感染还会导致黏液的产生和组成发生变化，影响其保护功能；黏膜屏障的破坏可能增加HPV传播和再次感染的风险，并为HPV相关疾病的发展提供条件^[28]。HPV感染能够引发宿主的炎症反应，这在HPV相关疾病的发病机制中起着重要作用。HPV的致癌蛋白E6和E7可诱导感染细胞产生多种促炎细胞因子，如IL-6、IL-8和肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)^[29]。这些细胞因子能够促进免疫细胞的招募和激活，引发局部组织的炎症反应。持续HPV感染引起的慢性炎症可能为病毒复制、免疫逃避和HPV相关恶性肿瘤的发展提供了有利环境；研究发现，炎症反应与HPV相关疾病的严重程度和预后情况密切相关，这进一步强调了炎症在HPV感染中的重要性^[30]。

2.3 HPV的致癌作用

黏膜癌症尤其是宫颈癌是HPV感染最严重的并发症之一。研究指出，HPV具有多重致癌机制，具体包括：(1) 增加基因组的不稳定性；(2) 激活致癌基因的表达；(3) 抑制抑癌基因的功能；(4) 引起肿瘤的表观遗传学改变^[31]。

在基因组复制过程中，DNA可能出现随机突变，造成细胞功能异常甚至癌变；而正常细胞具备基因组监测与维护系统，这些系统的正常运行可以纠正并修复DNA的突变，维持基因组的稳定性，防止癌症的发生^[32]。在HPV感染时，病毒通过整合进入宿主基因组实现慢性感染^[1,33]，而在这一过程中，病毒需要抑制细胞的DNA损伤应答(DNA damage response, DDR)反应，以维持长期整合的状态。因此，HPV的整合程度越高，越容易引起基因组不稳定，进而增加肿瘤发生的频率^[34-35]。

致癌基因如成视网膜母细胞瘤基因的异常激活是肿瘤发生的重要原因。研究指出，HPV整合进入宿主细胞后，其合成的E7蛋白与细胞的Rb基因产物结合，激活Rb-E2F转录因子，继而引起细胞过度增殖^[23]。同时，抑癌基因如p53基因可以阻断细胞的异常增殖，维持基因组稳定性。相比之下，HPV编码的E6蛋白可与宿主编码的E6AP形成复合体，该复合体能够靶向结合抑癌基因p53，导致p53的失活，进而丧失纠正基因组突变的功能，增加肿瘤发生的风险^[36]。

除了DNA突变导致细胞功能异常外，表观遗传学的异常也与肿瘤的发生、发展紧密相关。研究指出，表观遗传学修饰能够调控细胞在基因转录、修复及复制过程中的功能，其异常改变同样会成为肿瘤重要的驱动因素^[37]。相比之下，HPV感染能够对肿瘤细胞的表观遗传学特征产生影响。研究表明，HPV的长控制区包含潜在甲基化的CpG位点，当HPV整合入基因组后，长控制区的甲基化会导致E2功能的异常以及E6、E7的过表达，从而增加了宿主细胞癌病的风险^[38]。

