The Beginning

During gestation, the alimentary canal can be simply considered as the folding of endoderm and splanchnic mesoderm into a tube at the end of week 3 and the beginning of week 4.⁶ As the head fold forms, the cranial part of the yolk sac becomes enclosed within the embryo and becomes the foregut. Shortly thereafter, the caudal portion of the yolk sac becomes enclosed and forms the hindgut. The midgut resides between the foregut and the hindgut, near the yolk sac, which remains outside the embryo. The midgut remains in communication with the yolk sac until the yolk stalk closes during the 10th week of gestation. Initially the digestive tube ends blindly—cranially at the oropharyngeal membrane and caudally at the cloacal membrane. These membranes, made up of endoderm and ectoderm, break down, with the oropharyngeal going first at the start of week 4 followed by the cloacal at the start of week 6.

Esophagus

The esophagus is the only portion of the GI tract that has neither digestive nor absorptive function. Rather, it serves as a conduit between mouth and stomach and, at the gastroesophageal junction, functions to avoid reflux of stomach contents back up the esophagus. Although this task sounds simple, the esophagus performs its roles so well that no esophageal replacement has been found that does anywhere near as good a job. All efforts are made to keep a native esophagus, even a severely compromised one, rather than go with any replacement.

The fully developed esophagus extends from the pharynx and cricopharyngeal sphincter in the neck to the lower esophageal sphincter and gastroesophageal junction in the abdomen. The blood supply to the esophagus is segmental. The upper esophagus is supplied by branches descending from the inferior thyroid artery. The middle and lower thirds of the esophagus are supplied by branches arising directly from the bronchial vessels or the descending thoracic aorta. The abdominal and lower esophagus also receive blood supply from the left gastric and inferior phrenic arteries. The esophagus varies in length from 13 to 25 cm depending on the age and height of the patient. There are four areas of natural anatomic constriction of the esophagus: (1) at the level of the cricopharyngeal sphincter, (2) as the aortic arch crosses anteriorly, (3) as the left main stem bronchus crosses anteriorly, and (4) at the level of the lower esophageal sphincter. Foreign bodies in the esophagus tend to lodge at one of these areas of constriction, and burns from caustic ingestion tend to be more severe in these regions.

The esophagus is differentiated from the primitive foregut during the fourth week of gestation.7,9 A tracheoesophageal septum is evident at this time, initiating the division of the trachea anteriorly from the foregut posteriorly. The septum remains at about the same level in the fetus while the body grows cranially. This leads to elongation of the esophagus, primarily from “ascent” of the pharynx rather than “descent” of the stomach. It reaches its full length, relative to the size of the developing fetus, during the seventh week of gestation. Aberrations during this phase of development result in esophageal atresia and tracheoesophageal fistulas.

The lumen of the esophagus is nearly obliterated during the seventh and eighth weeks of gestation, secondary to rapid proliferation of mucosal epithelial cells. Temporary obliteration of the lumen (as in the duodenum) is thought not to occur. A single lumen is clearly present by the 10th week, with growth of the muscular wall.

The muscular wall of the esophagus is similar to that of the rest of the GI tract, with an outer longitudinal layer and a circular inner layer. The more highly developed longitudinal layer forms during the ninth week of gestation, whereas the circular layer forms during the sixth week. There is no serosa on the esophagus except in the short abdominal portion.

The epithelial lining of the esophagus is derived from the primitive endoderm. At the 10th week of gestation, this is ciliated, but a stratified, nonkeratinizing, squamous epithelium begins replacing the ciliated epithelium at about the fourth month of gestation. Some ciliated epithelium along the length of the esophagus may persist until birth. The striated muscle of the upper third arises from mesoderm of the branchial arches, whereas the smooth muscle of the distal two thirds is derived from splanchnic mesenchyme. Therefore, diseases of smooth muscle tend to affect the lower esophagus only.

Small glands of mucus- and bicarbonate-secreting cells with ducts opening onto the surface of the epithelium are scattered throughout the length of the esophagus, particularly in the lower third.

By 8 weeks’ gestation, immature neurons are identifiable within the wall of the esophagus. These nerves are derived from both parasympathetic and sympathetic fibers. The cervical sympathetic trunks send fibers along the inferior thyroid artery to the upper third of the esophagus, whereas the middle and lower thirds are supplied by branches from the greater splanchnic nerves. The thoracic esophagus is supplied by branches of the esophageal vagal plexus, arising directly from the vagus trunks in the chest.

The act of swallowing is initiated by impulses from the swallowing center, an area in the reticular formation of the rostral medulla where the nuclei of cranial nerves IX and X are located. The initial event in esophageal peristalsis is stimulation of the longitudinal muscle layer, which is followed by the segmental activation of the circular muscle and relaxation of the lower esophageal sphincter. The peristaltic wave begins in the pharynx and continues through to the gastroesophageal junction without interruption. Whereas primary waves are initiated from the swallowing center, secondary peristalsis is mediated by local intramural pathways to return refluxed material in the lower esophagus to the stomach.

