近日，瑞典乌普萨拉大学教授Mikael E. Sellin及其课题组的最新研究提出了可扩展的肠道上皮类器官模型揭示了人类适应病原体的全基因组定植景观。这一研究成果发表在2025年6月12日出版的国际学术期刊《自然—遗传学》上。

该课题组研究人员将肠道和结肠体的大规模志贺氏菌感染与转座子定向插入测序和贝叶斯统计建模相结合，以解决感染瓶颈，从而建立了感染人类肠上皮所需的志贺氏菌基因的全面全基因组图谱。这揭示了志贺氏菌毒力效应对上皮细胞在几何形状和肠段的定植至关重要，鉴定了参与该过程的100多个染色体基因，并揭示了tRNA修饰酶和差异密码子编码对细菌毒力程序进行全局控制的转录后机制。他们的发现提供了一个广泛适用的框架，将先进的器官型组织培养与功能基因组学和计算工具相结合，以大规模地绘制人与微生物的相互作用。

据介绍，研究人类适应微生物的发病机制是具有挑战性的，因为小动物模型往往不能概括人类生理学。因此，驱动主要人类病原体（如福氏志贺氏菌）感染过程的综合遗传和调控回路仍有待确定。

附：英文原文

Title: A scalable gut epithelial organoid model reveals the genome-wide colonization landscape of a human-adapted pathogen

Author: Di Martino, Maria Letizia, Jenniches, Laura, Bhetwal, Anjeela, Eriksson, Jens, Lopes, Ana C. C., Ntokaki, Angelika, Pasqua, Martina, Sundbom, Magnus, Skogar, Martin, Graf, Wilhelm, Webb, Dominic-Luc, Hellstrm, Per M., Mateus, Andr, Barquist, Lars, Sellin, Mikael E.

Issue&Volume: 2025-06-12

Abstract: Studying the pathogenesis of human-adapted microorganisms is challenging, since small animal models often fail to recapitulate human physiology. Hence, the comprehensive genetic and regulatory circuits driving the infection process of principal human pathogens such as Shigella flexneri remain to be defined. We combined large-scale Shigella infections of enteroids and colonoids with transposon-directed insertion sequencing and Bayesian statistical modeling to address infection bottlenecks, thereby establishing the comprehensive genome-wide map of Shigella genes required to infect human intestinal epithelium. This revealed the Shigella virulence effectors essential for epithelial cell colonization across geometries and intestinal segments, identified over 100 chromosomal genes involved in the process and uncovered a post-transcriptional mechanism whereby tRNA-modification enzymes and differential codon usage exert global control of a bacterial virulence program. Our findings provide a broadly applicable framework for combining advanced organotypic tissue culture with functional genomics and computational tools to map human–microorganism interactions at scale.

DOI: 10.1038/s41588-025-02218-x

Source: https://www.nature.com/articles/s41588-025-02218-x