Background Recently, intestinal microbiome has been involved in hepatic diseases due to the immunologic and metabolic communication between liver and intestine. Initiation of hepatocellular carcinoma (HCC) frequently attributes to conspiracy between immune cells and infectious carcinogens. Here, the hypothesis that the tumorigenesis of HCC with HBV infection will be aggravated by specific intestinal bacteria was verified in viral transgenic mouse models. Methods Comparative 16S rRNA sequencing was adopted to observe the intestinal enrichment of Helicobacter hepaticus in HCC. Oral administration of Helicobacter hepaticus was carried out to evaluate its hepatic carcinogenic effect in HBV transgenic mice or wildtype C57BL/6. The livers of experimental mice were collected and examined for the degree of tumorigenesis. Results We found that Helicobacter hepaticus more likely colonized at lower colon of HBV-infected mice with HCC, compared with C57BL/6 and HBV-infected mice without neoplasm. Pretreatment of Helicobacter hepaticus in transgenic mice aggravated tumor formation, with higher incidence, more tumor nodule and higher serum AFP. Then, a cytokines expression patterns with inclined IFN-γ, IFN-γR1, IL-17 and IL-23 was found in HBV-infected mice with Helicobacter hepaticus. Furthermore, innate lymphoid cells, especially Th17 and NK cells which can secret IL-17 and IFN-γ respectively, might be recruited by Helicobacter hepaticus cooperated with HBV. Besides, increased expression of CD69, NKG2D and IFN-γ showed activation of cytokine production in intrahepatic NK cells. Finally, IFN-γ decreased E-cadherin expression through p-STAT1 pathway, resulting in epithelial-mesenchymal transition with inclined expression of Snail2, SIP1 and CXCR4 in vitro. p-STAT1 inhibitor was able to reverse the expression of E-cadherin and EMT resulted from IFN-γ function on HBsAg-positive hepatocytes. Conclusions Helicobacter hepaticus generate a detrimental immune microenvironment by IFN-γ/p-STAT1 axis which can promote the tumorigenesis of hepatitis B via recruiting innate lymphoid cells.

中文翻译：

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源自先天淋巴细胞的细胞因子有助于肝螺杆菌加重病毒转基因小鼠的肝细胞肿瘤发生。

背景 最近，由于肝脏和肠道之间的免疫和代谢交流，肠道微生物组已参与肝脏疾病。肝细胞癌 (HCC) 的发生通常归因于免疫细胞和传染性致癌物之间的共谋。在这里，病毒转基因小鼠模型证实了特定肠道细菌会加重 HBV 感染 HCC 的肿瘤发生的假设。方法采用比较16S rRNA测序法观察肝螺杆菌在HCC中的肠道富集情况。进行肝螺杆菌的口服给药以评估其在HBV转基因小鼠或野生型C57BL/6中的致癌作用。收集实验小鼠的肝脏并检查肿瘤发生的程度。结果 我们发现，与没有肿瘤的 C57BL/6 和 HBV 感染小鼠相比，肝螺杆菌更可能在 HBV 感染的 HCC 小鼠的下结肠定植。转基因小鼠肝螺杆菌预处理可加重肿瘤形成，发病率较高，肿瘤结节较多，血清AFP较高。然后，在HBV感染的肝螺杆菌小鼠中发现了具有倾斜的IFN-γ、IFN-γR1、IL-17和IL-23的细胞因子表达模式。此外，先天性淋巴细胞，尤其是Th17和NK细胞，分别分泌IL-17和IFN-γ，可能被肝螺杆菌与HBV协同募集。此外，CD69、NKG2D 和 IFN-γ 的表达增加表明肝内 NK 细胞中细胞因子产生的激活。最后，IFN-γ 通过 p-STAT1 通路降低 E-cadherin 的表达，导致上皮-间质转化，在体外倾斜表达 Snail2、SIP1 和 CXCR4。p-STAT1 抑制剂能够逆转 HBsAg 阳性肝细胞上 IFN-γ 功能导致的 E-cadherin 和 EMT 的表达。结论肝螺杆菌通过IFN-γ/p-STAT1轴产生有害的免疫微环境，通过募集先天淋巴细胞促进乙型肝炎的肿瘤发生。