2.4 HPV对微生态的影响

随着生物技术的发展，研究者们逐渐认识到人体的健康不仅与自身细胞的功能有关，还受到机体共生微生物的影响。研究指出，HPV感染会导致皮肤黏膜，尤其是阴道黏膜微生态的失衡^[11,39]，具体表现为有益菌群的减少和病原菌的过度增殖，进而加剧黏膜局部的屏障功能损害与免疫功能紊乱。Brotman等^[40]通过对来自北美的32例绝经前女性的阴道菌群的分析发现，HPV感染会导致阴道黏膜的卷曲乳杆菌(Lactobacillus crispatus)菌群数量降低，由于卷曲乳杆菌具有产生大量乳酸和保护性蛋白、保护黏膜屏障完整性的作用，因此该菌群的丰度下降会导致黏膜屏障功能受损。此外，Brotman等^[40]和Łaniewski等^[41]在对100名西班牙绝经前妇女的阴道菌群研究中发现，HPV感染还会导致阴道黏膜中的乳酸菌数量减少，从而引发阴道pH值升高；进一步分析发现，HPV感染后女性患者阴道内合成细菌素的乳杆菌菌群数量下降，这些改变共同促进了阴道内病原微生物的过度生长，进而加剧了黏膜局部甚至全身的炎症反应。同时，研究指出，黏膜局部的微生态失衡也会影响宿主免疫监视的功能，为HPV的持续感染提供了重要条件，宫颈上皮内瘤变(cervical intraepithelial neoplasias, CIN)患者阴道黏膜的IL-1β水平升高，而抗炎分子——分泌性白细胞蛋白酶抑制因子(secretory leukocyte protease inhibitor, SLPI)水平降低，这些免疫异常导致固有免疫系统的病毒识别功能下降，从而引发HPV的持续感染^[42]。相比之下，深入了解HPV与微生态失衡的关系有助于更深入地揭示HPV感染的机制，并为开发微生态干预策略提供理论基础。

3 益生菌拮抗HPV感染的作用

收起

益生菌(probiotics)是一类当足量摄入时，能为宿主带来健康益处的活性微生物。益生菌广泛存在于各种食物中，如酸奶、酸菜等，是我们日常饮食的重要组成部分；研究已证实益生菌可以通过多种机制发挥有益效果，主要包括调节肠道微生物群、抑制有害微生物生长、促进有益微生物的生长，以及调节免疫、维护肠道屏障完整性等^[43] (图2)。此外，益生菌还通过影响宿主代谢、促进营养物质吸收和产生有益的短链脂肪酸来维护宿主的新陈代谢健康^[44-45]。目前，益生菌已在多个领域展现了潜在健康益处，包括改善胃肠健康、增强免疫功能、维护女性泌尿生殖健康以及维持心理精神稳态等^[32]。然而，益生菌的健康提升作用具有菌株特异性，而大部分菌株发挥功效的物质基础仍不清晰。因此，还需要更多研究来全面了解其机制和应用潜力。本文列举了近年来具有抗HPV感染作用的益生菌及其作用方式(表1)，并对其作用方法进行了概述。

在拮抗HPV研究方面，鉴于当前缺乏完善的病毒体外培养体系及动物感染模型，益生菌的效能验证及机制解析主要局限于感染高危型HPV16及HPV18的细胞及肿瘤模型中。

3.1 益生菌的直接抗病毒作用

HPV病毒在黏膜上皮侵染、复制、增殖是其在宿主体内引发疾病的主要原因。目前已有多项研究指出，某些特定的益生菌菌株能直接杀伤病毒，展现出抗病毒功效。Li等研究发现，长寿人群来源的发酵乳杆菌PV22可以直接抑制MNV病毒的复制，保护细胞免受病毒侵害^[64]；短乳杆菌SR52-2可以抑制HBV病毒的复制，减少病毒产生的HBsAg、HBeAg^[65]。此外，目前也有多项研究指出，无论是口服或外用益生菌，都能有效抑制HPV在体内的复制，降低病毒滴度。Cha等^[49]通过对细胞实验发现，青春双歧杆菌SPM1005-A能抑制SiHa细胞中HPV16的E6和E7致癌基因的表达；Nami等^[46]则研究发现，植物乳杆菌5BL的代谢产物能够抑制HeLa细胞的增殖，进而减少HPV病毒的复制，且该抑制作用在5BL代谢产物为50 μg/mL时最为显著。

更深入的研究指出，特定的益生菌菌株能刺激上皮细胞分泌抗菌肽以及各种具有抗病毒作用的细胞因子，从而减少HPV病毒的复制^[66]。Sungur等^[48]研究发现，格氏乳杆菌可以产生大量的胞外多糖，使益生菌更好地附着于宿主细胞，并聚集在细胞上直接发挥抑制病毒增殖的作用。Wang等^[51]通过研究发现，使用卷曲乳杆菌株SJ-3C-US、加氏乳杆菌菌株ATCC 9857和詹氏乳杆菌菌株ATCC 25258的发酵上清，可以直接抑制HPV16的E6和E7癌基因的mRNA水平，使其下调，同时这些菌株发酵上清液还能够直接抑制Caski细胞中cdk2和cyclin A基因的mRNA转录水平。

