Intestinal atresia and necrotizing enterocolitis (NEC) are two pathologies that affect the newborn gut. Although at first, they appear not to share other similarities, since the latter is an acquired disease, while the former is a congenital malformation, both present their origin rooted in changes in normal bowel development. Atresia develops as an intra-uterine event leading to the loss of bowel continuity, whereas NEC is established postnatally in the intestine that is prematurely exposed to nutrients and microbiota.

The intestines derive from all 3 layers of the human embryo (endoderm, mesoderm, and ectoderm) observed in the gastrulation phase.1 The endoderm gives origin to the epithelial lining and glands, and the mesoderm incorporates into the primitive gastrointestinal tract to develop the intestinal smooth muscle, connective tissue, mesentery, and blood vessels. The bowel innervation, intrinsic and extrinsic, originates in the ectoderm.2

The primitive gut or endoderm assumes the closed tube shape at week 3. The hollow tube evolves into three distinct segments, the foregut cranially, midgut medially, and hindgut caudally. The foregut gives rise to the upper gastrointestinal tract from the esophagus to the duodenum at the level of the papilla, including the liver, biliary apparatus, and pancreas. Derivatives from the midgut include the largest portion of the intestine, the duodenum distal to the papilla, jejunum, ileum, cecum, appendix, ascending, and 2/3rds of the proximal transverse colon. The remainder of the colon and rectum derive from the hindgut. In addition, all three original intestinal segments have different arterial supplies: 1) the foregut through the celiac axis 2) the midgut through the superior mesenteric artery and 3) the hindgut with the inferior mesenteric artery.3Table 1 describes the chronological events of intestinal development.4

There have been several advances in the understanding of the molecular mechanisms involved in the sequential developmental steps that lead to intestinal formation. Several genes, receptors, and pathways have been identified to understand normal gut development and pathological processes leading to malformations, helping to elucidate the development of various intestinal diseases. A broad review of these topics has been previously described.4,5 In this review, we will briefly address the most important pathways discovered thus far.

Foregut differentiation is marked by the expression of Sox2, while Cdx2 is essential for intestinal epithelium formation.6 Loss of one of those pathways causes incorrect epithelial differentiation in the primordial gastrointestinal tube. Moreover, experimental suppression of Cdx2 leads to the development of an esophageal-like or stomach-like epithelium in the bowel.7,8

Wnt signaling is a highly conserved pathway across species that seems to be broadly implicated in processes involving tissue homeostasis and regeneration.8, 9, 10 Wnt is needed for intestinal stem cell maintenance, with low Wnt signaling leading to stem cell differentiation and migration to the villus, while high Wnt signaling leads to stem cell proliferation.11 To elucidate this, intestinal organoids used as a robust three-dimensional in vitro model representing the epithelium, require Wnt to maintain their viability.12

Notch signaling has a negative feedback effect on Wnt signaling. Additionally, Notch is responsible for the differentiation of intestinal cells into absorptive or secretory (goblet, Paneth, or enteroendocrine). Low Notch signals lead to secretive cell differentiation, while high levels lead to the formation of the absorptive cell. Experimental blockage of Notch causes secretory hyperplasia in organoids and in vivo.11 Therefore, the balance between Wnt and Notch signaling is important for intestinal epithelium homeostasis and the equilibrium of cell type differentiation. Retinoic X receptor downregulates the expression of Notch ligand and increases Wnt signaling, resulting in increased villus length, goblets cell count, and improved intestinal barrier function.13

Villus morphogenesis starts at week 7, followed by cell differentiation into secretory or absorptive function. Toll-like receptor 4 (TLR4), a receptor of the innate immune system, has an important prenatal role in signaling for crypt development and intestinal cell differentiation. This happens via direct action on intestinal stem cells or via the Notch pathway. TLR4 is highly expressed before birth14, however, TLR4 immune function is restrained by the presence of inhibiting factors within the amniotic fluid and the sterile gut.15

In week 22 all different cell types are present in the intestine, although not presenting yet the mature gut functionalities. During the final 15 weeks of gestation, the intestine doubles in length and growth continues after birth. The final maturation of intestinal epithelial cells and their functionality is achieved via interaction with the microbiome and nutrition following birth.11

Novel insights into the genetic/molecular pathways of bowel embryology are revealing possible connections between bowel development, intestinal congenital pathologies, and the mechanism of why the immature epithelium is prone to the development of NEC.