Observational Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2022; 28(35): 5188-5202
Published online Sep 21, 2022. doi: 10.3748/wjg.v28.i35.5188
Gut microbiota of hepatitis B virus-infected patients in the immune-tolerant and immune-active phases and their implications in metabolite changes
Ya-Nan Li, Na-Ling Kang, Jia-Ji Jiang, Yue-Yong Zhu, Yu-Rui Liu, Da-Wu Zeng, Fei Wang
Ya-Nan Li, Na-Ling Kang, Jia-Ji Jiang, Yue-Yong Zhu, Yu-Rui Liu, Da-Wu Zeng, Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350001, Fujian Province, China
Fei Wang, Department of Pharmacy, Fujian Geriatric Hospital, Fuzhou 350001, Fujian Province, China
Author contributions: Zeng DW and Liu YR conceived and designed the experiments; Zeng DW and Li YN performed the experiments; Li YN, Kang NL, and Wang F analyzed the data; Zhu YY and Jiang JJ contributed reagents/materials/analysis tools; Zeng DW and Li YN wrote the manuscript.
Supported by the Fujian Provincial Health Technology Project, No. 2019-ZQN-60; and the Fujian Provincial Department of Science and Technology, No. 2019J01432.
Institutional review board statement: Institutional review board approval of our hospital was obtained for this study.
Informed consent statement: All patients involved in this study gave their informed consent.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE statement, and the manuscript was prepared and revised according to the STROBE statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Da-Wu Zeng, MD, Associate Chief Physician, Associate Professor, Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, No. 20 Chazhong Road, Fuzhou 350001, Fujian Province, China. zengdw1980@fjmu.edu.cn
Received: April 12, 2022
Peer-review started: April 12, 2022
First decision: July 13, 2022
Revised: July 26, 2022
Accepted: August 22, 2022
Article in press: August 22, 2022
Published online: September 21, 2022
Processing time: 151 Days and 7.2 Hours
ARTICLE HIGHLIGHTS
Research background

Chronic hepatitis B virus (HBV) infection (CHB) represents a public health problem that may progress to cirrhosis and hepatocellular carcinoma (HCC). HBV-infected individuals in immune tolerance (IT) are generally not recommended for anti-HBV treatment, owing to the absence of curative treatment and the evidence of a low risk of progressive liver injury in the IT patients. However, recent studies indicated hepatocarcinogenesis may occur in IT-phase patients; the body’s IT status is a key factor affecting the outcome of the disease. Therefore, finding out the factors that affect the prognosis of HBV infection is of paramount significance for the rapid elimination of virus and the reduction of CHB.

Research motivation

The bacterial diversity level and composition varied between CHB, hepatitis B-related liver cirrhosis, and HCC. Gut microbiota of healthy controls is more consistent, whereas those of CHB, hepatitis B-related liver cirrhosis and HCC varied substantially. As the first phase of HBV progression, IT phase provides a favorable immune environment for HBV invasion and long-term existence, then transitions to immune clearance in the third decade. Therefore, in-depth study of the disease status and changes in the body during the IT phase is conducive to the development of new antiviral treatment methods to break the IT of the body and improve the antiviral efficacy and thus improve the long-term prognosis.

Research objectives

This study aimed to find some potential bacteria, linking different pathological mechanisms of IT phase HBV infection and some related metabolites to the IT phase of CHB infection.

Research methods

Clinical fecal samples from healthy individuals and patients in the IT and IA phases of HBV infection were collected. Next, non-target metabolomics, bioinformatics, and 16S rDNA sequencing analyses were performed.

Research results

A total of 293 different metabolites in 14 phyla, 22 classes, 29 orders, 51 families, and 190 genera were identified. The four phyla of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria were the most abundant, accounting for 99.72%, 99.79%, and 99.55% in the healthy controls, IT-phase patients, and IA-phase patients, respectively. We further identified 16 genera with different richness in the IT phase and IA phase of HBV infection. Of the 134 named metabolites, 57 were upregulated and 77 were downregulated. A total of 101 different metabolic functions were predicted in this study, with 6 metabolic pathways having the highest enrichments, namely carbohydrate metabolism (14.85%), amino acid metabolism (12.87%), lipid metabolism (11.88%), metabolism of cofactors and vitamins (11.88%), xenobiotic biodegradation (9.9%), and metabolism of terpenoids and polyketides (7.92%).

Research conclusions

The composition of the gut microbiota changed in the early stages of HBV infection, and changes in the composition of the gut microbiota can significantly alter gene function, which may have a potential role in HBV-infected patients.

Research perspectives

It is relatively difficult to fully understand the causal relationship between gut microbiota and HBV-induced chronic liver disease at different stages in this real-world cross-sectional study. Nevertheless, it should be noted that germ-free animals are good models to study the effect of gut microbiota on human diseases. In a future study, it is imperative to use germ-free animal models and additional biofunctional assays to reveal the cause-effect relationship between gut microbiota and chronic HBV infection.