Distinct Bile Acid Profiles in Patients With Chronic Hepatitis B Virus Infection Reveal Metabolic Interplay Between Host, Virus and Gut Microbiome

Zeyu Sun; Chenjie Huang; Yixian Shi; Rusha Wang; Jun Fan; Ye Yu; Zhehua Zhang; Kundan Zhu; Minwei Li; Qin Ni; Zhi Chen; Min Zheng; Zhenggang Yang

doi:10.3389/fmed.2021.708495

Distinct Bile Acid Profiles in Patients With Chronic Hepatitis B Virus Infection Reveal Metabolic Interplay Between Host, Virus and Gut Microbiome

Front Med (Lausanne). 2021 Oct 4:8:708495. doi: 10.3389/fmed.2021.708495. eCollection 2021.

Authors

Zeyu Sun¹, Chenjie Huang^{1

2}, Yixian Shi^{1

3}, Rusha Wang¹, Jun Fan¹, Ye Yu¹, Zhehua Zhang¹, Kundan Zhu¹, Minwei Li¹, Qin Ni¹, Zhi Chen¹, Min Zheng¹, Zhenggang Yang¹

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
² Kidney Disease Center, Shulan (Hangzhou) Hospital, Hangzhou, China.
³ Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.

Abstract

Hepatitis B virus (HBV) can hijack the host bile acids (BAs) metabolic pathway during infection in cell and animal models. Additionally, microbiome was known to play critical role in the enterohepatic cycle of BAs. However, the impact of HBV infection and associated gut microbiota on the BA metabolism in chronic hepatitis B (CHB) patients is unknown. This study aimed to unveil the distinct BA profiles in chronic HBV infection (CHB) patients with no or mild hepatic injury, and to explore the relationship between HBV, microbiome and BA metabolism with clinical implications. Methods: Serum BA profiles were compared between CHB patients with normal ALT (CHB-NALT, n = 92), with abnormal ALT (CHB-AALT, n = 34) and healthy controls (HCs, n = 28) using UPLC-MS measurement. Hepatic gene expression in CHB patients were explored using previously published transcriptomic data. Fecal microbiome was compared between 30 CHB-NALT and 30 HCs using 16S rRNA sequencing, and key microbial function was predicted by PICRUSt analysis. Results: Significant higher percentage of conjugated BAs and primary BAs was found in CHB patients even without apparent liver injury. Combinatory BA features can discriminate CHB patients and HCs with high accuracy (AUC = 0.838). Up-regulation of BA importer Na+ taurocholate co-transporting peptide (NTCP) and down-regulation of bile salt export pump (BSEP) was found in CHB-NALT patients. The microbial diversity and abundance of Lactobacillus, Clostridium, Bifidobacterium were lower in CHB-NALT patients compared to healthy controls. Suppressed microbial bile salt hydrolases (BSH), 7-alpha-hydroxysteroid dehydrogenase (hdhA) and 3-dehydro-bile acid Delta 4, 6-reductase (BaiN) activity were found in CHB-NALT patients. Conclusion: This study provides new insight into the BA metabolism influenced both by HBV infection and associated gut microbiome modulations, and may lead to novel strategy for clinical management for chronic HBV infection.

Keywords: NTCP; bile acid metabolism; chronic hepatitis B; gut microbiome; metabolomics.