The upper esophageal sphincter corresponds to the cricopharyngeal muscle. There is no morphologic distinction in the muscular wall of the lower esophagus that would identify this sphincter, although clearly one functionally exists. The primary role of this sphincter is to prevent the reflux of gastric contents back into the lower esophagus. The lower esophageal sphincter relaxes as the primary peristaltic wave traverses the esophageal body, and it remains open until the peristaltic wave enters the sphincter and closes it. Disordered lower esophageal sphincter function is thought to be the primary mechanism for gastroesophageal reflux.

Stomach

The stomach first appears as a fusiform dilation of the caudal part of the foregut at the end of the fourth week of gestation.⁵ At this time, the stomach is suspended between the posterior and anterior body walls by a ventral and dorsal mesentery. During weeks 6 through 10, the stomach undergoes rotation in two planes, as well as growth differentials that lead to the appropriate size and orientation of the organ as seen at birth. One rotation is 90 degrees counterclockwise (viewed from below upward) along the longitudinal axis of the stomach. This brings the dorsal aspect of the stomach toward the fetus’ left side, and the ventral aspect now points to the right. The two mesenteries follow this rotation, with the ventral mesentery finally extending horizontally from the stomach to the liver as the lesser omentum. The cranial portion of the dorsal mesentery runs horizontally to the spleen laterally as the gastrosplenic ligament, and it contains the short gastric vessels. A second, lesser rotation, in conjunction with a growth differential favoring greater growth on the dorsal (now left lateral) side of the stomach, leads to the organ’s final position. This rotation is clockwise around the body’s anterior-posterior axis when viewed from the front and brings part of the now left lateral (formerly dorsal) side of the stomach to point caudally. This part of the stomach still has the caudal portion of the stomach’s dorsal mesentery attached, which now grows quite quickly caudally, forming a two-layer fat pad that covers the bowel and extends to the pelvis. The two fat layers fuse to each other and to the colon and become the greater omentum. The space now created behind the stomach is called the lesser sac. It has one entrance, the epiploic foramen (foramen of Winslow), which is located beneath the free edge of the ventral mesentery that now extends from the area of the gastroduodenal junction to the liver.

The final shape of the stomach along with the various epithelial cell types that constitute its mucosal lining create distinct areas: the cardia around the gastroesophageal (GE) junction; the fundus, which projects cephalad from the gastroesophageal junction; the body, which is the vast majority of the gastric reservoir; and the antrum, the portion of the stomach immediately before the pylorus. There are three muscle layers of the stomach: the outer longitudinal, the intermediate circular, and the inner oblique. The three layers permit complex mixing and churning movements that help begin the process of digestion.

The blood supply to the stomach is extremely rich and is derived principally from the celiac axis. Four major vessels are felt to provide the stomach with blood: the right and left gastric and the right and left gastroepiploic. Also important are the short gastric arteries off the splenic artery. Venous drainage is via the portal system, with the exception of the gastroesophageal junction, which can drain to the systemic system via esophageal veins (critical to the development of esophageal varices). The blood supply to the stomach is so redundant that the organ can survive if three of the four major arteries are divided.

The gastric epithelium is made up of a diverse cell population distributed in a regionally specific manner. The early gastric mucosa is initially a stratified or pseudostratified columnar epithelium that later becomes cuboidal. This mucus-secreting cuboidal epithelium then becomes peppered with gastric pits that are first observed between gestational weeks 6 and 9. By 20 weeks, the mucosa of the stomach is mature in appearance. At the base of the gastric pits are the gastric glands, which contain the effector and regulator cells of gastric secretion.

The different cell populations of the gastric glands in various regions of the stomach allow the stomach to be histologically and functionally compartmentalized. Parietal cells are found predominantly in the gastric fundus and body and less often in the proximal antrum and can be identified in gastric glands as early as week 10. They produce both hydrochloric acid and intrinsic factor under complicated regulatory control. Chief cells are found principally in the gastric fundus and body, first appearing in gestational week 12. They are located exclusively at the base of the gastric glands, where they synthesize, store, and secrete pepsinogen. Pepsinogen is hydrolyzed to the active proteolytic enzyme pepsin in the acid environment of the stomach.

Enteroendocrine cells are present throughout the stomach, duodenum, and distal intestine. Because of their ability to produce biologically active amines and peptides and to internalize certain precursor molecules, they are referred to as amine precursor uptake and decarboxylation (APUD) cells. There are many distinct types of enteroendocrine and neuroendocrine cells found in the gastric mucosa. These cells are among the first to populate the gastric glands, appearing at 8 to 9 weeks. The most common and well-characterized are the G cells, which produce gastrin, and the D cells, which produce somatostatin and amylin. These cells predominate in the gastric antrum. Other enteroendocrine cells are ubiquitous both within the gastric glands and within the duodenal wall. They are responsible for producing such diverse amines and peptides as histamine (from the enterochromaffin-like cells), serotonin, dopamine, vasoactive intestinal peptide (VIP), glucagon, gastric-releasing peptide (GRP), motilin, and ghrelin. Interestingly, the A cells, which produce glucagon, are present only in fetal and neonatal glands. Considered along with the trophic effect of many GI hormones, this suggests a growth and differentiation role for these substances, along with the digestive and regulatory roles they are currently known to have.