在本团队尚未发表的研究中，我们依据肿瘤细胞模型筛选出了具有直接抗病毒作用的益生菌菌株。我们选用感染了HPV 16分型的SiHa细胞进行实验，并发现了一株植物乳杆菌，该菌株不仅能抑制SiHa细胞增殖，还能有效抑制SiHa细胞中HPV16的E6和E7致癌基因的表达。

3.2 益生菌的免疫调节作用

免疫系统是人体清除HPV病毒感染的重要手段之一，大多数的HPV感染都是依靠宿主自身的免疫反应来清除的。因此，宿主免疫监视功能的下降是导致HPV持续感染的重要原因之一，研究指出益生菌具有提升机体免疫监视功能的作用，因此可以通过服用益生菌的方式来增强人体自身免疫能力，从而达到预防以及清除HPV感染的目的^[58]。

Ilhan等^[67]的研究调查了益生菌对免疫反应的影响，发现部分乳杆菌菌株能够上调上皮细胞中防御素的表达，从而提升宿主对HPV感染的防御能力。除了抗菌肽，益生菌还能刺激干扰素的产生，进而直接杀伤病毒，Mokrozub等^[68]的研究表明，益生菌的使用导致免疫细胞中干扰素的产生增加。这些干扰素能够抑制病毒复制并增强对HPV的免疫反应。Dellino等^[62]对160名感染了HPV病毒的妇女进行研究发现，口服冻干的卷曲乳杆菌M247可使患者阴道中HPV的清除率明显提升；进一步的研究指出M247能够调节局部免疫系统的炎症反应，进而抑制癌变细胞过度增殖和促进凋亡。

3.2.1 增强机体对病毒的免疫监视与防御

宿主对病原菌的免疫监视与防御作用是机体清除HPV的重要手段，在HPV感染过程中，病毒能逃逸免疫系统的监视，并中和免疫细胞的杀伤作用，实现免疫逃逸。研究指出，特定的益生菌能够增强机体的免疫监视，激活NK细胞的杀伤作用，进而减少HPV病毒在体内的复制^[20]。Nanno等发现每天摄入含有干酪乳酪杆菌(Lacticaseibacillus casei, LcS)的发酵乳可以恢复NK细胞活性较低的受试者的NK细胞活性^[69]。Abdolalipour等^[70]在研究中发现，静脉注射或口服两歧双歧杆菌可有效诱导小鼠抗肿瘤免疫反应并抑制表达了HPV16型的肿瘤生长；向荷瘤小鼠静脉注射益生菌两歧双歧杆菌可激活肿瘤特异性IL-12和IFN-γ的产生、促进淋巴细胞增殖以及增强CD8⁺细胞的溶解反应，从而控制和根除肿瘤生长，这些观察结果表明，静脉注射益生菌是激活并调节免疫系统抗癌的有效方法。

