Short bowel syndrome (SBS) is a growing problem in the human neonatal population. In infants, SBS is the leading cause of intestinal failure, the state of being unable to absorb sufficient nutrients for growth and development. Neonates with SBS are dependent on long-term parenteral nutrition therapy, but many succumb to the complications of sepsis and liver disease. Research in neonatal SBS is challenged by the ethical limits of studying sick human neonates and the heterogeneous nature of the disease process. Outcomes in SBS vary depending on residual intestinal anatomy, intestinal length, patient age, and exposure to nutrition therapies. The neonatal piglet serves as an appropriate translational model of the human neonate because of similarities in gastrointestinal ontogeny, physiological maturity, and adaptive processes. Re-creating the disease process in a piglet model presents a unique opportunity for researchers to discover novel insights and therapies in SBS. Emerging piglet models of neonatal SBS now represent the entire spectrum of disease seen in human infants. This review aims to contextualize these emerging piglet models within the context of SBS as a heterogeneous disease. We first explore the factors that account for SBS heterogeneity and then explore the suitability of the neonatal piglet as an appropriate translational animal model. We then examine differences between the emerging piglet models of neonatal SBS and how these differences affect their translational potential to human neonates with SBS.
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