Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Microbiol.

Sec. Microorganisms in Vertebrate Digestive Systems

Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1683451

This article is part of the Research TopicMicrobiome and its Roles in Disease Diagnosis and Treatment: Pathogen Resistance Spectrum, Metabolism, Risk Model, and Vaccine DesignView all articles

Species-Level Enterosignatures Predict Clinical Phenotypes in Chronic Hepatitis B and Causal Triangulation of Gut-Metabolite-CHB Interactions

Provisionally accepted
  • 1Nankai University, Tianjin, China
  • 2Chinese Center for Disease Control and Prevention, Beijing, China
  • 3Shandong University, Jinan, China
  • 4Capital Medical University Beijing Ditan Hospital, Beijing, China
  • 5Dynamiker Biotechnology Tianjin Co Ltd, Tianjin, China
  • 6Shanghai Public Health Clinical Center, Shanghai, China

The final, formatted version of the article will be published soon.

Chronic hepatitis B remains a significant global health challenge, with research indicating the gut microbiota's influence on disease progression, although investigations have primarily been limited to the genus level. This study conducted species-level research using the HGMAD to examine differences in gut microbiota between CHB patients and healthy controls, to investigate enterotype associations with CHB, to assess the predictive capacity of enterosignatures for CHB phenotypes, and to determine causal relationships among gut microbiota, metabolites, and CHB. The cross-sectional investigation included 129 CHB patients and 58 HC, with fecal samples analyzed by 16S rRNA gene sequencing of the V3–V4 region. Significant differences in α-diversity and β-diversity (P < 0.05) were observed between the CHB and HC groups. Taxonomic analysis revealed that the high prevalent bacteria group was lower in CHB patients (61.15%) than in HC (98.05%), indicating increased gut microbiota heterogeneity in CHB. Among known bacterial species, pathogens showed higher prevalence in CHB patients (22.80% vs 11.49%), with several potential enteropathogenic bacteria enriched in CHB. Dimensionality reduction and clustering analysis of gut microbiota in CHB patients revealed two distinct enterotypes: ET-P(Prevotella) and ET-B(Bacteroides). ET-P demonstrated a correlation with elevated levels of HBV DNA, HBsAg, HBeAg, CD4+T-cell count and CD8+T-cell count, and AFP. The enterosignatures of ET-P and ET-B effectively predicted key clinical indicators: the area under the curve (AUC) was 0.78 (95% confidence interval [CI]: 0.69–0.86) for HBeAg levels, 0.86 (95% CI: 0.79– 0.93) for HBV DNA levels, 0.75 (95% CI: 0.65–0.84) for AFP status, and 0.85 (95% CI: 0.77–0.92) for CD4+T-cell count status. Mendelian randomization analysis, provided genetic evidence for causal relationships between 16 species-level gut microbes and CHB. An elevated abundance of Prevotella copri was associated with an increased risk of CHB (OR = 1.42, 95% CI: 1.01–2.00, P = 0.045). Additionally, mediation MR analyses revealed potential metabolite-mediated mechanisms underlying the role of gut microbiota in CHB. Two enterotypes were identified in CHB patients, ET-P demonstrated positive associations with HBV activity and viral load. The enterosignatures derived from both enterotypes effectively predicted key CHB clinical indicators, establishing causal links and potential underlying mechanisms between gut microbiota and CHB.

Keywords: Chronic hepatitis B, species level, Gut Microbiota, enterotype, Genetic causation

Received: 11 Aug 2025; Accepted: 07 Oct 2025.

Copyright: © 2025 Yuan, Chen, Yang, Li, Lu, Pu, Sun, Lin, Lu, Zhu, Zheng and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Han Zheng, zhenghan@icdc.cn

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.