Peyer’s Patch-Involved Gut Commensal Microbiota Modulates Systemic Anti-HBV Adaptive Immune Response

BackgroundAlthough the available of preventive vaccine and first-line antiviral treatment regimens,hepatitis B virus(HBV)infection remains a substantial cause of morbidity and mortality.Previous studies have revealed that the persistence of the virus in chronic hepatitis B(CHB)patients is associated with exhausted immune response,among which adaptive immune response is extremely important for the control of HBV infection.In chronic HBV infection,HBV-specific B lymphocyte and T lymphocyte function get impaired significantly,with exhausted HBV-specific CD4+T cells and CD8+T cells,the expression of IL-21,IFN-γ was also down-regulated.Gut commensal microbiota is crucial for immune homeostasis and associates with the prognosis of CHB infection.Peyer’s patch(PP),characterized by intestinal mucosa localization,involve in the gut commensal microbiota-mediated immune response.However,whether and how PPs orchestrate gut commensal microbiota-modulated anti-HBV response remain elusive.AimsThis study aims to elucidate the effect of gut commensal microbiota on immune response of germinal centers in PPs and characteristics of chronic HBV infection,as well as the effect of PPs on the "gut-liver axis" in the process of CHB,and explore the possibility of regulating systemic adaptive immune response by regulating gut commensal microbiota or immune response in PPs to cure chronic HBV infection.MethodsWe investigated the effects of gut commensal microbiota and PPs on adaptive immune responses by serology,transcriptomic,phenotypic,and functional analyses from an HBV mouse model with gut commensal microbiota and PPs depleting interventions.Results1.Depletion of gut commensal microbiota results in delayed HBV antigen clearance,and impedes anti-HBs production;2.Depletion of gut commensal microbiota disturbs systemic anti-HBV humoral immune response;3.Depletion of gut commensal microbiota impairs systemic anti-HBV cellular immunity;4.Adaptive immunity-related pathways were downregulated in PPs after the depletion of gut microbiota;5.The impact of gut commensal microbiota on HBV-related immune response is partially dependent on PPs,and PP depletion partially impeded cellular immune response in the liver and HBV clearance.ConclusionOur findings suggest that PPs orchestrate gut commensal microbiota-mediated intrahepatic anti-HBV cellular immunity,underlining the significance of remote manipulating "gut microbiota-PPs" axis for achieving optimum anti-HBV response.