Gut Microbiota Dysbiosis Strengthens Kupffer Cell-mediated Hepatitis B Virus Persistence through Inducing Endotoxemia in Mice  

作　　者：Wenqing Zhou Jinzhuo Luo Xiaohong Xie Shangqing Yang Dan Zhu Hongming Huang Dongliang Yang Jia Liu 

机构地区：[1]Department of Infectious Diseases,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China

出　　处：《Journal of Clinical and Translational Hepatology》2022年第1期17-25,共9页临床与转化肝病杂志（英文版）

基　　金：This work was supported by grants from the National Sci-ence and Technology Major Project for Infectious Diseases of China(Nos.2017ZX10202203-007-006,2017ZX10202202-001-009,2017ZX10202202-002-008,2017ZX10202201-002-003);the National Natural Science Foundation of China(Nos.81461130019,91642118,91742114,8181101231);the Integrated Innovative Team Project for Major Human Dis-eases Program of Tongji Medical College,Huazhong Universi-ty of Science and Technology(HUST),the Double First-Class Disciplines Program of HUST(International Joint Laboratory for Infection and Immunity),the International Cooperation Base of Hubei Province for Infection and Immunity,and Deutsche Forschungsgemeinschaft(Transregio TRR60).

摘　　要：Background and Aims:Change of gut microbiota com-position is associated with the outcome of hepatitis B virus(HBV)infection,yet the related mechanisms are not fully characterized.The objective of this study was to investigate the immune mechanism associated with HBV persistence induced by gut microbiota dysbiosis.Methods:C57BL/6 mice were sterilized for gut-microbiota by using an antibi-otic(ABX)mixture protocol,and were monitored for their serum endotoxin(lipopolysaccharide[LPS])levels.An HBV-replicating mouse model was established by performing HBV-expressing plasmid pAAV/HBV1.2 hydrodynamic injec-tion(HDI)with or without LPS,and was monitored for se-rum hepatitis B surface antigen,hepatitis B e antigen,HBV DNA,and cytokine levels.Kupffer cells(KCs)were purified from antibiotic-treated mice and HBV-replicating mice and analyzed for IL-10 production and T cell suppression ability.Results:ABX treatment resulted in increased serum LPS levels in mice.The KCs separated from both ABX-treated and LPS-treated HBV-replicating mice showed significantly increased IL-10 production and enhanced ability to suppress IFN-γproduction of TCR-activated T cells than the KCs sep-arated from their counterpart controls.HDI of pAAV/HBV1.2 in combination with LPS in mice led to a delayed HBV clear-ance and early elevation of serum IL-10 levels compared to pAAV/HBV1.2 HDI alone.Moreover,IL-10 function blockade or KC depletion led to accelerated HBV clearance in LPS-treated HBV-replicating mice.Conclusions:Our results suggest that dysbiosis of the gut microbiota in mice leads to endotoxemia,which induces KC IL-10 production and strengthens KC-mediated T cell suppression,and thus fa-cilitates HBV persistence.

关 键 词：Chronic hepatitis B Gut microbiota Kupffer cells T cell IL-10 

分 类 号：R51[医药卫生—内科学]