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Mechanism of Bacterial Extracellular Vesicles in Disease Development and Prospects for Application
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摘要: 细菌外囊泡(bacterial extracellular vesicles，BEVs)是细菌衍生的细胞外囊泡。作为细菌间或细菌-宿主间相互作用的关键新媒介，BEVs是一把“双刃剑”：一方面在宿主多种病理过程，包括肠道炎性疾病、中枢神经系统相关疾病、肝脏疾病、代谢性疾病、自身免疫性疾病及肿瘤中发挥“致病”作用；另一方面作为潜在生物标志物、疫苗、抗肿瘤制剂等发挥“治病”作用，为疾病的诊治打开了新思路。但关于BEVs的研究目前尚处于起步阶段，在囊泡分离技术、疾病诊断特异性、囊泡储运优化等方面仍面临挑战，未来需设计严谨的临床研究以证实其诊断和治疗价值。Abstract: Bacterial extracellular vesicles (BEVs), bacteria-derived extracellular vesicles, are key intermediates of bacteria-bacteria and bacteria-host interactions. They are a "double-edged sword". On one hand, they play a negative role in the onset and progression of various diseases, including intestinal inflammatory disease, neurological disease, liver disease, metabolic disease, autoimmune disease and cancer. On the other hand, they play a positive role as potential biomarkers, vaccines, antitumor agents. The application of BEVs may provide novel strategies for the diagnosis and treatment of diseases. However, research on BEVs is still in its infancy, and challenges remain in vesicle isolation techniques, disease diagnostic specificity, optimization of vesicle storage and transport. Thus rigorously designed clinical studies are required to verify their diagnostic and therapeutic value.
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Key words:
- bacterial extracellular vesicles /
- diseases /
- biomarkers /
- vaccines /
- probiotics /
- antitumor agents
作者贡献：罗晓霞、覃思华负责文献检索及论文撰写；王晖迪负责论文构思及修订；周宏伟、何彦负责选题设计及论文审校。利益冲突：所有作者均声明不存在利益冲突 -
表 1 BEVs作为潜在生物标志物的最新研究
第一作者
(发表时间)BEVs
来源疾病 研究对象
(实验组/对照组)研究方法 生物标志物 诊断模型 标志物
类型Dey[43] (2019年) 血清 葡萄球菌菌血症 21例幸存者/23例因菌血症死亡者 对感染金黄色葡萄球菌菌血症幸存者和死亡者血清中的BEVs进行分离 BEVs含量 301相对荧光单位：特异度90%/灵敏度78% 预警标志物 Wei[44] (2019年) 粪便 AD 9例AD患者/9名健康者 对来自AD患者和健康者的BEVs进行差异代谢物分析 4-半醛/PGE2/20-羟基-二十碳四烯酸/菌素/L -岩藻吡喃糖/吲哚-3-乙酸/4-甲基伞形酮/胆碱/咪唑-4-醋酸/ L-天冬氨酸/富马酸/十三酸 4-半醛/PGE2/20-羟基-二十碳四烯酸/菌素/L-岩藻吡喃糖/吲哚-3-乙酸/4-甲基伞形酮/胆碱：各自AUC＞0.900咪唑-4-醋酸/ L-天冬氨酸/富马酸/十三酸：各自AUC＞0.800 预测和诊断标志物 Yang[45](2020年) 血清 脑肿瘤 152例脑肿瘤患者/198名健康者 对BEVs进行16S rRNA基因测序 微生物组成 - 诊断标志物 