此外，益生菌还能增强抗原呈递细胞(antigen-presenting cells, APCs)的功能，尤其是树突状细胞(dendritic cells, DCs)，这对于启动针对HPV的适应性免疫反应至关重要。树突状细胞能够捕获和呈递HPV抗原给T细胞，从而启动特异性免疫反应^[71]。Shi等^[71]的研究显示，益生菌的补充促进了树突状细胞的成熟和激活，从而导致对HPV的更强大的免疫反应。在Gao等^[55]的研究中，格氏乳杆菌LGV03通过调节IRF3信号通路增强了聚肌胞苷酸[Poly(I:C)]诱导的干扰素的产生，并通过调节NF-κB信号通路减轻了Poly(I:C)诱导的促炎介质的释放，这些结果提示LGV03具有维持先天免疫系统持续激活状态的作用，从而更高效地减少患者体内病毒复制。Abdolalipour等^[57]在一项通过干酪乳杆菌TD-2联合粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor, GM-CSF)诱导宫颈癌小鼠免疫应答的研究中发现，干酪乳杆菌TD-2能够提升小鼠体内IFN-α、IL-4和IL-12的水平，进而刺激机体的特异性抗肿瘤免疫应答，抑制肿瘤的生长。Jacouton等^[58]研究发现，干酪乳杆菌BL23能够刺激小鼠体内高水平IL-2的产生，并促进NK细胞的局部富集，从而减少HPV病毒的复制及肿瘤的形成。

3.2.2 减轻炎症反应

益生菌具有抗炎特性，有助于减轻HPV感染所引发的炎症反应。它们能够减少促炎细胞因子的产生，如白细胞介素-6 (IL-6)和白细胞介素-8 (IL-8)，从而减轻炎症负担并减少相关组织损伤^[72]。例如，Jacouton等^[73]的研究表明，将干酪乳杆菌BL23用于感染HPV16的小鼠后，BL23治疗显著降低了宫颈组织中IL-6的水平，显示出其抗炎作用。Giralt等^[74]的研究发现，干酪乳杆菌DN-114 001能够在人体内减少IL-8的释放，并增加IL-10的释放。这些研究均表明，益生菌在HPV感染环境中具有减轻炎症的潜力。

此外，益生菌能够促进抗炎细胞因子的产生，如IL-10和TGF-β，这有助于维持免疫稳态，并限制过度的炎症反应^[74]。Petrof等^[75]的研究显示，益生菌抑制了结肠上皮细胞中促炎细胞因子的产生，同时诱导了IL-10的产生，从而促进了抗炎环境的形成。Di Pierro等^[76]的研究表明，卷曲乳杆菌M247能够减少IL-8的释放。Chen等^[77]研究发现，发酵乳杆菌XJC60具有降低皮肤细胞IL-6和IL-1β水平的作用，能够很好地缓解皮肤黏膜炎症。这些研究均表明，益生菌通过调节促炎和抗炎细胞因子之间的平衡来调节免疫反应，从而有效减轻与HPV感染相关的炎症。

益生菌通过调节机体炎症反应，对HPV感染的清除具有重要的意义。慢性炎症可能会营造一个有利于HPV持续感染和发展的环境，从而增加罹患宫颈癌、肛门癌和咽峡癌等HPV相关疾病的风险^[72]。

3.3 增强黏膜屏障功能

益生菌通过多种机制对黏膜屏障产生有益影响。首先，益生菌能够增强上皮细胞层的完整性，形成对抗病原体的物理屏障，它们促进紧密连接蛋白(如Occludin和Claudins)的表达，在维持上皮细胞完整性和阻挡病原体侵入方面发挥着关键作用^[78]。例如，Mastromarino等^[79]的研究表明，乳酸菌属细菌能够增强阴道上皮细胞中紧密连接蛋白的表达，从而改善黏膜屏障功能，降低HPV感染风险。在Vemuri等^[80]的研究中，为老化小鼠补充嗜酸乳杆菌(Lactobacillus acidophilus) DDS-1可以改善肠道黏膜屏障功能，具体表现为紧密连接蛋白的表达增加和黏液分泌的增强。Li等^[81]研究发现，戊糖片球菌IM96具有修复黏膜损伤的能力，并能提高黏膜细胞间紧密连接蛋白Occludin和MUC-2的表达水平。这些发现进一步强调了益生菌在强化黏膜屏障功能以及预防HPV感染方面的潜力。

