Overview of the development of the gastrointestinal tract

INTRODUCTION — The anatomic formation of the esophagus, stomach, intestine, liver, and pancreas are achieved in the fourth fetal week through a series of evaginations, elongations, and dilatations. Anatomic development progresses through cell proliferation, growth, and morphogenesis.

CEPHALOCAUDAD DIFFERENTIATION — Three distinct regions of the intestine give rise to specific portions of the gastrointestinal (GI) tract:

●The foregut is the precursor of the pharynx, esophagus, stomach, liver, gall bladder, pancreas, and the cranial portion of the duodenum (figure 1).

●The midgut gives rise to the caudal portion of the duodenum, the jejunum, ileum, the ascending colon, and two-thirds of the transverse colon (figure 2A-B).

●The hindgut is the precursor of the distal one-third of the transverse colon, the descending colon, the rectum, and the urogenital sinus (figure 3).

As the process of maturation proceeds, the mucosal surface of the intestine rapidly increases and folds to form villi. As a general rule, maturation tends to occur along craniocaudal and proximodistal axes (table 1). Each step of development can be influenced by a variety of processes, including genetic endowment; the biologic clock; cellular, neural, and hormonal regulatory mechanisms; and the environment [1], which includes the microbiota [2]. On a cellular level, these mechanisms most likely are regulated by the homeobox (Hox) genes, cell-to-cell interactions, epithelial-mesenchymal interactions, and transcription factors.

Determination of the specific program of an intestinal region (ie, anterior, mid, or posterior) occurs first, followed by detailed differentiation within that region [3]. The signal pathways for midgut development may be a default pathway [4], with plasticity imposed on the anterior or posterior regions by Hox genes. It is in these areas that more specialized organs develop (eg, stomach and distal colon, respectively).

LEFT-RIGHT ASYMMETRY — The asymmetry of the contents of the abdomen is more obvious than in any other part of the body. Only in congenital disorders of the heart are the clinical consequences of deranged asymmetry greater than in the GI tract (figure 4).

Examples of disorders that may be caused by disturbances of lateral development include:

●Situs inversus abdominus

●Polysplenia or asplenia

●Pancreas divisum or annular pancreas (figure 5) (see "Pancreas divisum: Clinical manifestations and diagnosis")

●Malrotation (see "Intestinal malrotation in children")

A series of genes (Lefty, Nodal, and Pitx2) regulate lateral development. They, in turn, are controlled by Gaf1, a member of the transforming growth factor beta (TGFB) gene family. Pitx2 (and its partner, Isl1) has been identified in the dorsal mesentery, which anchors the gut to the embryo. It is in this area that extracellular matrix proteins first show asymmetry, tilting the gut to the left [5], the side in which Pitx2 expression is greater. The Pitx2 control of the development of the cecum also involves fibroblast growth factors [6]. It has become increasingly apparent that Pitx2 is not sufficient in itself to control left-right asymmetry. Hyaluronan, an extracellular matrix glycosaminoglycan, plays a critical role [7]. Hyaluronan molecules on the right side of the embryo become covalently modified with peptides, requiring the enzyme TGFB-related secreted protein 6, encoded by Tsg6. Lack of expression of Tsg6 results in a failure to modify the hyaluronan and a consequent lack of coordinated asymmetry. Furthermore, nascent hyaluronan on the left is required for full Pitx2 expression on that side.

Pitx2 has a second action, detected in both mouse and chick [8]. The right-sided expansion is mechanically sensed to induce TGFB. The TGFB-dependent Pitx2 expression then acts to condense mesenchyme in the left dorsal mesentery, resulting in increased tissue stiffness on this side. Thus, the initiation of rotation depends on two active mechanisms at the dorsal mesentery: expansion on the right and tissue condensation on the left.

Other intracellular events are not fully elucidated but involve hedgehog (Hh) proteins and retinoic acid [9]. Primary ciliary dyskinesia also is associated with situs inversus but through different mechanisms. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)".)

