目的：探讨牙龈卟啉单胞菌（P. gingivalis）诱导的炎症微环境在小鼠食管鳞状细胞癌（ESCC）发生中的作用。方法：将180只C57BL/6小鼠随机分为6组，即对照组、牙龈卟啉单胞菌组、4NQO组、4NQO牙龈卟啉单胞菌组、4NQO牙龈卟啉单胞菌塞来昔布组、4NQO牙龈卟啉单胞菌抗生素鸡尾酒组（ ABC，包括甲硝唑、新霉素、氨苄西林、万古霉素）组，每组30只，采用随机数字表法。所有小鼠均通过饮用水中 ABC 治疗 2 周而恢复正常。接下来的2周内，对照组和牙龈卟啉单胞菌组小鼠给予饮用水，其余4组则在饮用水中加入30μg/ml 4NQO。第11-12周，对牙龈卟啉单胞菌组、4NQO牙龈卟啉单胞菌组、4NQO牙龈卟啉单胞菌塞来昔布组、4NQO牙龈卟啉单胞菌ABC组小鼠进行口腔第二磨牙结扎，然后口腔牙龈卟啉单胞菌感染，每周三次，持续 24 周（第 11-34 周）。第13-34周，4NQO牙龈卟啉单胞菌塞来昔布组和4NQO牙龈卟啉单胞菌ABC组小鼠分别给予塞来昔布和ABC，疗程22周。 34 周结束时，检查了总体和微观变化，然后通过 RT-qPCR 和免疫组织化学检查小鼠食管中炎症分子和肿瘤分子的表达谱。结果：34周时，单独4NQO治疗对乳头过度增殖灶、病变面积和食管壁厚度没有影响，但显着增强过度增殖灶（中位数1.00，P＜0.05）和轻/中度不典型增生（中位数2.00，P＜0.01）。此外，IL-6[8.35(3.45,8.99)]、IL-1β[6.90(2.01,9.72)]、TNF-α[12.04(3.31,14.08)]、c-myc[2.21(1.80)的表达水平,3.04)]、pSTAT3、Ki-67和pH2AX均高于对照组。 4NQO牙龈卟啉单胞菌组食管黏膜病理变化在乳头过度增生灶（中位2.00）、病变面积（中位2.51 mm2）、食管壁厚度（中位172.52 μm）方面明显更明显。 、过度增殖病灶（中位数1.00，P＜0.05）和轻/中度不典型增生病灶（中位数1.00，P＜0.01）。 4NQO牙龈卟啉单胞菌组小鼠IL-6[12.27(5.35,22.08)]、IL-1β[13.89(10.04,15.96)]、TNF-α[19.56(6.07,20.36)]、 IFN-γ[11.37(8.23,20.07)]、c-myc[2.62(1.51,4.25)]、cyclin D1[4.52(2.68,7.83)]、核pSTAT3、COX-2、Ki-67和pH2AX显着与对照组小鼠相比有所增加。在4NQO牙龈卟啉单胞菌组的小鼠中，塞来昔布显着减弱了患病区域、侵袭性恶性病灶以及pSTAT3和pH2AX的表达。 ABC 治疗显着降低了乳头状过度增殖灶、侵袭性恶性灶和 pSTAT3 表达，但不降低 pH2AX。结论：牙龈卟啉单胞菌通过诱导由 4NQO 诱导的 DNA 损伤引发的炎症微环境，促进小鼠食管鳞状细胞癌的发生。用 ABC 或抗炎干预清除牙龈卟啉单胞菌有望通过阻断 IL-6/STAT3 信号传导和改善炎症来预防食管鳞状细胞恶性发病机制。

Objective: To investigate the role of an inflammatory microenvironment induced by Porphyromonasgingivalis (P. gingivalis) in the occurrence of esophageal squamous cell carcinoma (ESCC) in mice. Methods: A total of 180 C57BL/6 mice were randomly divided into 6 groups, i.e. control group, P. gingivalis group, 4NQO group, 4NQO + P. gingivalis group, 4NQO + P. gingivalis + celecoxib group, and 4NQO + P. gingivalis + antibiotic cocktail (ABC, including metronidazole, neomycin, ampicillin, and vancomycin) group, with 30 mice in each group, using the random number table. All mice were normalized by treatment with ABC in drinking water for 2 weeks. In the following 2 weeks, the mice in the control group and the P. gingivalis group were given drinking water, while the other 4 groups were treated with 30 μg/ml 4NQO in the drinking water. In weeks 11-12, the mice in the P. gingivalis group, the 4NQO + P. gingivalis group, the 4NQO + P. gingivalis + celecoxib group, and the 4NQO + P. gingivalis + ABC group were subjected to ligation of the second molar in oral cavity followed by oral P. gingivalis infection thrice weekly for 24 weeks in weeks 11-34. In weeks 13-34, the mice in 4NQO + P. gingivalis+celecoxib group and 4NQO + P. gingivalis + ABC group were administered with celecoxib and ABC for 22 weeks, respectively. At the end of 34 weeks, gross and microscopic alterations were examined followed by RT-qPCR and immunohistochemistry to examine the expression profiles of inflammatory- and tumor-molecules in esophagi of mice. Results: At 34 weeks, 4NQO treatment alone did not affect the foci of papillary hyperproliferation, diseased area, and the thickness of the esophageal wall, but significantly enhanced the foci of hyperproliferation (median 1.00, P＜0.05) and mild/moderate dysplasia (median 2.00, P＜0.01). In addition, the expression levels of IL-6 [8.35(3.45,8.99)], IL-1β [6.90(2.01,9.72)], TNF-α [12.04(3.31,14.08)], c-myc [2.21(1.80,3.04)], pSTAT3, Ki-67, and pH2AX were higher than those in the control group. The pathological changes of the esophageal mucosa were significantly more overt in the 4NQO + P. gingivalis group in terms of the foci of papillary hyperproliferation (median 2.00), diseased area (median 2.51 mm2), the thickness of the esophageal wall (median 172.52 μm), the foci of hyperproliferation (median 1.00, P＜0.05), and mild/moderate dysplasia (median 1.00, P＜0.01). In mice of the 4NQO + P. gingivalis group, the expression levels of IL-6 [12.27(5.35,22.08)], IL-1β [13.89(10.04,15.96)], TNF-α [19.56(6.07,20.36)], IFN-γ [11.37(8.23,20.07)], c-myc [2.62(1.51,4.25)], cyclin D1 [4.52(2.68,7.83)], nuclear pSTAT3, COX-2, Ki-67, and pH2AX were significantly increased compared with the mice in the control group. In mice of the 4NQO + P. gingivalis group, the diseased area, invasive malignant foci as well as pSTAT3 and pH2AX expression were significantly blunted by celecoxib. Treatment with ABC markedly reduced the papillary hyperproliferative foci, invasive malignant foci, and pSTAT3 expression but not pH2AX. Conclusions: P. gingivalis promotes the occurrence of esophageal squamous cell carcinoma in mice by inducing an inflammatory microenvironment primed with 4NQO induced DNA damage. Clearance of P. gingivalis with ABC or anti-inflammatory intervention holds promise for prevention of esophageal squamous cell malignant pathogenesis via blockage of IL-6/STAT3 signaling and amelioration of inflammation.