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

Abstract

<h3>Background</h3><p>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.</p><h3>Methods</h3><p>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.</p><h3>Findings</h3><p>All patients (n = 110) were characterized into three distinct microbial clusters by their dominant genus: c-<em>Bacteroides,</em> c-<em>Blautia,</em> and c-<em>Prevotella.</em> Patients with c-<em>Bacteroides</em> 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-<em>Bacteroides</em> was associated with higher odds of plasma HBV-DNA undetectability when compared with non-c-<em>Bacteroides</em> clusters (OR 3.49, 95% CI 1.43–8.96, p = 0.01). c-<em>Blautia</em> 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 <em>Escherichia coli</em> 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 <em>Escherichia coli</em>.</p><h3>Interpretation</h3><p>Collectively, unique bacterial signatures, including c-<em>Bacteroides</em> and <em>c-Blautia</em>, were associated with virological undetectability and fibrosis evolution during NAs therapy in chronic HBV, setting up intriguing possibilities in optimizing HBV treatment.</p>