除增强物理屏障外，益生菌还能调节黏膜免疫反应，有助于维持健康的黏膜屏障。它们刺激抗微生物肽(如防御素和抗菌肽)的产生，这些肽对包括HPV在内的病原体具有广谱抗菌活性^[82]。此外，益生菌还能调控黏液的分泌，为上皮表面构筑起一道保护层。它们促进黏液的合成与分泌，进而强化黏膜屏障的功能^[83]。研究表明，乳酸菌可以诱导黏液基因的表达，并提升胃肠道和呼吸道中黏液的产生量^[84]。

益生菌对黏膜屏障功能的调节对于HPV感染具有重要意义。健康且完整的黏膜屏障能够阻止HPV进入并在黏膜组织中定植，进而降低感染和疾病进展的风险。通过增强黏膜屏障，益生菌可能为抵御HPV感染提供额外的保护屏障^[60]。

3.4 调节阴道微生态环境

在对HPV的研究中，阴道微生物群落已经得到广泛研究。研究指出，某些特定种属的微生物，如乳杆菌的存在，与健康的阴道环境以及HPV持续感染和宫颈异型增生风险降低有关；乳酸杆菌除了提供一种保护性的物理屏障外，还产生乳酸、过氧化氢和其他抗微生物物质，以抑制潜在病原体(包括HPV)的生长和活动^[85]。

多项研究探索了阴道微生物群落与HPV感染之间的关系。Gao等^[86]通过前瞻性队列研究发现，女性体内乳杆菌(尤其是卷曲乳杆菌)的丰度较高时，其感染HPV的风险相对较低；反之，拟杆菌属和阴道弯曲菌属的丰度较高则与HPV感染风险增加相关。Chen等^[87]则利用大鼠模型建立了一种阴道菌群失调的情境，以研究阴道菌移植(vaginal microbiome transplant, VMT)对其的改善效果，他们从健康雌性大鼠的阴道中提取分泌物作为移植材料，结果显示，VMT能够显著减轻由细菌引发的子宫壁炎症，并减少阴道内促炎细胞因子IL-1β和TNFα的积累，从而将受干扰的阴道微生物群落恢复到正常水平。此外，Mhatre等^[88]开展了一项调查阴道微生态对HPV持续感染和宫颈异型增生影响的纵向研究，对一组女性进行了长期跟踪调查，发现惰性乳杆菌丰度较高的女性面临更高的HPV持续感染和高度宫颈异型增生风险；相反，卷曲乳杆菌丰度较高的女性，其HPV持续感染和宫颈异型增生的风险相对较低。di Pierro等^[76]的研究表明，在35名HPV阳性受试女性中，经过90 d口服卷曲乳杆菌M247后，仅1名女性的阴道微生物群中乳杆菌数量极少，其余33名女性的阴道微生物群以乳酸菌(CST I)为主，另有1名女性的阴道微生物群以惰性乳杆菌(CST III)为主；在口服90 d后，25名女性(71%)的高危型HPV和低危型HPV检测均呈阴性，而10名女性(29%)的HR-DNA检测仍呈阳性。另一方面，Edelman等^[89]通过分离鉴定，发现了一种定殖于鸡消化道中的卷曲乳杆菌菌株ST1，该菌株能够分泌乳杆菌上皮黏附素(late embryogenesis abundant proteins, LEA)，与人阴道上皮细胞结合，从而使乳酸菌黏附在阴道黏膜上，进而改善阴道内的微生物环境。这些研究结果显示，阴道微生物群落的组成和平衡与HPV感染的风险和进展之间存在密切的关联，乳酸杆菌等有益菌的存在有助于维持阴道健康环境，抑制HPV的持续感染，并降低宫颈异型增生的发展风险。

进一步研究了这些微生物的相互作用机制，并探索了基于微生物群落调节的抗HPV相关干预措施。研究发现，卷曲乳杆菌M247在口服或局部给药后，具有在阴道组织定殖的特性^[59,90]。di Pierro等研究发现，M247能够分泌细菌素(如elveticins、penocin)和2种肠溶素，因此具有调节人体微生态的功效^[76]。同时，Du等研究发现，长双歧杆菌020402能够产生一种新型溶菌酶样蛋白020402_LYZ M1，该蛋白具有调节机体微生态的作用^[91]。这些研究结果均证实，益生菌能够通过调节黏膜局部微生态，进而发挥抗HPV的功效。