Mechanistic studies, such as those described above, are only possible in laboratory animals. However, messenger ribonucleic acid (mRNA) sequencing has been performed at a cellular level in both time and space in human fetal tissue [10,11]. The resulting atlases describe the expression of genes in every tissue of the GI tract throughout development. This method assumes that the detection of the transcripts correlates with the expression of the active proteins. These data present the opportunity for future research that triangulates mechanistic studies in mice or chicks with these human RNA-sequencing atlases. If the developmental regulation of a gene of interest observed in mechanistic animal studies correlates with that of the human mRNA from that gene in the sequencing studies [10,11], this supports the relevance of the animal studies to human development. Such an association also negates that concern that the atlas describes only the RNA transcribed by that gene and not the protein.

VASCULARIZATION — The supportive elements that will provide the vascular supply, the neural and hormonal regulation, and the host defenses of the GI tract evolve concurrently with its anatomic development. The arterial bed develops as three ventral outbuddings from the aorta to form the celiac axis and the superior and inferior mesenteric arteries (figure 6).

Mesenteric blood flow is regulated at two points (the arteriole and the precapillary sphincter) and controlled at two levels (intrinsic and extrinsic). Intrinsic control by local factors regulates blood flow in response to changes in arterial pressure and tissue oxygenation, such as those caused by vascular constriction or feeding. Extrinsic regulation is mediated by sympathetic input from the splanchnic nerves.

Several other factors are important. Circulating endogenous and exogenous factors (eg, hormones) may modulate vascular tone. The mesenteric blood flow also exhibits "autoregulatory escape," which refers to the restoration of gut blood flow in the face of extrinsic regulation [12]. When gut blood flow is decreased artificially by stimulating periarterial mesenteric nerves (ie, the extrinsic system of control) or by infusing norepinephrine, blood flow is restored within minutes by the intrinsic system of control, which is triggered by local changes (eg, tissue hypoxia). The clinical advantages of this phenomenon have long been debated, but it is likely that they relate to the unique functions of the mesenteric vasculature. The mesenteric venous system not only removes the products of tissue metabolism (as do other vascular beds), but it also transports molecules and electrolytes that have been absorbed by the intestine. An escape from arteriolar constriction will enhance the distribution of absorbed nutrients at a time when blood flow would otherwise have been reduced by increased systemic sympathetic activity.

DIGESTION AND ABSORPTION — Both digestive and absorptive functions of the intestine are present at term in the human neonate. This is also true of the villous architecture, which greatly increases the intestinal surface area. Abnormal villous formation will result in intestinal failure, necessitating parenteral nutrition. (See "Pathophysiology of short bowel syndrome".)

●Brush border enzymes – Disaccharidases expressed in the brush border become active in mid-gestation and are all active during infancy in healthy children. Because lactase activity in the fetus increases late in gestation, premature infants born at 28 to 32 weeks of gestation have reduced lactase activity. After approximately five years, lactase activity declines in many racial groups as part of a normal process of gene inactivation. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management", section on 'Developmental lactase deficiency' and "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management", section on 'Primary lactose malabsorption'.)

●Absorption – Active electrogenic transport of glucose is present in the human fetal small intestine due to the high-affinity sodium-dependent system (the SGLT1 co-transporter) [13]. The duodenum-to-ileum gradient of glucose absorption is established between the 17^th and 30^th weeks of gestation. The developmental expression of facilitated glucose transporter isoform GLUT2, which is responsible for exit of glucose across the basolateral membrane, follows that of SGLT1. Amino acid transporters follow a similar developmental trajectory and are fully active at birth.

Prenatal expression of genes that code for nutrient transporters and disaccharidases occurs in both the colon and small intestine, but the expression disappears from the colon during the third trimester when the villous structure of the colon turns into a flat mucosa.

●Villous morphogenesis – Hedgehog (Hh) proteins are involved in the molecular regulation of villous morphogenesis. Together with bone morphogenetic protein and platelet-derived growth factor, their signaling pathways direct mesenchymal cells into organized clusters. These cell clusters, in turn, form the site from which villi develop [14]. Conditionally deleting negative regulators of Hh signaling in the intestinal mesenchyme of mice [15] showed that Hh proteins acted on a set of transcription factors, termed glioma-associated oncogene (GLi). GLi acts on two adhesion molecules (Dachsous and Fat) that control mesenchymal clustering. Although it is not clear how these events interact with proteins whose defects cause congenital enteropathies, like microvillous inclusion disease and tufting enteropathy, the molecular basis of the initiation of villous formation has now been elucidated. (See "Approach to chronic diarrhea in neonates and young infants (<6 months)", section on 'Congenital diarrheas and enteropathies'.)

