核苷（酸）类似物治疗慢性乙型肝炎患者的病毒学应答与拟杆菌为主的肠道微生物群有关。

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

机构信息

Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.

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.

出版信息

EBioMedicine. 2024 May;103:105101. doi: 10.1016/j.ebiom.2024.105101. Epub 2024 Apr 6.

DOI:10.1016/j.ebiom.2024.105101

PMID:38583259

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11002572/

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).

摘要

背景

肠道菌群失调存在于慢性乙型肝炎病毒（HBV）感染中。在这项研究中，我们整合了微生物组和代谢组学分析，以研究肠道微生物组在核苷（酸）类似物（NAs）治疗病毒学应答中的作用。

方法

前瞻性招募慢性 HBV 患者进行脂肪变性和纤维化评估，通过肝弹性成像进行，同时进行全长 16S 测序以确定组成性肠道微生物群的差异。通过液相色谱-串联质谱法定量测定空腹血浆胆汁酸。

发现

所有患者（n=110）根据其优势属分为三个不同的微生物群：c-拟杆菌、c-布劳特氏菌和 c-普雷沃氏菌。与其他菌群相比，c-拟杆菌患者的胆汁酸水平更高，7-α-羟甾醇脱氢酶（次级胆汁酸生物转化）增加。在 NAs 治疗患者（n=84）中，与非 c-拟杆菌菌群相比，c-拟杆菌与血浆 HBV-DNA 不可检测的几率更高（OR 3.49，95%CI 1.43-8.96，p=0.01）。c-布劳特氏菌与晚期纤维化呈正相关（OR 2.74，95%CI 1.09-7.31，p=0.04）。在未接受治疗的患者中未发现这种关联。在治疗期间（中位治疗时间 98.1 个月），尽管 HBV DNA 不可检测，但仍发现大肠杆菌相对丰度增加（0.21%比 0.03%，p=0.035）的患者存在晚期纤维化。在晚期纤维化患者中观察到 l-色氨酸生物合成富集，其与大肠杆菌呈正相关。