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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Lactococcus garvieae aggravates cholestatic liver disease by increasing intestinal permeability and enhancing bile acid reabsorption
Man Liu, Ying-Lan Ji, Yu-Jie Hu, Ying-Xi Su, Jie Yang, Xiao-Yi Wang, Hong-Yu Chu, Xue Zhang, Shi-Jing Dong, Hui Yang, Yu-Hang Liu, Si-Min Zhou, Li-Ping Guo, Ying Ran, Yan-Ni Li, Jing-Wen Zhao, Zhi-Guang Zhang, Mei-Yu Piao, Lu Zhou
Man Liu, Ying-Lan Ji, Yu-Jie Hu, Ying-Xi Su, Jie Yang, Hong-Yu Chu, Xue Zhang, Shi-Jing Dong, Hui Yang, Yu-Hang Liu, Si-Min Zhou, Li-Ping Guo, Ying Ran, Yan-Ni Li, Jing-Wen Zhao, Mei-Yu Piao, Lu Zhou, Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
Ying-Lan Ji, Zhi-Guang Zhang, Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Jie Yang, Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin 300308, China
Xiao-Yi Wang, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin 300170, China
Co-first authors: Man Liu and Ying-Lan Ji.
Co-corresponding authors: Mei-Yu Piao and Lu Zhou.
Author contributions: Zhou L, Piao MY, Liu M and Ji YL designed the study; Zhou L and Liu M contributed to the financial support; Liu M, Ji YL and Hu YJ conducted the experimental research, and acquired and analyzed the data; Hu YJ, Su YX, Yang J, Wang XY, Chu HY, Zhang X, Dong SJ, Yang H, Liu YH, Zhou SM, Guo LP, Ran Y, Li YN, Zhao JW, and Zhang ZG provided the research software and experimental methods; Liu M, Hu YJ and Ji YL wrote the original draft. All authors reviewed and approved the final version of the article. Liu M and Ji YL contributed equally to this work as co-first authors. Both Zhou L and Piao MY have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Zhou L applied for and obtained the funds for this research project. Zhou L conceptualized, designed, and supervised the whole process of the project. Piao MY was instrumental and responsible for data re-analysis and re-interpretation, comprehensive literature search, preparation and submission of the current version of the manuscript. This collaboration between Zhou L and Piao MY is crucial for the publication of this manuscript.
Supported by Tianjin Health Research Project, No. TJWJ2024QN005; and Beijing iGandan Public Welfare Foundation Artificial Liver Special Fund, No. iGandanF-1082024-RGG122.
Institutional review board statement: The study was approved by the Ethics Committee of Tianjin Medical University General Hospital, and written informed consent was provided by all patients before any study-related procedures were performed (IRB2021-KY-318).
Institutional animal care and use committee statement: The animal study was performed in accordance with all legal, ethical and institutional requirements, and was approved by the Animal Ethical and Welfare Committee of Tianjin Medical University, Tianjin, China, No. IRB2021-DWFL-001.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data analyzed in this study are available from the corresponding author on reasonable request at
003640@hnucm.edu.cn.
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: Lu Zhou, MD, Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, No. 154 Anshan Road, Tianjin 300070, China.
zhou_lu@126.com
Received: September 3, 2024
Revised: December 19, 2024
Accepted: February 5, 2025
Published online: March 14, 2025
Processing time: 176 Days and 1.3 Hours
BACKGROUND
Although an association between gut microbiota and cholestatic liver disease (CLD) has been reported, the precise functional roles of these microbes in CLD pathogenesis remain largely unknown.
AIM
To explore the function of gut microbes in CLD pathogenesis and the effects of gut microbiota on intestinal barrier and bile acid (BA) metabolism in CLD.
METHODS
Male C57BL/6J mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet for 2 weeks to induce CLD. The sterile liver tissues of mice were then meticulously harvested, and bacteria in homogenates were identified through culture methods. Furthermore, 16S ribosomal DNA sequencing was employed to analyze sterile liver samples collected from eight patients with primary biliary cholangitis (PBC) and three control individuals with hepatic cysts. The functional roles of the identified bacteria in CLD pathogenesis were assessed through microbiota transfer experiments, involving the evaluation of changes in intestinal permeability and BA dynamics.
RESULTS
Ligilactobacillus murinus (L. murinus) and Lactococcus garvieae (L. garvieae) were isolated from the bacterial culture of livers from CLD mice. L. murinus was prevalently detected in PBC patients and controls, whereas L. garvieae was detected only in patients with PBC but not in controls. Mice inoculated with L. garvieae exhibited increased susceptibility to experimental CLD, with both in vitro and in vivo indicating that L. garvieae disrupted the intestinal barrier function by down-regulating the expression of occludin and zonula occludens-1. Moreover, L. garvieae administration significantly upregulated the expression of the apical sodium-dependent BA transporter in the terminal ileum and increased serum BA levels.
CONCLUSION
L. garvieae contributes to excessive BA-induced hepatobiliary injury and liver fibrosis by increasing intestinal permeability and enhancing BA reabsorption.
Core Tip: Mice gavaged with Lactococcus garvieae (L. garvieae) exhibited marked aggravation of cholestasis, portal edema, portal infiltrates, liver fibrosis during cholestatic liver disease (CLD) compared with control mice. Mechanically, L. garvieae treatment decreased the expression of intestinal tight junction proteins and enhanced bile acid reabsorption in CLD mice.
