Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges

Abstract

Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus, and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, and nutritional and pharmacological interventions. Animal studies are needed to carefully evaluate the cellular mechanisms, safety, and translational relevance of new procedures. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rats and mice have specifically addressed the fundamental physiological processes underlying adaptation at the cellular level, such as regulation of mucosal proliferation, apoptosis, transport, and digestive enzyme expression, and easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g., glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g., PN, milk diets, long-/short-chain lipids, pre- and probiotics). Conversely, newborn pigs (preterm or term) and weanling rats provide better insights into the developmental aspects of treatment for SBS in infants owing to their immature intestines. The review shows that a balance among practical, economical, experimental, and ethical constraints will determine the choice of SBS model for each clinical or basic research question.

Keywords: glucagon-like peptide 2; intestine; mouse; newborn; parenteral and enteral nutrition; pig; rat; resection.

Fig. 1.

Schematic illustration of different types of intestinal resections in mice (A), rats (B), and pigs (C). Adapted with permission from drawings of the gross anatomy of the gastrointestinal tract in different species (230).

Fig. 2.

Procedures involved in using newborn pigs as models for infant short bowel syndrome (SBS). Both normal newborn pigs (top left; Refs. 104, 234, 247) and caesarean-delivered term or preterm pigs (bottom left; Refs. 7, 245, 252) can be subjected to intestinal resection, with establishment of a jejunostomy or with anastomosis to the remnant ileum or colon. Postsurgical rearing requires intensive care but allows advanced dietary or medical interventions. Artificially reared, colostrum-deprived pigs require intensive care and passive immunization even before resection, especially if born preterm. Immature organ functions and high necrotizing enterocolitis (NEC) sensitivity make preterm pigs similar physiologically to preterm infants, but the increased technical, clinical, and ethical challenges must be weighed against the apparent translational advantage. Thus intestinal resection following NEC outbreak in preterm pigs is in principle possible (broken line) but has not yet been investigated. PN, parenteral nutrition; EN, enteral nutrition.

Fig. 3.

Schematic overview indicating how nutrient-stimulated release of glucagon-like peptide 2 (GLP-2) from intestinal L cells mediates trophic, anti-inflammatory, and vascular intestinal effects via a combination of endo-, para-, and neurocrine pathways. GLP-2 receptors are present throughout the gut and signal decreased gastric emptying and increased blood flow, cell proliferation, and nutrient uptake.

Fig. 4.

Spontaneous intestinal adaptation following resection depends on the action of intestinal growth factors, and exogenous supply of growth factors may enhance adaptation during SBS. GLP-2 from L cells and growth hormone (GH) from the pituitary may both work via local intestinal release of insulin-like growth factor 1 (IGF-1). The interacting effects of other growth factors, such as keratinocyte growth factor (KGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) may exert trophic effects via pathways that are similar to those of IGF-1 and GLP-2.