4 总结与展望

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HPV是一种易于通过性接触传播的DNA病毒，感染后可引发癌症。HPV感染的致病机制包括病毒感染、免疫逃逸、持续感染、细胞病变及基因整合等多个环节^[1]。近年来，研究指出阴道微生态的失衡是HPV持续致病的重要因素之一。流行病学研究显示，若HPV在感染早期未能及时被免疫系统清除，则会形成慢性感染，进而可能发展为癌症，治疗难度增大。因此，寻找安全、高效的新型生物制剂以防控HPV感染，对于防控该病毒流行感染、提升女性健康水平具有重要意义^[92]。

目前，口服或外用益生菌治疗已被证实对HPV感染具有一定的疗效。研究指出，益生菌可通过直接抗病毒、提升免疫力、减轻炎症、增强黏膜屏障功能等多种机制，对HPV感染产生防控作用^[9]。在HPV感染中，益生菌具有抗病毒和免疫调节作用，特定的益生菌菌株能够刺激上皮细胞分泌抗菌肽及具有抗病毒活性的细胞因子，从而减少HPV病毒的复制；某些益生菌菌株还能强化机体的免疫监视功能，激活NK细胞的杀伤活性，进而抑制HPV病毒在体内的复制^[27]；同时，益生菌可促进抗炎细胞因子的产生，维持免疫稳态，并限制过度炎症反应的发生。除此之外，益生菌通过维持阴道微生态平衡，能够有效抑制HPV的持续感染，阻止宫颈异型增生的发展^[85]。然而，目前HPV完整病毒颗粒的培养技术依旧十分繁琐，分离HPV病毒颗粒需借助动物或者类器官，经济成本和时间成本都极高。因此，未来还需进一步探索分离HPV病毒颗粒的简便方法。目前用于筛选抗HPV益生菌的模型尚缺乏统一标准，亟须建立更为完善的筛选体系，以便为后续研究者更好地开展益生菌抗HPV方向的研究提供便利。

基金

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国家重点研发计划(2023YFF1104110)
广东省科学院技术创新平台专项(2022GDASZH-2022020402-01)

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2025年第65卷第2期

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doi: 10.13343/j.cnki.wsxb.20240472

接收时间：2024-07-30
首发时间：2026-02-05
出版时间：2025-02-04

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收稿日期：2024-07-30
录用日期：2024-10-17

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National Key Research and Development Program of China(2023YFF1104110)

国家重点研发计划(2023YFF1104110)

Guangdong Academy of Sciences Technology Innovation Platform Special Project(2022GDASZH-2022020402-01)

广东省科学院技术创新平台专项(2022GDASZH-2022020402-01)

