Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges

Abstract

Necrotizing enterocolitis is the leading cause of morbidity and mortality from gastrointestinal disease in premature infants and is characterized by initial feeding intolerance and abdominal distention followed by the rapid progression to coagulation necrosis of the intestine and death in many cases. Although the risk factors for NEC development remain well accepted, namely premature birth and formula feeding, the underlying mechanisms remain incompletely understood. Current thinking indicates that NEC develops in response to an abnormal interaction between the mucosal immune system of the premature host and an abnormal indigenous microflora, leading to an exaggerated mucosal inflammatory response and impaired mesenteric perfusion. In seeking to understand the molecular and cellular events leading to NEC, various animal models have been developed. However, the large number and variability between the available animal models and the unique characteristics of each has raised important questions regarding the validity of particular models for NEC research. In an attempt to provide some guidance to the growing community of NEC researchers, we now seek to review the key features of the major NEC models that have been developed in mammalian and nonmammalian species and to assess the advantages, disadvantage, challenges and major scientific discoveries yielded by each. A strategy for model validation is proposed, the principal models are compared, and future directions and challenges within the field of NEC research are explored.

Keywords: TLR4; animal model; innate immunity; microflora; necrotizing enterocolitis.

Fig. 1.

Pathogenesis of necrotizing enterocolitis (NEC). Graphical representation of the mechanisms that lead to the development of NEC, as well as protection from NEC, based on findings from experiments performed in animal models as discussed in this review.

Fig. 2.

Histological appearance of necrotizing enterocolitis in the human, piglet, and mouse. Representative micrographs showing hematoxylin and eosin-stained sections of the terminal ileum from a premature human infant (A), piglet (B), and mouse (C) without (left) or with (right) NEC as described in this review. Size bar = 50 μm.

Fig. 3.

Cultured enteroids from human and mouse crypts. Representative confocal micrographs of enteroids that were derived from the intestinal stem cell compartment of a newborn mouse (A) or premature infant (B) and maintained for 5 days in culture. Size bar = 10 μm.