Invited Review: The preterm pig as a model in pediatric gastroenterology

Abstract

At birth, the newborn mammal undergoes a transition from a sterile uterine environment with a constant nutrient supply, to a microbe-rich environment with intermittent oral intake of complex milk nutrients via the gastrointestinal tract (GIT). These functional challenges partly explain the relatively high morbidity and mortality of neonates. Preterm birth interrupts prenatal organ maturation, including that of the GIT, and increases disease risk. Exemplary is necrotizing enterocolitis (NEC), which is associated closely with GIT immaturity, enteral feeding, and bacterial colonization. Infants with NEC may require resection of the necrotic parts of the intestine, leading to short bowel syndrome (SBS), characterized by reduced digestive capacity, fluid loss, and dependency on parenteral nutrition. This review presents the preterm pig as a translational model in pediatric gastroenterology that has provided new insights into important pediatric diseases such as NEC and SBS. We describe protocols for delivery, care, and handling of preterm pigs, and show how the immature GIT responds to delivery method and different nutritional and therapeutic interventions. The preterm pig may also provide a sensitive model for postnatal adaptation of weak term piglets showing high mortality. Attributes of the preterm pig model include close similarities with preterm infants in body size, organ development, and many clinical features, thereby providing a translational advantage relative to rodent models of GIT immaturity. On the other hand, the need for a sow surgical facility, a piglet intensive care unit, and clinically trained personnel may limit widespread use of preterm pigs. Studies on organ adaptation in preterm pigs help to identify the physiological basis of neonatal survival for hypersensitive newborns and aid in defining the optimal diet and rearing conditions during the critical neonatal period.

Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine

“…On this background, it is of relevance to clarify how TGF-␤2 of endogenous or dietary origin interacts with bacterial colonization and IL-8 production to reduce intestinal inflammation and NEC. We investigated this interaction in preterm pigs, probably the most clinically relevant animal model of NEC (36). Because of the high cost of providing purified recombinant TGF-␤2 to preterm pigs, we first studied the relations between TGF-␤2 and IL-8 using colostrum as an exogenous natural source of TGF-␤2 and manipulating bacterial colonization with oral antibiotic treatment, and then coupled these in vivo studies with a series of in vitro cell studies on TGF-␤2, IL-8, and LPS.…”

“…When preterm pigs are fed formula for up to 10 days, most pigs develop NEC, unless oral antibiotics are given to reduce gut bacterial colonization (14). On the other hand, a reduced risk of NEC and reduced levels of inflammatory mediators are observed in preterm pigs fed donor human milk, bovine colostrum, and amniotic fluid (16,36,37). These enteral diets have greater levels of bioactive components, such as TGF-␤2 and epidermal growth factor (10,17), which may reduce NEC, at least in the more artificial models of NEC in mice (10,19).…”

“…In preterm pigs, formula-fed individuals spontaneously develop NEC within 5 days with an incidence of 40 -80%, depending on dietary and microbiota conditions (36). When preterm pigs are fed formula for up to 10 days, most pigs develop NEC, unless oral antibiotics are given to reduce gut bacterial colonization (14).…”

Physical activity level is impaired and diet dependent in preterm newborn pigs

“…Pigs were kept individually in transparent incubators with controlled ventilation and a local heat source (39). Incubators were equipped with foam pads and diapers on top of plastic grid for temperature optimization and comfort.…”

Are EGF and TLR-4 crucial to understanding the link between milk and NEC?

“…This translational approach can be conducted in large animal models including pigs, sheep, and primates since organ development, the developmental biology, and the physiology of such large animals closely resembles the human situation. 30,31 In addition, studies in babies were till recent hampered by lack of (noninvasive) markers for intestinal inflammation, damage, and maturation. Importantly, we recently reported on the availability of such human gut-specific biomarkers, which enable us to measure gut maturation and to early diagnose systemic and intestinal inflammation in NEC patients, which may be of help for the implementation of these findings into clinical practice.…”