Abstract
Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.
Highlights
Necrotizing enterocolitis (NEC) is the most serious gastrointestinal (GI) disease of prematurity and the most common cause of death in extremely preterm infants aged 2 to 8 weeks of age [1]
Blackwood et al [56] observed in intestinal epithelial cells (IECs)-6 and FHs 74 Int cells that both LPS and Cronobacter sakazakii caused an increase in Cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA) that contributed to cellular apoptosis
In vitro models of NEC have provided important tools to observe the molecular mechanisms involved in the disease, such as cell proliferation, apoptosis, and gene expression variation, and can serve as low-cost screening platforms for the discovery of the effect of new therapies and protective strategies, including human milk, and their mechanisms
Summary
Necrotizing enterocolitis (NEC) is the most serious gastrointestinal (GI) disease of prematurity and the most common cause of death in extremely preterm infants aged 2 to 8 weeks of age [1]. The gut microbiota of preterm infants, together with a unique set of environmental exposures, is made of a dramatically lower number of beneficial species, lower bacterial diversity, and higher proportion of pathogens compared to healthy breastfed term infants [8,9] Such dysbiosis may result in a hyperinflammatory response by the premature immune system, causing a violent inflammatory storm that leads to increased intestinal permeability, bacterial translocation, and inflammation [10]. It would be highly desirable to develop novel in vitro models of NEC using human tissue, leading to a better understanding of complex intestinal pathophysiology and, to promising prevention or therapeutic strategies This narrative review is aimed at summarizing available in vitro studies about NEC pathogenesis and innovative approaches used to disentangle NEC molecular underpinnings
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