●Tracheal-esophageal separation – Hh and GLi are central to another important developmental process: the separation of the trachea and esophagus, which occurs between 25 to 35 days gestation in the human fetus. Disruption of this process results in tracheoesophageal anomalies, including tracheoesophageal fistula (see "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula"). In Xenopus and mouse models, the Hh/GLi signals regulate multiple steps of tracheoesophageal separation [16], especially the activation of a GTPase (Rab11), which is crucial in generating a tracheoesophageal cleft, an essential step in the separation of the two structures.

Because the respiratory system is much younger in evolution than the GI tract, proteins such as Hh, GLi, and others must have been repurposed to regulate the development of the respiratory system when animals evolved to live on land. It is tempting to speculate that tracheoesophageal defects in human infants result from the relatively recent adoption of these proteins to regulate the ontogeny of an evolutionarily novel organ, which is not always successful. The high prevalence of tracheoesophageal defects (whose normal development depends on repurposed regulators of development) compared with the low prevalence of defective villous formation (whose normal developmental pathways existed early in the evolution of the animal kingdom) adds weight to this possibility.

NEURAL AND MOTOR FUNCTION — The neural structures of the alimentary tract are formed when neural crest cells migrate into the rapidly growing gut. Precursors migrate from the embryonic central nervous system [17]. The neural crest cells and muscle cells differentiate to form the three layers of muscle that surround the mucosa and the neural network that regulates its function.

Control of motor function is provided primarily by the enteric nervous system (a subsystem of the autonomic nervous system), which is composed of a variety of plexuses of nerve cell bodies and interneuronal circuits. Immunohistochemical staining demonstrates the presence of neurotransmitters by 24 weeks gestation, but the adult distribution may not be achieved until near term. Abnormalities in the migration and differentiation of neural crest cells result in an array of GI problems, including [18,19]:

●Hirschsprung disease (see "Congenital aganglionic megacolon (Hirschsprung disease)")

●Waardenburg-Shah syndrome (pigmentary abnormalities in association with aganglionic megacolon; this condition is also called Waardenburg syndrome type IV and Waardenburg-Hirschsprung disease) (see "The genodermatoses: An overview", section on 'Waardenburg syndrome')

●Haddad syndrome (with congenital central hypoventilation syndrome; this condition is also called Ondine-Hirschsprung syndrome) (see "Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children")

●Intestinal neuronal dysplasias (see "Functional constipation in infants, children, and adolescents: Clinical features and diagnosis", section on 'Other causes')

●Chronic intestinal pseudo-obstruction (certain congenital forms) (see "Chronic intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis", section on 'Genetic')

Motor activity is immature in the preterm infant. The sucking mechanism does not appear until 32 to 34 weeks gestation [20]. Regulation of lower esophageal sphincter tone and small intestinal motor contractions are also immature and continue to develop into adulthood [21,22]. Gastric contents are emptied more slowly in preterm infants than in term infants, and small intestinal transit is slower [23].

HORMONAL REGULATION — Glucocorticoids and thyroid hormone interact with cellular signals in the maturation of the intestinal epithelium [24]. Numerous regulatory gut peptides are also produced in the developing GI tract. Some of these peptides function as true hormones (eg, gastrin, cholecystokinin, motilin, pancreatic polypeptide, and somatostatin), whereas others have paracrine or neurocrine function (eg, gastric inhibitory peptide, bombesin, vasoactive intestinal polypeptide, neurotensin, enteroglucagon, and peptide YY). All of these peptides are present by the end of the first trimester in the fetus, but adult distribution may not be established until term [25].

Many of these hormones are released in response to feeding. The release of some of these is limited in the newborn compared with the adult [25,26]. In older (prepubertal) children, GI hormones have been implicated in the development of obesity [27]. For example, glucagon-like peptide-1 (GLP-1) has an inverse relationship to body mass index and waist circumference. GLP-2A, which is cosecreted with GLP-1 [28], markedly increases intestinal mass. Analysis of the molecule has resulted in the production of teduglutide as a treatment for short bowel syndrome. (See "Management of short bowel syndrome in children", section on 'Pharmacologic therapy'.)

