Virological response to nucleos(t)ide analogues treatment in chronic hepatitis B patients is associated with Bacteroides-dominant gut microbiome

Saisai Zhang; Hau-Tak Chau; Hein Min Tun; Fung-Yu Huang; Danny Ka-Ho Wong; Lung-Yi Mak; Man-Fung Yuen; Wai-Kay Seto

doi:10.1016/j.ebiom.2024.105101

Virological response to nucleos(t)ide analogues treatment in chronic hepatitis B patients is associated with Bacteroides-dominant gut microbiome

EBioMedicine. 2024 Apr 6:103:105101. doi: 10.1016/j.ebiom.2024.105101. Online ahead of print.

Authors

Saisai Zhang¹, Hau-Tak Chau¹, Hein Min Tun², Fung-Yu Huang¹, Danny Ka-Ho Wong³, Lung-Yi Mak³, Man-Fung Yuen⁴, Wai-Kay Seto⁵

Affiliations

¹ Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
² The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; System Microbiology and Antimicrobial Resistance (SMART) Lab, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
³ Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
⁴ Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China. Electronic address: mfyuen@hkucc.hku.hk.
⁵ Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Electronic address: wkseto@hku.hk.

Abstract

Background: Gut dysbiosis is present in chronic hepatitis B virus (HBV) infection. In this study, we integrated microbiome and metabolome analysis to investigate the role of gut microbiome in virological response to nucleos(t)ide analogues (NAs) treatment.

Methods: Chronic HBV patients were prospectively recruited for steatosis and fibrosis assessments via liver elastography, with full-length 16S sequencing performed to identify the compositional gut microbiota differences. Fasting plasma bile acids were quantified by liquid chromatography-tandem mass spectrometry.

Findings: All patients (n = 110) were characterized into three distinct microbial clusters by their dominant genus: c-Bacteroides, c-Blautia, and c-Prevotella. Patients with c-Bacteroides had a higher plasma ursodeoxycholic acids (UDCA) level and an increase in 7-alpha-hydroxysteroid dehydrogenase (secondary bile acid biotransformation) than other clusters. In NAs-treated patients (n = 84), c-Bacteroides was associated with higher odds of plasma HBV-DNA undetectability when compared with non-c-Bacteroides clusters (OR 3.49, 95% CI 1.43-8.96, p = 0.01). c-Blautia was positively associated with advanced fibrosis (OR 2.74, 95% CI 1.09-7.31, p = 0.04). No such associations were found in treatment-naïve patients. Increased Escherichia coli relative abundance (0.21% vs. 0.03%, p = 0.035) was found in on-treatment patients (median treatment duration 98.1 months) with advanced fibrosis despite HBV DNA undetectability. An enrichment in l-tryptophan biosynthesis was observed in patients with advanced fibrosis, which exhibited a positive correlation with Escherichia coli.

Interpretation: Collectively, unique bacterial signatures, including c-Bacteroides and c-Blautia, were associated with virological undetectability and fibrosis evolution during NAs therapy in chronic HBV, setting up intriguing possibilities in optimizing HBV treatment.

Funding: This study was supported by the Guangdong Natural Science Fund (2019A1515012003).

Keywords: Bacteroides; Bile acid; Fibrosis; HBV; Microbiota.