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

文献类型： 外文期刊

第一作者： Liu, Kuan

作者： Liu, Kuan;van der Laan, Luc J. W.;Liu, Kuan;Wang, Yang;Zhou, Jiangrong;van der Meij, Joy Joan;Li, Pengfei;Pan, Qiuwei;Wang, Yang

作者机构：

关键词： Hepatitis E virus; Primary organoids; Gut-liver axis; Enteric infection; Bile acid

期刊名称：VIROLOGY （ 影响因子：2.4； 五年影响因子：2.5 ）

ISSN： 0042-6822

年卷期： 2025 年 610 卷

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收录情况： SCI

摘要： Hepatitis E virus (HEV), a leading cause of acute viral hepatitis worldwide, is primarily transmitted via the fecaloral 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.

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