Large Animal Models: The Key to Translational Discovery in Digestive Disease Research

Abstract

Gastrointestinal disease is a prevalent cause of morbidity and mortality and the use of animal models have been instrumental in studying mechanisms of digestive pathophysiology. As investigators attempt to translate the wealth of basic science information developed from rodent, models, large animal models provide a number of translational advantages. The pig, in particular, is arguably one of the most powerful models of human organ systems, including the gastrointestinal tract. The pig has provided important tools and insight into intestinal ischemia/reperfusion injury, intestinal mucosal repair, as well as new insights into esophageal injury and repair. Porcine model development has taken advantage of the size of the animal, allowing increased surgical and endoscopic access. In addition, cellular tools such as the intestinal porcine epithelial cell line and porcine enteroids are providing the methodology to translate basic science findings using in-depth mechanistic analyses. Further opportunities in porcine digestive disease modeling include developing additional transgenic pig strains. Collectively, porcine models hold great promise for the future of clinically relevant digestive disease research.

Keywords: Ischemia/Reperfusion Injury; Mucosal Repair; Pig; Tight Junction.

Figure 1

Schematic diagram for comparison of murine, porcine, and human gastrointestinal tract anatomy and histology.

Figure 2

Illustration showing the phases of intestinal epithelial barrier repair. Restoration of barrier function after damage to the epithelium is well characterized to occur in 3 phases. (1) Contraction of villus occurs by smooth muscle fibroblasts in the lamina propria to reduce denuded surface area. (2) Depolarization and migration of wound-associated epithelial cells occurs across the denuded basement membrane to cover the wounded surface. (3) Repolarization and reformation of tight junction structure to seal the paracellular spaces occurs, effectively restoring barrier function. (A) Transmission electron microscopy showing open paracellular space between 2 intestinal epithelial cells with a leaky tight junction (white arrows). (B) TEM showing closed paracellular space and tight junction (white arrows) coinciding with restoration of intestinal barrier function.