牙周炎关键病原体牙龈卟啉单胞菌（P. gingivalis）的致病作用已远超口腔局部范畴，P. gingivalis可在消化系统肿瘤组织中被特异性检出，且其感染丰度与肿瘤的侵袭转移能力、患者不良预后密切相关。本研究系统梳理P. gingivalis与口腔癌、食管癌、胰腺癌、肝癌及结直肠癌等消化系统肿瘤关联的基础与临床研究，深入剖析该菌诱导肿瘤发生发展的潜在分子机制，旨在为消化系统肿瘤的风险预警、早期诊断及靶向治疗提供新的理论依据与研究方向。

牙龈卟啉单胞菌（Porphyromonas gingivalis，P.  gingivalis）可特异性黏附于牙龈上皮细胞及牙龈成纤维细胞，与牙周病的发生发展存在密切关联[1]。流行病学研究表明，P. gingivalis在健康人群中感染率约20%，而肿瘤患者感染率可超过40%[2-3]。P. gingivalis可通过脂多糖（lipopolysaccharide，LPS）、牙龈蛋白酶、菌毛蛋白（fimbrillin，FimA）等多种毒力因子参与消化系统疾病的发生发展。例如，LPS可调控口腔癌相关基因的表达[4]；牙龈蛋白酶能通过多种机制影响结直肠癌的进展[5]；而FimA可通过调控上皮间质转化（epithelial-mesenchymal transition，EMT）[6]、免疫及代谢相关基因表达[7]等机制促进癌症进展。多项研究在消化系统肿瘤患者的口腔、血清及肿瘤样本中检出P. gingivalis[4, 8-9]，且检出差异与肿瘤进展及不良预后密切相关[10-11]。

上述证据提示，P. gingivalis可能参与并介导消化系统肿瘤的发生与发展过程。基于此，本文综述P. gingivalis与口腔癌、食管癌、胰腺癌、肝癌及结直肠癌相关的临床和基础研究证据，旨在揭示其在消化系统肿瘤发生发展中的作用及潜在分子机制。

1 P. gingivalis与消化系统肿瘤的流行病学研究

流行病学研究显示，P. gingivalis与消化系统肿瘤的发生发展密切相关。口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）患者的P. gingivalis唾液检出率、血清抗体水平均显著高于健康人群[4, 12-13]，且癌组织内P. gingivalis丰度与患者生存期缩短相关[14-16]。食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）患者牙龈菌斑中P. gingivalis丰度及血清抗体水平显著升高[3, 17]，癌组织内该菌定植状态与肿瘤分化程度、淋巴结转移、临床分期及疾病预后密切相关[18-20]。在胰腺癌中，患者口腔P. gingivalis检出率显著高于健康人群，血清抗体水平升高与胰腺癌发病风险增加相关[8, 21-22]；同时，唾液中该菌丰度越高，患者生存期越短，且胰腺癌组织中也可检测到P. gingivalis定植[23-24]。研究表明，P. gingivalis感染与非酒精性脂肪性肝炎（non-alcoholic steatohepatitis，NASH）的发生和进展相关，而NASH可发展为NASH相关肝癌（NASH-associated liver cancer，NALC）[25-26]。此外，在代谢功能障碍相关性脂肪性肝炎相关肝细胞癌（hepatocellular carcinoma，HCC）患者唾液中，P. gingivalis丰度显著高于脂肪性肝炎患者，提示该菌可能参与HCC的发生过程[27]。结直肠癌（colorectal cancer，CRC）患者粪便中P. gingivalis检出率显著升高，且与黏液腺癌分型、不良预后密切相关[28-29]；同时，肠黏膜及癌组织中P. gingivalis定植状态与CRC微卫星不稳定性免疫分型存在显著关联[30]。综上所述，P. gingivalis可能通过多种潜在机制参与消化系统肿瘤的发生、进展及预后调控。

2 P. gingivalis与消化系统肿瘤发生发展相关机制的研究证据

2.1 P. gingivalis与口腔癌

P. gingivalis可通过调控细胞EMT、增殖、侵袭及自噬多种生物学过程，参与OSCC发生与进展。P. gingivalis通过上调OSCC细胞中白介素-8（interleukin-8，IL-8）、基质金属蛋白酶-1（matrix metalloproteinase-1，MMP-1）及MMP-10的表达诱导EMT[31]，同时活化整合素αV及黏着斑激酶（focal adhesion kinase，FAK）信号，协同增强OSCC细胞的迁移与侵袭能力[32]。此外，该菌可通过诱导癌症干细胞标志物CD44、CD133的表达[31]，并通过激活含核苷酸结合寡聚化结构域1（NOD1）/Krüppel样因子5通路，上调脂质代谢关键酶硬脂酰辅酶A去饱和酶1的表达，进而增强OSCC细胞的干性特征[33]。P. gingivalis标准株33277与W83可通过miR 21/程序性细胞死亡因子4/激活蛋白1负反馈环路调控细胞周期蛋白D1的表达，其中33277菌株还可通过诱导自噬、抑制细胞凋亡，进一步调控OSCC细胞的增殖与存活[34-35]。

