小类杆菌调节肠杆菌丰度并抑制TLR4/NF-κB通路从而改善慢性乙型肝炎的作用机制

Recently, the remission or clearance of HBV infection by the host immune response regulated by fecal microbiota transplantation are highlighted while the causality mechanism research by single bacterium strain still lacks. In our previous study, we found that Dialister succinatiphilus from healthy individuals induced HBsAg decline in chronic hepatitis B (CHB) mouse. Meanwhile, the abundance of Enterobacteriaceae, LPS content, HBsAg and cytokine declined in CHB patients who positively responded to fecal microbiota transplantation. Report has shown that LPS which is secreted by Enterobacteriaceae, influence the immune response by TLR4 pathway. Given this, we speculate that D.succinatiphilus regulate the abundance of Enterobacteriaceae and LPS, improve the immune response of mouse model via inhibiting TLR4/NF-κB pathway. To test the hypothesis, we will investigate:1)the changes of gut bacterial community composition and intestinal mucosa colonization, especially that of Enterobacteriaceae exerted by D.succinatiphilus; 2)influence of D.succinatiphilus on inflammatory cytokines via TLR4/NF-κB; 3)the mechanism how D.succinatiphilus influence the immune cell and liver microenvironmental damage repair. We aim to reveal the immune response mechanism induced by D.succinatiphilus and provide theory basis and technology foundation for the clinical intervention of CHB patients by adjusting the gut microbiota.

粪菌移植可改善慢性乙型肝炎患者临床指征，但其中关键菌株改善乙肝的作用机制尚不清楚。本课题组前期发现源自健康供体的小类杆菌可使乙肝模型小鼠的HBsAg含量下降，而且粪菌移植治疗有效的乙肝患者肠杆菌丰度与内毒素LPS含量降低，NF-κB通路相关的炎症因子及HBsAg含量下降，结合肠杆菌分泌的LPS可被TLR4受体识别从而影响机体免疫应答的文献报道，我们提出小类杆菌调节肠杆菌丰度并抑制TLR4/NF-κB通路从而改善乙肝模型小鼠的假说。为此，本课题将：1、明确小类杆菌对乙肝模型小鼠的肠杆菌丰度及其肠粘膜定植的影响；2、阐明小类杆菌对TLR4/NF-κB通路及相关细胞因子表达的调控作用；3、探讨小类杆菌改善乙肝模型小鼠免疫应答及微环境损伤修复的作用特点。从而揭示小类杆菌诱导宿主免疫应答的作用机制，为粪菌移植或者肠菌制剂治疗乙肝提供理论依据及技术基础。

粪菌移植可改善慢性乙型肝炎患者临床指征，但其中关键菌株改善乙肝的作用机制尚不清楚。本课题组前期发现源自健康供体的小类杆菌可使乙肝模型小鼠的HBsAg含量下降，而且粪菌移植治疗有效的乙肝患者肠杆菌丰度与内毒素LPS含量降低，NF-κB通路相关的炎症因子及HBsAg含量下降，结合肠杆菌分泌的LPS可被TLR4受体识别从而影响机体免疫应答的文献报道，我们提出小类杆菌调节肠杆菌丰度并抑制TLR4/NF-κB通路从而改善乙肝模型小鼠的假说。为此，本课题将：1、明确小类杆菌对乙肝模型小鼠的肠杆菌丰度及其肠粘膜定植的影响；2、阐明小类杆菌对TLR4/NF-κB通路及相关细胞因子表达的调控作用；3、探讨小类杆菌改善乙肝模型小鼠免疫应答及微环境损伤修复的作用特点。从而揭示小类杆菌诱导宿主免疫应答的作用机制，为粪菌移植或者肠菌制剂治疗乙肝提供理论依据及技术基础。基于本项目的实施，在本领域专业期刊发表SCI论文(JCR 一区)8篇,申请国家专利18项，参与领域内国际/国内学术会议并进行会议报告5人次，培养研究生4名。本项目的研究为从微生态角度理解乙肝疾病的发生发展提供了理论基础。