Decoding the role of the intestinal epithelium in hepatitis E virus infection using a human organoid prototype of "gut-liver" axis

Kuan Liu; Yang Wang; Jiangrong Zhou; Joy Joàn van der Meij; Luc J W van der Laan; Pengfei Li; Qiuwei Pan

doi:10.1016/j.virol.2025.110615

Decoding the role of the intestinal epithelium in hepatitis E virus infection using a human organoid prototype of "gut-liver" axis

Virology. 2025 Jun 27:610:110615. doi: 10.1016/j.virol.2025.110615. Online ahead of print.

Authors

Kuan Liu¹, Yang Wang², Jiangrong Zhou³, Joy Joàn van der Meij³, Luc J W van der Laan⁴, Pengfei Li³, Qiuwei Pan⁵

Affiliations

¹ Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, 3015CE, Rotterdam, NL-3015 CN, the Netherlands; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NL-3015 CN, the Netherlands.
² Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NL-3015 CN, the Netherlands; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
³ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NL-3015 CN, the Netherlands.
⁴ Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, 3015CE, Rotterdam, NL-3015 CN, the Netherlands.
⁵ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NL-3015 CN, the Netherlands. Electronic address: q.pan@erasmusmc.nl.

PMID: 40596796
DOI: 10.1016/j.virol.2025.110615

Abstract

Hepatitis E virus (HEV), a leading cause of acute viral hepatitis worldwide, is primarily transmitted via the fecal-oral route. A clinical study has reported that the intestine of a chronic hepatitis E patient is positive for HEV. However, whether the intestinal epithelium acts as a barrier for HEV transmission or whether productive enteric infection enhances transfer of the virus to the liver remains unclear. The advent of organoid technology provides a valuable platform for advancing the study of HEV-host interactions in a more physiologically relevant context. In this study, we demonstrate that primary human intestinal organoids (HIOs) efficiently support HEV replication. The infection was sustained in differentiated HIOs with specific phenotypes of intestinal cell types, namely enterocyte, goblet cell, and enteroendocrine cell lineages. Next, we constructed a gut-liver axis model using a transwell system by co-culturing HIOs with human liver-derived organoids. Importantly, infectious viral particles produced in HIOs were capable of transmission to human liver-derived organoids in this model. Bile acids are essential mediators of gut-liver crosstalk. We found that supplementing human bile or the primary bile acid chenodeoxycholic acid inhibited HEV replication in organoids via the farnesoid X receptor (FXR) signaling pathway. The effects of the secondary bile acid, ursodeoxycholic acid, were opposite and promoted viral replication. In conclusion, this model provides a novel approach to study the gut-liver axis in HEV transmission and the impact of bile acids in modulating HEV infection.

Keywords: Bile acid; Enteric infection; Gut-liver axis; Hepatitis E virus; Primary organoids.