除核心调控机制外，P. gingivalis的不同菌株及多种菌体成分也可通过特异性途径影响OSCC的发生发展。其中，33277菌株可通过上调口腔上皮细胞中磷酸化糖原合酶激酶-3β的水平，以及Slug、Snail等EMT相关分子及MMP-2表达，诱导口腔上皮细胞EMT及恶性转化[36]。33277菌株还可通过募集肿瘤相关中性粒细胞，激活C-X-C趋化因子配体（CXCL）2/C-X-C趋化因子受体2轴及JAK1/STAT3信号通路，增强肿瘤侵袭与增殖能力并促进OSCC生长[15]。此外，381菌株可通过Toll样受体（toll-like receptor，TLR）与口腔上皮细胞相互作用，诱导小鼠口腔肿瘤发生，并通过IL-6/STAT3轴促进肿瘤进展 [37]；不同菌株的FimA可通过调控锌指E盒结合同源框1（ZEB1）表达及核定位启动EMT，诱导OSCC细胞中CCL20、CXCL8等促炎因子上调，进而促进OSCC进展[7]。在菌体组分方面，外膜囊泡可通过激活核因子κB（nuclear factor kappa-B，NF-κB）通路抑制铁死亡[38]，而牙龈蛋白酶可通过激活蛋白酶激活受体-2（PAR2）和PAR4、ERK1/2等信号通路增强OSCC细胞侵袭能力[39-40]，LPS能够促进口腔上皮癌前病变[4]，上述效应共同参与OSCC的恶性进展。

P. gingivalis还可通过多种途径介导OSCC细胞免疫逃逸和化疗耐药，从而促进肿瘤进展。免疫逃逸方面，P. gingivalis可诱导中性粒细胞胞外诱捕网释放，包裹OSCC细胞，增强其迁移和侵袭能力，同时诱导OSCC细胞程序性死亡受体配体1（programmed death-ligand 1，PD-L1）和B7-DC受体表达，抑制T细胞活化[41-42]。P. gingivalis菌膜可上调TLR、NF-κB及丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）通路基因，调控免疫逃逸[43]。膜蛋白抑制骨髓来源巨噬细胞对OSCC细胞的吞噬，诱导其向M2型极化[44]。化疗耐药方面，P. gingivalis通过活化Notch1信号及上调IL-6表达，增强OSCC细胞对紫杉醇的耐药性，增加移植瘤成瘤及肺转移风险[45-46]。

综上所述，P. gingivalis通过多种机制参与OSCC发生发展，清除口腔内 P. gingivalis及靶向其促癌分子可能成为 OSCC的有效防治策略。

2.2 P. gingivalis与食管癌

P. gingivalis可通过调控细胞恶性转化、肿瘤微环境、免疫逃逸及化疗耐药等多种机制，参与ESCC的发生与发展。该菌可通过下调紧密连接相关基因的表达，诱导正常食管上皮细胞恶性转化 [47]，并通过激活miR-194/GRHL3/PTEN/AKT信号通路，显著增强ESCC细胞增殖与迁移能力[48]。此外，P. gingivalis可下调ESCC细胞干扰素-γ受体1（interferon γ receptor subunits 1，IFNGR1）表达并促进IFNGR1蛋白122位点棕榈酰化，及激活NF-κB信号通路，促进ESCC细胞增殖、侵袭及迁移[49-50]。P. gingivalis可通过调控EMT及募集骨髓来源抑制细胞，诱发促炎肿瘤微环境，加速肿瘤细胞生长和进展[51-52]；其FimA还可通过上调ESCC细胞糖蛋白A为主的重复序列表达，激活转化生长因子β/Smad信号通路，促进肿瘤生长和肺转移[53]。

在ESCC免疫逃逸与化疗耐药调控中，P. gingivalis同样发挥重要作用。该菌通过上调赖氨酸去甲基化酶5B表达抑制T细胞聚集，同时上调免疫检查点分子B7-H4表达抑制活化CD8+ T细胞增殖，两种分子共表达加剧抑制效应，协同促进ESCC免疫逃逸[54]；同时，P. gingivalis可通过上调YTH N6-甲基腺苷RNA结合蛋白2表达，降低ESCC细胞中Fas蛋白表达水平，协助肿瘤细胞逃避免疫系统的监视[55]。生物信息学分析显示，P. gingivalis感染与肿瘤微环境促炎表型相关，可导致树突细胞活化水平、2型T辅助细胞及中性粒细胞等免疫细胞浸润水平降低[56]。在化疗耐药方面，FimA可通过抑制程序性细胞死亡因子 4表达诱导ESCC细胞中癌症干细胞富集，或上调磷酸化糖原合酶激酶-3β蛋白表达并通过其介导的线粒体氧化磷酸化途径，增强细胞对紫杉醇等化疗药物的耐药性，加剧恶性表型[57-58]。

综上，P. gingivalis可通过上述多种机制参与 ESCC 病理进程，而靶向P. gingivalis及其介导的关键分子机制进行干预有望为 ESCC 防治提供新策略。