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1 陕西科技大学食品科学与工程学院，陕西西安

3 广东科环生物科技有限公司，广东广州

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Strain	Form	Models for validation	Effect	Mechanism	Reference
Lactobacillus plantarum 5BL	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Reduce cellular apoptosis, lead to cytotoxicity, thereby inhibit the proliferation of HPV18	[46]
Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 33323	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Reduce caspase-3 expression and activity, leading to decreased LDH release and upregulate hCG β expression and autophagy	[47]
Lactobacillus gasseri G10+Lactobacillus gasseri H15	Cell-free supernatant	HeLa cells (infected with HPV18)	Anti-inflammatory effects	Produce extracellular polysaccharide, which enables acid bacteria to better adhere to host cells	[48]
Bifidobacterium adolescentis SPM1005-A	Cell-free supernatant	SiHa cells (infected with HPV16)	Inhibition of gene expression	Downregulate the expression of HPV16 E6 and E7 genes at the mRNA and protein levels	[49]
Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Downregulate the expression of CASP3, MMP-2, and MMP-9 while upregulate of the expression of TIMP-1 and TIMP-2	[50]
Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 9857+Lactobacillus jensenii ATCC 25258	Cell-free supernatant	CaSki cells (infected with HPV16)	Antitumor effect and inhibition of gene expression	Downregulate the mRNA levels of HPV16 E6 and E7 oncogenes as well as CDK2 and cyclin A	[51]
Lactobacillus casei SR1+Lactobacillus casei SR2	Cell-free supernatant	HeLa cells (infected with HPV18)	Inhibition of gene expression	Upregulate the expression of BAX, BAD, caspase-3, caspase-8, and caspase-9 genes and downregulate bcl-2 gene	[52]
Lactobacillus delbrueckii DM8909	Cell-free supernatant	U4 cells and HeLa cells (infected with HPV18)	Antitumor effect	Upregulate the expression of E-cadherin	[53]
Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG	Cell-free supernatant	HeLa cells (infected with HPV18)	Antitumor effect	Downregulate the expression of HPV18 E6 gene as well as caspase-3 and ATG14 genes	[54]
Lactobacillus gasseri LGV03	Cell-free supernatant	CaSki cells (infected with HPV16)	Anti-inflammatory effects	Regulate the IRF3 signaling pathway and the NF-κB signaling pathway, while enhance the production of IFN-γ	[55]
Lactobacillus crispatus 2743+Lactobacillus gasseri 3396	Cell-free supernatant	SiHa cells (infected with HPV16)	Antitumor effect	Silence ARHGAP5 expression and reduces the levels of E6 and E7 proteins	[56]
Lactobacillus casei TD-2	Cell-free supernatant	C57BL/6 mice	Antitumor effect	Increase IFN-c, IL-4, and IL-12 level as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumor	[57]
Lactobacillus casei BL23	Cell-free supernatant	TC-1-Challenged Mice	Immune regulation	Increase IL-2 production around the tumor	[58]
Lactobacillus crispatus M247	Cell-free supernatant	Colitis mice	Anti-inflammatory effects and mucosal barrier enhancement	Release hydrogen peroxide which upregulate PPAR-γ and TLR-2, and downregulate TLR-4	[59]
Lactobacillus crispatus M247	Freeze-dried cell-free supernatant	35 females with HPV cervical infection	Mucosal barrier enhancement	Enhance probiotic colonization and encode fibronectin type III domain-containing proteins and N-terminal fibronectin-binding protein A	[60]
Lactobacillus rhamnosus BMX54	Freeze-dried bacteria	117 females with bacterial vaginosis or vaginal inflammation accompanied by HPV infection	Mucosal barrier enhancement	Inhibit colonization of pathogens and improve the vaginal environment	[61]
Lactobacillus crispatus M247	Cell-free supernatant	160 females with HPV cervical infection	Antitumor effect	Release hydrogen peroxide, lactic acid, and bacteriocins to regulate mucosal inflammation and control celluar proliferation/apoptosis	[62]
Lactobacillus casei Shirota	Probiotic drink	54 women with low-grade HPV-infection	Mucosal barrier enhancement and anti-inflammatory effects	Reconstruct vaginal microbiota, directly kill pathogens, compete for host cell receptors, and interfere with the gene expression of pathogens	[63]

Strain

Form

Models for validation

Effect

Mechanism

Reference

Lactobacillus plantarum 5BL

Cell-free supernatant

HeLa cells (infected with HPV18)

Antitumor effect

Reduce cellular apoptosis, lead to cytotoxicity, thereby inhibit the proliferation of HPV18

[46]

Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri

ATCC 33323

Cell-free supernatant

HeLa cells (infected with HPV18)

Antitumor effect

Reduce caspase-3 expression and activity, leading to decreased LDH release and upregulate hCG β expression and autophagy

[47]

Lactobacillus gasseri G10+Lactobacillus gasseri H15

Cell-free supernatant

HeLa cells (infected with HPV18)

Anti-inflammatory effects

Produce extracellular polysaccharide, which enables acid bacteria to better adhere to host cells