Kim[46](2020年) 血清 卵巢癌 166例卵巢癌患者/76例良性肿瘤患者 对BEVs进行宏基因测序，构建卵巢癌与良性卵巢肿瘤的诊断模型 BEVs宏基因组图谱 年龄+ CA-125 +不动杆菌相对丰度：AUC=0.846 鉴别标志物 Kim[47](2020年) 粪便 结直肠癌 32例结直肠癌患者/40名健康者 联合BEVs的宏基因组学数据和代谢组学数据构建诊断结直肠癌的模型 两种细菌(Collinsella、Solanum melongena)/两种代谢物(leucine、oxalic acid) 宏基因组学+代谢组学：AUC=1 诊断标志物 Yang[48](2020年) 血清 特发性皮炎 24例特发性皮炎患者/49名健康者 16S rDNA宏基因组分析 BEVs细菌类群 血清BEVs生物标志物(LDA评分＞3)：AUC=1 诊断标志物 Yang[49](2020年) 血清 哮喘、COPD、肺癌 239例哮喘患者、205例COPD患者、324例肺癌患者/88名健康者 16S rDNA宏基因组分析，基于ELISA的抗BEVs抗体滴度分析作为肺部疾病的诊断工具 BEVs细菌类群 哮喘：AUC=0.78; COPD：AUC=0.79; 肺癌：AUC=0.80 BEVs抗体滴度的肺部疾病诊断工具 Han[50](2021年) 唾液 牙周炎 7例牙龈炎患者、8例牙周炎患者/7名健康者 对健康者、牙龈炎和牙周炎患者唾液小细胞BEVs的DNA表观遗传模式、LPS阳性OMVs群体和特异性牙周病原体来源的OMVs进行分析 具核梭杆菌OMVs 具核梭杆菌OMVs：AUC=0.94 鉴别牙龈炎和牙周炎的标志物 Yoon[51](2023年) 尿液 结直肠癌 91例结直肠癌患者/116名健康者 对BEVs进行16S rRNA基因测序，分析两组间的差异微生物群 微生物组成 - 诊断标志物 BEVs: 细菌外囊泡；AUC：受试者工作特征曲线下面积；AD: 阿尔茨海默病；CA-125：糖类抗原-125；LDA: 线性判别分析；COPD: 慢性阻塞性肺疾病；LPS: 脂多糖；OMVs: 外膜囊泡；-：未描述 
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表 2 益生菌细胞外囊泡在疾病治疗中可能发挥的作用
第一作者(发表时间) 微生物名称 疾病 研究内容 作用 Ñahui Palomino[56](2019年) 卷曲乳杆菌BC3(Lactobacillus crispatus) HIV感染 介导病毒-细胞相互作用的包膜蛋白暴露减少，减少HIV-1对宿主细胞的附着 抑制病原菌黏附 加氏乳杆菌BC12(Lactobacillus gasseri) Kim[57](2018年) 植物乳杆菌APsulloc 331261(Lactobacillus plantarum) 特发性皮炎 诱导抗炎细胞因子IL-10的分泌及免疫调节细胞因子IL-1β和GM-CSF的分泌; 诱导单核细胞向巨噬细胞转变及巨噬细胞向M2b状态极化 抗炎作用/免疫调节 Tong[58](2021年) 鼠李糖乳杆菌GG(Lacticaseibacillus rhamnosus) 结肠炎 抑制结肠组织TLR4-NF-κB-NLRP3轴的激活; 降低TNF-α、IL-1β、IL-2和IL-6水平 抗炎作用/免疫调节 Hu[59](2021年) 罗伊氏乳杆菌BBC3(Lactobacillus reuteri) 结肠炎 降低TNF-α、IL-1β和IL-6的基因表达，增强IL-10和TGF-β的基因表达; 激活巨噬细胞，抑制Th1和Th17介导的炎症反应 抗炎作用/免疫调节 Lee[60](2022年) 乳链球菌(Lactococcus lactis) 过敏性哮喘 气道高反应性、嗜酸性粒细胞数量、细胞因子分泌和黏液产生显著降低; 刺激DC产生IL-12，诱导Th2转变Th1，降低Ig4 免疫调节 Croatti[61](2022年) 乳杆菌(lactobacilli) 阴道感染 支持有益物种的定植及防止大肠杆菌、金黄色葡萄球菌、无乳链球菌和粪肠球菌等条件致病菌的黏附 抑制病原菌 Choi[62](2022年) 嗜黏蛋白阿克曼氏菌ATCC BA 835(Akkermansia muciniphil) 抑郁 恢复海马中MeCP2、Sirt1及神经营养因子的表达 抗抑郁作用 枯草芽孢杆菌(Bacillus subtilis) Ye[63](2023年) 植物乳杆菌(Lactobacillus plantarum) 肝损伤 降低肝细胞氧化损伤、改善脂质代谢、调节肠道菌群 - HIV：人类免疫缺陷病毒；IL: 白细胞介素；GM-CSF：粒细胞巨噬细胞刺激因子；TLR4：Toll样受体4；TNF-α：肿瘤坏死因子α；TGF-β: 转化生长因子β；Th：辅助性T细胞；DC：树突状细胞；MeCP2：甲基CpG结合蛋白2；Sirt1：NAD依赖的脱乙酰化酶；-：不作分类
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