Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus

Tixiao Wang; Yuchen Fan; Siyu Tan; Zehua Wang; Mengzhen Li; Xiaowei Guo; Xiangguo Yu; Qinghai Lin; Xiaojia Song; Leiqi Xu; Lixiang Li; Shiyang Li; Lifen Gao; Xiaohong Liang; Chunyang Li; Chunhong Ma

doi:10.1016/j.xcrm.2024.101822

Probiotics and their metabolite spermidine enhance IFN-γ⁺CD4⁺ T cell immunity to inhibit hepatitis B virus

Cell Rep Med. 2024 Nov 7:101822. doi: 10.1016/j.xcrm.2024.101822. Online ahead of print.

Authors

Tixiao Wang¹, Yuchen Fan², Siyu Tan³, Zehua Wang³, Mengzhen Li³, Xiaowei Guo³, Xiangguo Yu³, Qinghai Lin³, Xiaojia Song³, Leiqi Xu⁴, Lixiang Li⁴, Shiyang Li⁵, Lifen Gao³, Xiaohong Liang⁶, Chunyang Li⁷, Chunhong Ma⁸

Affiliations

¹ Department of Endocrinology and Metabolism and Department of Immunology, Qilu Hospital, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
² Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
³ Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
⁴ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
⁵ Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China.
⁶ Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
⁷ Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
⁸ Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].

PMID: 39536754
DOI: 10.1016/j.xcrm.2024.101822

Abstract

The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ⁺CD4⁺ T cell immune response. Depletion of CD4⁺ T cells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ⁺CD4⁺ T cell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ⁺CD4⁺ T cell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.

Keywords: IFN-γ(+)CD4(+) T cell; autophagy; fecal microbiota transplantation; gut microbiota; hepatitis B virus; probiotics; spermidine.