2.3 P. gingivalis与胰腺癌

P. gingivalis可通过诱导胰腺导管上皮细胞恶性转化、重塑肿瘤免疫微环境等多种途径参与胰腺癌的发生发展进程。P. gingivalis可从口腔迁移定植于胰腺，改变局部微生态结构，诱导腺泡细胞增殖，直接驱动胰腺癌前病变胰腺上皮内瘤变（pancreatic intraepithelial neoplasia，PanIN）的发生与进展[59]。动物实验表明，P. gingivalis可下调转基因小鼠EMT标志物Snail-1、ZEB1，以及胶原纤维、Gal-3、PD-L1的表达，进一步推动PanIN进展[60]。P. gingivalis-LPS可诱导小鼠胰腺胰岛再生源蛋白表达上调，进一步参与胰腺癌发生过程[61]。缺氧微环境能够显著促进P. gingivalis在胰腺癌细胞内增殖，以不依赖TLR2的方式增强癌细胞增殖与成瘤能力，并保护癌细胞免受活性氧介导的细胞死亡[59, 62]。同时，P. gingivalis可重塑肿瘤微环境，形成以中性粒细胞为主导的促炎状态，提升癌细胞体内成瘤能力，而中性粒细胞释放的趋化因子与弹性蛋白酶可进一步促进胰腺癌进展[23]。

综上，现有研究证实P. gingivalis参与胰腺癌发生和发展，针对该菌靶向干预有望成为调控胰腺癌发病风险、延缓疾病进展的潜在策略。

2.4 P. gingivalis与非酒精性脂肪性肝炎相关肝癌

P. gingivalis可通过调节整合素信号通路与TNF-α介导的DNA氧化损伤，加速高脂饮食诱导的NASH小鼠模型肿瘤结节形成[63]。而且，在体外肝癌细胞模型中，P. gingivalis可诱导小鼠肝癌细胞株Hepa-1.6分泌TNF-α、IL-6等促炎因子，通过诱发持续性炎症反应推动肿瘤进展[64]。

综上，P. gingivalis通过促使NASH进展间接参与NALC发生发展，但其在直接诱导HCC发生发展分子机制上有待更多深入研究予以证实。

2.5 P. gingivalis与结直肠癌

研究表明 P. gingivalis可通过塑造促炎微环境、调控免疫逃逸及影响肿瘤血管生成等多重机制，参与CRC的发生与发展进程。在APC基因突变小鼠中，P. gingivalis能选择性富集肿瘤浸润髓系细胞，诱导TNF-α、IL-6、IL-1β 等促炎因子水平升高，构建促炎微环境，驱动肿瘤发生与发展；同时，激活血源性 NOD样受体家族蛋白3炎性小体，进一步强化促癌免疫微环境，促进结肠肿瘤进展[29]。此外，P. gingivalis可通过上调壳多糖酶3样蛋白1的表达，阻碍恒定自然杀伤T细胞裂解，损害其细胞毒性功能并诱导其向促肿瘤表型转化，促进宿主肿瘤细胞免疫逃避，加速CRC进展[65]。P. gingivalis 33277菌株可通过激活 MAPK/ERK 信号通路促进 CRC 细胞增殖，而牙龈蛋白酶突变缺陷株KDP136的促增殖能力显著减弱，提示牙龈蛋白酶活性是P. gingivalis介导 CRC 细胞增殖的关键毒力因子[28]。

在免疫逃逸与血管生成调控中，菌体成分发挥关键作用。P. gingivalis W83菌株的全膜成分和肽聚糖，可通过激活 NOD1/NOD2、受体相互作用蛋白2、MAPK信号通路，上调CRC细胞 PD-L1 表达，介导免疫逃逸[30]。此外，P. gingivalis 的热休克蛋白GroEL可通过上调内皮型一氧化氮合酶表达、活化p38 MAPK信号促进内皮祖细胞迁移及小管形成，促进结肠癌移植瘤生长并加速荷瘤小鼠死亡，表明 GroEL 可能通过促进肿瘤新生血管生成，加速 CRC 恶性进展[66]。

综上，P. gingivalis 可通过直接定植及促炎机制参与CRC发生与进展，清除该菌及靶向其致病机制有望为 CRC 的防治提供新策略。

3 结语

P. gingivalis可通过调控肿瘤微环境、炎症反应、细胞迁移与侵袭、免疫逃逸及治疗耐药等多种途径，在消化系统肿瘤进展中发挥关键驱动作用，其LPS、牙龈蛋白酶、FimA等关键毒力因子介导的局部及全身免疫调控，是决定该菌影响不同消化系统肿瘤发生发展模式与分子机制的核心要素。因此，深入解析P. gingivalis调控肿瘤细胞恶性表型的具体机制，挖掘其介导消化系统肿瘤进展的关键治疗靶点与诊断标志物，并建立针对不同毒力成分的靶向干预与清除策略，有望为消化系统肿瘤的临床防治提供全新思路与有效策略。

伦理声明：不适用

作者贡献：文献查阅与整理：李婧雅、孔金玉；论文撰写：李婧雅；文章修改：孙佳春；文章审阅与经费支持：孙佳春、高社干

数据获取：不适用

利益冲突声明：无

致谢：不适用

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