Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases

New models to study the intestine are key to understanding intestinal diseases and developing novel treatments. Intestinal organ-like culture systems (organoids and enteroids) have substantially advanced the study of the human gastrointestinal tract. Stem cell–derived cultures produce self-organizing structures that contain the multiple differentiated intestinal epithelial cell types including enterocytes, goblet, Paneth, and enteroendocrine cells. Understanding host–microbial interactions is one area in which these cultures are expediting major advancements. This review discusses how organoid and enteroid cultures are biologically and physiologically relevant systems to investigate the effects of commensal organisms and study the pathogenesis of human infectious diseases. These cultures can be established from many donors and they retain the genetic and biologic properties of the donors, which can lead to the discovery of host-specific factors that affect susceptibility to infection and result in personalized approaches to treat individuals. The continued development of these cultures to incorporate more facets of the gastrointestinal tract, including neurons, immune cells, and the microbiome, will unravel new mechanisms regulating host–microbial interactions with the long-term goal of translating findings into novel preventive or therapeutic treatments for gastrointestinal infections

Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation

Intestinal stem cells (ISCs) maintain and repair the intestinal epithelium. While regeneration after ISC-targeted damage is increasingly understood, injury-repair mechanisms that direct regeneration following injuries to differentiated cells remain uncharacterized. The enteric pathogen, rotavirus, infects and damages differentiated cells while sparing all ISC populations, thus allowing the unique examination of the response of intact ISC compartments during injury-repair. Upon rotavirus infection in mice, ISC compartments robustly expand and proliferating cells rapidly migrate. Infection results specifically in stimulation of the active crypt-based columnar ISCs, but not alternative reserve ISC populations, as is observed after ISC-targeted damage. Conditional ablation of epithelial WNT secretion diminishes crypt expansion and ISC activation, demonstrating a previously unknown function of epithelial-secreted WNT during injury-repair. These findings indicate a hierarchical preference of crypt-based columnar cells (CBCs) over other potential ISC populations during epithelial restitution and the importance of epithelial-derived signals in regulating ISC behavior