Intestinal epithelium in early life

Abstract

Rapid development of the fetal and neonatal intestine is required to meet the growth requirements of early life and form a protective barrier against external insults encountered by the intestinal mucosa. The fetus receives nutrition via the placenta and is protected from harmful pathogens in utero, which leads to intestinal development in a relatively quiescent environment. Upon delivery, the intestinal mucosa is suddenly tasked with providing host defense and meeting nutritional demands. To serve these functions, an array of specialized epithelial cells develop from intestinal stem cells starting in utero and continuing postnatally. Intestinal disease results when these homeostatic processes are interrupted. For preterm neonates, the most common pathology resulting from epithelial barrier dysfunction is necrotizing enterocolitis (NEC). In this review, we discuss the normal development and function of the intestinal epithelium in early life as well as how disruption of these processes can lead to NEC.

Fig. 1. Comparison of the small intestinal epithelium in the fetus and term neonate.

In utero, the intestinal epithelium is exposed to amniotic fluid, which contains growth factors essential for proper intestinal development. The crypt and villus structures mature with increasing gestational age and Lgr5+ intestinal stem cells transition from localization throughout the intestine to the intestinal crypt. Goblet cells and Paneth cells also increase in number throughout fetal development and early life, leading to increased mucus formation and antimicrobial peptide production. Both beneficial and pathogenic microorganisms can be found in the intestinal lumen as the microbiome develops after delivery. Secretory IgA provided by breast milk is a central component of the immune repertoire of the developing intestine and is crucial for establishing control of intraluminal bacteria. Figure created with Biorender.com.

Fig. 2. The neonatal intestinal epithelium during necrotizing enterocolitis.

Injury to the developing intestinal epithelium underlies the pathophysiology of necrotizing enterocolitis (NEC, circular inset). Preterm neonates are at risk for NEC due to a myriad of factors related to their stage of intestinal development and critical illness. When an infant is delivered preterm, their intestinal epithelium is composed of lower numbers of mature specialized epithelial cells relative to term infants. For example, lower goblet and Paneth cell numbers are associated with associated impairments in mucus and antimicrobial peptide production. These deficits lead to an increase in potentially pathogenic Gram-negative bacteria in the intestinal lumen. These bacteria can activate TLR4 signaling on the intestinal epithelium leading to the induction of an inflammatory cascade. Inflammation subsequently results in patchy intestinal epithelial injury, reduced barrier integrity, and translocation of bacteria from the intestinal lumen. When this occurs, infants are also at risk for sepsis, irreparable intestinal injury, and death. Figure created with Biorender.com.