HOST DEFENSE — Many aspects of host defense are mechanical in nature and appear early in gestation. Mucus production, for example, is present in the very preterm infant. Transcription factors involved in early ontogeny, such as FOXQ, regulate genes that control mucin expression [29]. On the other hand, gastric emptying and peristalsis, which prevent stasis of intestinal contents, appear later and may not be fully functional in the preterm infant.

T cells and B cells are produced as early as 14 weeks gestation [30]. However, antigenic stimulation of the lamina propria cells does not occur until after birth [31]. Secretory immunoglobulin A (IgA) is present in very low concentrations in fetal life as the fetal intestine has few IgA-producing plasma cells. Therefore, preterm infants are unable to form antibodies to exogenous protein [32]. However, the production and release of cytokines are brisk.

Until the advent of technologies able to identify microbiota with rapid deoxyribonucleic acid (DNA) sequencing (which allows detection of nonculturable bacteria), the gut was believed to be sterile in utero. Bacteria have been identified in both placenta and amniotic fluid in utero [33,34], although this is not universally accepted [35]. While the major phase of bacterial colonization begins at birth, the pattern of bacteria (at least in the meconium of infants born by caesarian section) is influenced by maternal intrauterine bacteria [36]. A variety of other factors influence colonization, including mode of delivery, type of feeding, and use of antibiotics [37]. In healthy infants, aerobic organisms become abundant within a few hours and anaerobic organisms by 24 hours [38]. These organisms are capable of metabolizing bile acids, nonabsorbed proteins, lipids, and carbohydrates. Thus, they potentially may play an important role in the processing of nutrients in preterm infants. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Benefits of mother's milk'.)

In addition, the microbiota directs the maturation of the host immune system, including direct interaction with dendritic cells [39] and the regulation of T cell maturation [40,41]. These create reciprocal interactions between the microbiota and the immune system [42-44]. (See "An overview of the innate immune system", section on 'The microbiome'.)

SUMMARY

●Anatomic maturation

•Cephalocaudad differentiation – The first steps in gastrointestinal (GI) development involve the formation of the foregut, midgut, and hindgut from the embryonic gut tube (figure 1 and figure 3 and figure 4). (See 'Cephalocaudad differentiation' above.)

•Lateralization – Lateralization occurs in the developing embryo to form distinct left-right asymmetry. Some of the genetic and cellular mediators involved in lateralization have been identified. Disorders of lateralization include situs inversus abdominus, malrotation of the gut, and some congenital malformations of the pancreas and spleen. (See 'Left-right asymmetry' above.)

•Vascularization – The arterial supply to the gut develops as three ventral outbuddings from the aorta to form the celiac axis and the superior and inferior mesenteric arteries (figure 6). Mesenteric blood flow is subject to extrinsic and intrinsic regulation; intrinsic regulation may compensate for extrinsic disturbances in a process termed "autoregulatory escape." (See 'Vascularization' above.)

●Functional maturation

•Digestion and absorption – The molecular basis determining the development of villi has been elucidated and uses some of the same regulatory proteins that are involved in the separation of the trachea from the intestine in early fetal life. (See 'Digestion and absorption' above.)

•Motility – Control of motor function is provided primarily by the enteric nervous system (a subsystem of the autonomic nervous system). Abnormalities in the migration and differentiation of neural crest cells result in an array of GI problems, including Hirschsprung disease. (See 'Neural and motor function' above.)

•Gut regulatory hormones – Regulatory gut peptides that are produced in the developing GI tract include gastrin, cholecystokinin, motilin, pancreatic polypeptide, and somatostatin, as well as some paracrine or neurocrine mediators. All of these peptides are present by the end of the first trimester in the fetus, but adult distribution may not be established until term (table 1). (See 'Hormonal regulation' above.)

•Gut immune defense – The development of immune defenses in the gut is distributed across embryonal maturation and continues to develop after birth. Preterm infants have immature gut defenses because of decreased motility and reduced secretion of IgA. (See 'Host defense' above.)