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

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

doi:10.3389/fmed.2021.708495

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.

Highlights

Human hepatitis B virus (HBV) infection remains a major public health problem, affecting over 250 million population globally [1]
This study aimed to investigate the association between HBV infection, microbiome modulation and bile acids (BA) metabolism in CHB patients with mild hepatic inflammation
Exclusion criteria including: [1] cases complicated with other infectious diseases or liver diseases such as alcoholic hepatitis, non-alcoholic fatty liver disease, biliary diseases, liver cancer, liver cirrhosis, liver failure; [2] patients with history of using ursodeoxycholic acid (UDCA) supplements, or drugs lead to cholestasis such as ademetionine and silymarin, antibiotics or probiotics or herbal medicine within 24 weeks; [3] cases with gastrointestinal tract abnormalities; [4] pregnant or lactating women

Summary

Introduction

Human hepatitis B virus (HBV) infection remains a major public health problem, affecting over 250 million population globally [1]. The Na+ taurocholate co-transporting polypeptide (NTCP, encoded by SLC10A1), originally known as a major hepatic transporter for BAs [2,3,4], was recently discovered as the receptor permitting the hepatotropic entry of HBV [5,6,7]. This interesting dual role of NTCP played in both HBV entry and BA transportation was further confirmed by a report showing inhibition of taurocholate uptake by HBsAg pre-S1 polypeptide in NTCP-expressing HepG2 cells [8]. The host inflammatory response to the HBV activity modulates the BA metabolism, as excessive cytokine activities was found to suppress NTCP and leads to cholestasis and jaundice in CHB patients [19,20,21]

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