Organoids as a tool to study the impact of heterogeneity in gastrointestinal epithelium on host-pathogen interactions

The epithelium of the gastrointestinal (GI) tract has been extensively characterized using advanced histological and RNA sequencing techniques, which has revealed great cellular diversity. Pathogens, such as viruses and bacteria, are highly adapted to their host and often exhibit not only species-specificity but also a preference or tropism for specific GI segments or even cell types-some of these preferences are so specific, that these pathogens still cannot be cultured invitro. Organoid technology now provides a tool to generate human cell types, which enables the study of host cell tropism. Focussing on the GI tract, we provide an overview about cellular differentiation in vivo and in organoids and how differentiation in organoids and their derived models is used to advance our understanding of viral, bacterial, and parasitic infection. We emphasize that it is central to understand the composition of the model, as the alteration of culture conditions yields different cell types which affects infection. We examine future directions for wider application of cellular heterogeneity and potential advanced model systems for GI tract infection studies.