[48]

Bifidobacterium adolescentis SPM1005-A

Cell-free supernatant

SiHa cells (infected with HPV16)

Inhibition of gene expression

Downregulate the expression of HPV16 E6 and E7 genes at the mRNA and protein levels

[49]

Lactobacillus crispatus SJ-3C-US+Lactobacillus rhamnosus GG

Cell-free supernatant

HeLa cells (infected with HPV18)

Antitumor effect

Downregulate the expression of CASP3, MMP-2, and MMP-9 while upregulate of the expression of TIMP-1 and TIMP-2

[50]

Lactobacillus crispatus SJ-3C-US+Lactobacillus gasseri ATCC 9857+Lactobacillus jensenii

ATCC 25258

Cell-free supernatant

CaSki cells (infected with HPV16)

Antitumor effect and inhibition of gene expression

Downregulate the mRNA levels of HPV16 E6 and E7 oncogenes as well as CDK2 and cyclin A

[51]

Lactobacillus casei SR1+Lactobacillus casei SR2

Cell-free supernatant

HeLa cells (infected with HPV18)

Inhibition of gene expression

Upregulate the expression of BAX, BAD, caspase-3, caspase-8, and caspase-9 genes and downregulate bcl-2 gene

[52]

Lactobacillus delbrueckii DM8909

Cell-free supernatant

U4 cells and HeLa cells (infected with HPV18)

Antitumor effect

Upregulate the expression of E-cadherin

[53]

Lactobacillus crispatus

SJ-3C-US+Lactobacillus rhamnosus GG

Cell-free supernatant

HeLa cells (infected with HPV18)

Antitumor effect

Downregulate the expression of HPV18 E6 gene as well as caspase-3 and ATG14 genes

[54]

Lactobacillus gasseri LGV03

Cell-free supernatant

CaSki cells (infected with HPV16)

Anti-inflammatory effects

Regulate the IRF3 signaling pathway and the NF-κB signaling pathway, while enhance the production of IFN-γ

[55]

Lactobacillus crispatus 2743+Lactobacillus gasseri 3396

Cell-free supernatant

SiHa cells (infected with HPV16)

Antitumor effect

Silence ARHGAP5 expression and reduces the levels of E6 and E7 proteins

[56]

Lactobacillus casei TD-2

Cell-free supernatant

C57BL/6 mice

Antitumor effect

Increase IFN-c, IL-4, and IL-12 level as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumor

[57]

Lactobacillus casei BL23

Cell-free supernatant

TC-1-Challenged Mice

Immune regulation

Increase IL-2 production around the tumor

[58]

Lactobacillus crispatus M247

Cell-free supernatant

Colitis mice

Anti-inflammatory effects and mucosal barrier enhancement

Release hydrogen peroxide which upregulate PPAR-γ and TLR-2, and downregulate TLR-4

[59]

Lactobacillus crispatus M247

Freeze-dried cell-free supernatant

35 females with HPV cervical infection

Mucosal barrier enhancement

Enhance probiotic colonization and encode fibronectin type III domain-containing proteins and N-terminal fibronectin-binding protein A

[60]

Lactobacillus rhamnosus

BMX54

Freeze-dried bacteria

117 females with bacterial vaginosis or vaginal inflammation accompanied by HPV infection

Mucosal barrier enhancement

Inhibit colonization of pathogens and improve the vaginal environment

[61]

Lactobacillus crispatus M247

Cell-free supernatant

160 females with HPV cervical infection

Antitumor effect

Release hydrogen peroxide, lactic acid, and bacteriocins to regulate mucosal inflammation and control celluar proliferation/apoptosis

[62]

Lactobacillus casei Shirota

Probiotic drink

54 women with low-grade HPV-infection

Mucosal barrier enhancement and anti-inflammatory effects

Reconstruct vaginal microbiota, directly kill pathogens, compete for host cell receptors, and interfere with the gene expression of pathogens

[63]