All three components of the autonomic nervous system—sympathetic, parasympathetic, and enteric—innervate the stomach. The parasympathetic and enteric predominate. Sympathetic innervation is predominantly inhibitory to GI function and primarily uses the postganglionic neurotransmitter norepinephrine.³ The parasympathetic pathways mediated by acetylcholine are generally stimulatory. The enteric nervous system (ENS), on the other hand, uses a variety of neurotransmitters, including dopamine, somatostatin, VIP, GRP, ghrelin, and cholecystokinin. The ENS is the largest and most complex compartment of the autonomic nervous system and comprises more than 10⁸ resident neurons within the wall of the GI tract. The ENS is anatomically separate from the CNS (i.e., the sympathetic and parasympathetic systems).

Sympathetic innervation originates from cell bodies within the thoracic spinal cord and extends through presynaptic fibers in the greater splanchnic nerve to postsynaptic neurons in the celiac ganglion, whose axonal fibers follow blood vessels into the gastroduodenal wall. Parasympathetic presynaptic nerves originate in the brainstem and follow the vagus nerves to the stomach. ENS precursors differentiate from neuroblasts located in the vagal area of the neural crest and migrate with the vagus nerves to the developing GI tract. These ENS neurons then further differentiate, proliferate, and establish connections to each other, to other autonomic pathways, and to developing gastric secretory and muscle cells. There is significantly more ENS than CNS activity within the GI tract, suggesting a more powerful role for intrinsic (ENS) control than for extrinsic (CNS) control.

The stomach has two distinct functional zones based on motor activity differences. The proximal zone, which includes the fundus and the proximal third of the body of the stomach, serves as a reservoir in which an ingested meal is stored. Its ability to distend without increasing intraluminal pressure is important during bolus feeding. The proximal stomach generates slow, sustained tonic contractions under CNS control via the vagus. This action creates a constant pressure gradient that controls the passage of material through the stomach. Vagotomy significantly impairs this function, causing rapid emptying of fluids.

Motor activity in the stomach distal to the proximal third of the body of the stomach is characterized by spontaneous depolarizations that result in phasic, directional contractions. This gives this portion of the stomach the ability to mix and grind solid food and to empty mixed food particles into the duodenum in a controlled fashion. During the fasting state, gastric activity follows a 90- to 120-minute repetitive pattern called the interdigestive migrating motor complex. This four-phase complex runs from mechanically silent to coordinated contractions that empty the gastric lumen of all indigestible materials. The fed state occurs when the migrating motor complex is interrupted by the arrival of ingested food. Now, the stomach begins forceful, nonpropogated contractions in the distal stomach coupled with coordinated contractions of the pyloric sphincter that churn food into small particles. A gastric pacemaker located along the greater curvature at the proximal boundary of the distal zone triggers these contractions at a rate of three to four cycles per minute. When the average particle size reaches 1 mm, chyme is allowed to empty into the duodenum. Complex CNS and ENS coordination permits adequate breakdown of the food and ensures that the rate of gastric emptying is adjusted to provide an isocaloric flow of nutrients into the duodenum over time.

Gastric secretory function evolves early in development. By 10 weeks’ gestation, parietal and enteroendocrine cells have begun to differentiate, and by 12 to 13 weeks, gastrin, hydrochloric acid, pepsin, and intrinsic factor (IF) can all be detected. Mucus and bicarbonate secretion commences later, at about the 16th week. The gastric luminal pH of full-term newborns is neutral, but it is as low as 3.5 within a few hours. By 48 hours, the pH is between 1.0 and 3.0. Premature infants have a prolonged period of alkalinity, often many days, that is related to the degree of prematurity.

The production and secretion of hydrochloric acid by gastric parietal cells is governed by complex neurocrine, endocrine, and paracrine pathways, with little evidence for a final common pathway. The parietal cell can receive input and respond to a large variety of inputs, making its regulation by medical and surgical treatments difficult. Gastric acid has many functions. One is to facilitate protein digestion, but the lack of malabsorption problems in patients with achlorhydria indicates that this role may not be critical. Normal acid secretion does, however, play an integral role in initiating the digestive process. Gastric acid also creates a barrier to the entrance of bacteria into the GI tract. This not only protects the upper aerodigestive tract, but also insulates the bacteria downstream from constant challenges from above. This is consistent with data that acid suppression therapy for gastroesophageal reflux may be associated with a higher incidence of lower respiratory tract infections.⁸