Animal Models of Slow-Transit Constipation: Current Progress, Limitations, and Future Perspectives

Slow-transit constipation (STC) is a subtype of chronic constipation characterized by delayed colonic transit without obstructive defecation. Because in vivo human experimentation is constrained, animal models remain the primary tool for probing STC pathogenesis and testing therapies, yet no unified framework exists for judging howwell current models reproduce human disease. This review systematically appraises the reported STC animal models against a single validity framework and identifies design criteria for the next generation of models.

We reviewed pharmacological agent-induced models (loperamide, diphenoxylate, alosetron, morphine, atropine), a physical stimulus model (ice-water gavage), surgical models (rectal distension, partial outlet obstruction, chemical ablation of the enteric plexus), and a naturally occurring inbred strain (the CFP/Yit mouse), and appraised each using the Face-Construct-Predictive validity framework.

Existing models show substantial gaps in face validity (drug-withdrawal-dependent, self-limiting constipation rather than chronic progressive dysmotility), construct validity (few reproduce enteric glial cell loss, enteric neuronde generation, interstitial cell of Cajal depletion, and inflammatory infiltration), and predictive validity (induction agents confound therapeutic readouts). Advances in enteric glial biology, microbiota-short-chain fatty acid-motility signalling, single-cell transcriptomics of enteric glia, and genetic susceptibility point toward transgenic, pelvic-nerve-intervention, selective enteric glial ablation, and organoid-enteric nervous system co-culture designs, with sex-stratified evaluation and systematic clinical translation studies.

The Face-Construct-Predictive framework exposes the translational shortfall of current STC animal models and defines concrete design criteria for clinically relevant successors, guiding model selection and prioritizing future research.