Research in a time of enteroids and organoids: how the human gut model has transformed the study of enteric bacterial pathogens

Abstract

Enteric bacterial pathogens cause significant morbidity and mortality globally. Studies in tissue culture and animal models shaped our initial understanding of these host-pathogen interactions. However, intrinsic shortcomings in these models limit their application, especially in translational applications like drug screening and vaccine development. Human intestinal enteroid and organoid models overcome some limitations of existing models and advance the study of enteric pathogens. In this review, we detail the use of human enteroids and organoids to investigate the pathogenesis of invasive bacteria Shigella, Listeria, and Salmonella, and noninvasive bacteria pathogenic Escherichia coli, Clostridium difficile, and Vibrio cholerae. We highlight how these studies confirm previously identified mechanisms and, importantly, reveal novel ones. We also discuss the challenges for model advancement, including platform engineering to integrate environmental conditions, innate immune cells and the resident microbiome, and the potential for pre-clinical testing of recently developed antimicrobial drugs and vaccines.

Keywords: Human intestinal enteroids; bacterial pathogens; enteric bacteria; organoids.

Figure 1.

(a) Illustration of the origin and lineage composition of organoids and enteroids. Organoids are derived from induced pluripotent stem cells (iPSCs) and contain cells of epithelial and mesenchymal lineages. Enteroids are derived from intestinal tissue and contain cells of epithelial lineage only. Both enteroids and organoids contain multiple epithelial cell types. (b) Schematic diagram showing an outline of the molecular pathogenesis mechanisms of invasive and noninvasive enteric bacteria in organoids and enteroids discussed in this review. Invasive bacteria such as Shigella, Salmonella and Listeria infect and gain entry into the epithelial cells whereas noninvasive bacteria such as pathogenic E. coli, C. difficile and V. cholerae exert their effect on epithelial cells via toxins or effectors.