3D intestinal organoids: Functional studies on nutrient uptake, drug bioavailability and gut hormone secretion

Abstract: Research on intestinal nutrient transport, sensing and incretin hormone secretion is of high interest for the therapy of metabolic disorders such as obesity and diabetes. Appropriate in vitro models that would allow a replacement or significant reduction of animal experiments have been lacking to date. Immortalized mammalian cell lines are currently the prime in vitro model used for functional studies on gastrointestinal processes including drug bioavailability. Although well-established and easy in handling, these cultures are a very simplified and artificial model system not reflecting the complexity of the intestinal epithelium with multiple cell types and a region-specific architecture.

We demonstrate that 3-dimensional intestinal organoids, so-called mini-guts in a dish, represent an excellent in vitro model system enabling concurrent investigations of intestinal transport, hormone secretion and intracellular signaling. We generated organoids derived from wild type mice and from mice lacking different intestinal transporters such as the peptide transporter PEPT1 or the glucose transporter SGLT1. Functional studies on intestinal transport and incretin hormone secretion using wildtype and knockout organoids clearly reflect key findings from our previous in vivo experiments. Our data confirm that intestinal organoids preserve the main phenotypic and functional characteristics of the native intestine.

Furthermore, intestinal organoids are suitable for screenings on bioavailability of drugs and prodrugs. We investigated intestinal transport of novel peptidomimetics binding to specific integrin subtypes such as alphaVbeta3. These compounds are highly promising targets for cancer therapy and tumor characterization. We recently succeeded to transfer our experimental setups to human intestinal organoids providing an excellent in vitro model system for nutritional, biomedical and pharmacological applications.