Biological Insights into Intestinal Adaptation from Preclinical Models of Short Bowel Syndrome

Short bowel syndrome is a rare and clinically heterogeneous condition resulting from extensive intestinal resections or functional impairment, leading to malabsorption, fluid and electrolyte losses, and potential progression to intestinal failure requiring long-term parenteral nutrition. The long-term outcome of SBS is largely determined by intestinal adaptation, a progressive physiological response involving epithelial remodeling, intestinal stem cell expansion, lineage-specific proliferation, vascular remodeling, and the activity of trophic mediators—most notably glucagon-like peptide-2 (GLP-2)—whose clinical relevance is exemplified by teduglutide. Despite significant therapeutic advances, the mechanisms underlying adaptation remain incompletely understood, and preclinical models are essential tools for addressing this gap. In vitro systems—including Caco-2 epithelial cultures, intestinal organoids and enteroids, and tissue-engineered intestinal constructs—enable pathway-specific mechanistic investigation and hold promise as regenerative platforms. Murine surgical models of small bowel resection and ileocecal resection provide an integrated in vivo context for dissecting cellular and molecular mechanisms of adaptation. Large animal models, particularly minipig platforms, offer anatomical and physiological proximity to humans required for translational and therapeutic evaluation. In this narrative review, we provide an updated overview of these preclinical systems, critically examining their respective strengths, limitations, and translational relevance to advance the understanding of intestinal adaptation and inform the development of more effective therapeutic strategies for SBS (graphical abstract).