Development of Gastrointestinal Tract
We will take a very short tour of early development prior to the trilaminar embryo stage, at which time we will follow the development of the gastrointestinal tract in detail. Thereafter, for each region of the gastrointestinal tract, we will begin with a short summary of the specific embryology relevant to the structures in that region. The single-celled zygote begins dividing roughly 30 hours after an oocyte is fertilized by a spermatozoa. It continues dividing without growing substantially until it reaches the 16-cell stage and is then referred to as a morula. The morula consists of an outer cell mass surrounding an inner cell mass, which will become the placenta and the embryo, respectively. For the purpose of this section we will focus on the inner cell mass as it morphs to create the body and the organs within.
As the zona pellucida (a protective covering of the oocyte and later the zygote) gradually disappears, fluid penetrates the morula and creates a space between the inner and outer cell masses. The inner cell mass remains in contact with the outer cell mass in one section, which will eventually form the connecting stalk and umbilical cord, connecting the embryo to the placenta. The fluid- filled space between the two cell masses is called the blastocyst cavity and at this time, roughly 4 days after fertilization, the entire structure is called a blastocyst. Normally, the blastocyst implants into the uterine lining starting on the sixth day and further development occurs within.
On the eighth day, another fluid-filled space forms between the inner cell mass and the rest of the blastocyst. This is the amniotic cavity; despite its small initial size, it will eventually enlarge to surround the entire embryo. The portion of the inner cell mass that is in contact with the amniotic cavity, and amniotic fluid therein, is called the epiblast, and the portion that is in contact with the blastocyst cavity is called the hypoblast. The epiblast cells are tall columnar cells, and the smaller hypoblast cells appear cuboidal or squamous (flat). The epiblast and hypoblast layers constitute the bilaminar disc. By the ninth day, when the blastocyst has fully implanted into the uterus, the blastocyst cavity is referred to as the primary yolk sac. Cells that separate the primary yolk sac, bilaminar disc, and amniotic cavity from the developing placenta (cytotrophoblast and syncytiotrophoblast) form the extraembryonic mesoderm.
By the 12th day, fluid-filled gaps within the extraembryonic mesoderm converge and form yet another space, the extraembryonic cavity, which will compress the primary yolk sac before physically separating it and the bilaminar disc from the rest of the developing placenta except for a connecting stalk that will eventually become the umbilical cord. As the 13th and 14th days proceed, the primary yolk sac is compressed and pinched in two by the expanding extraembryonic cavity. One small remnant moves away from the bilaminar disc while the larger piece remains in contact with the hypoblast and is now called the secondary yolk sac. The secondary yolk sac is lined by cells that are derived from the hypoblast. In one region, these hypoblast cells enlarge and form the prechordal plate, a structure that marks the cranial/ superior pole of the developing embryo. Opposite the prechordal plate, epiblast cells begin to proliferate near the embryo’s caudal/inferior pole. These cells will form a structure called the primitive streak. This will eventually result in the process of gastrulation, during which the bilaminar disc is replaced by a trilaminar disc. Gastrulation begins on the 15th day and results in the replacement of the epiblast and hypoblast layers by three new germ cell layers, collectively called the trilaminar embryo. It consists of the embryonic ectoderm, embryonic mesoderm, and embryonic endoderm. As these layers are referred to hereafter, the word “embryonic” will be dropped.
To form the trilaminar disc, the primary streak extends from the caudal end of the epiblast toward the prechordal plate but does not quite reach it. As it extends cranially, replicating epiblast cells involute into it, invading the space between the epiblast and hypo- blast, creating a fissure called the primitive groove. This process occurs along the entirety of the primitive streak, but there are some important features that occur at its cranial end, at an area called the primitive node. The epiblast cells that migrate through the primitive node migrate between the epiblast and hypoblast layers, moving directly toward the prechordal plate, forming a signaling structure called the notochordal process, an important structure in directing further development of the three germ cell layers. As gastrulation proceeds, the hypoblast is entirely replaced by cells that migrate through the primitive streak and settle in contact with the secondary yolk sac. This layer is the endoderm and will produce many of the body’s glands as well as the cells that line the respiratory, urogenital, and gastrointestinal tracts. The cells of the former epiblast are now referred to as ectoderm; this layer will produce the epidermis, central nervous system, peripheral ganglia, and other cells of neural crest derivation. Between the endoderm and ectoderm is the mesoderm, a layer that will produce the kidneys and gonads, as well as the vascular, muscular, and connective tissue structures of the body. At this stage, we could choose to follow the development of any of the organ systems, but for the purpose of this volume we will focus on the development of the gastrointestinal system. Other systems will be mentioned in a more cursory manner when their development affects the gastrointestinal system.
The central region of the ectoderm pinches together to invade the mesoderm and form the midline neural groove on the 14th day of development. As development proceeds from the 16th to 18th day, the neural groove pinches together and invades the mesoderm as the neural tube, which differentiates to form the spinal cord, brainstem, and cerebral cortex. After the neural tube has detached from the ectoderm, other ectodermal cells, called the neural crest cells, migrate into the mesoderm. These cells migrate throughout the developing mesoderm to form the sympathetic chain ganglia, ganglia of the cranial nerves, and postsynaptic parasympathetic ganglia, among others. The mesoderm also undergoes several changes: the paraxial mesoderm is found to the immediate left and right of the neural tube and will form somites, which in turn form the axial skeleton, musculature, and dermis. Just lateral to the par- axial mesoderm is the intermediate mesoderm, which differentiates into gonads and precursors of the kidneys. Lateral to the intermediate mesoderm is the lateral plate mesoderm, which contributes to the body wall, limbs, and connective tissue structures that anchor the organs within the body cavities. In the case of the digestive system, the lateral plate mesoderm forms the abdominal wall that contains the contents of the peritoneal cavity but it also forms the smooth muscle and connective tissues that surround and support the gastrointestinal tract. It also creates the mesenteries that connect the digestive organs to the anterior and posterior abdominal wall. As mentioned already, the endoderm forms the lining of the gastrointestinal tract and several of the organs that develop from it. We will now describe how the trilaminar embryo morphs to create the abdominal cavity and organs within.
The lateral plate mesoderm is continuous on its lateral edge with the extraembryonic mesoderm that surrounds the developing embryo. It is sandwiched by the ectoderm and amniotic cavity dorsally; the endoderm and secondary yolk sac are located ventral to it. At 14 days of development, the lateral plate mesoderm constitutes a single mesodermal region, but shortly there-after, gaps form within it that create a continuous, horseshoe-shaped space that extends from right to left, going around the cranial end of the embryo. This space is the intraembryonic cavity; as it enlarges, it becomes continuous with the extraembryonic cavity and it splits the lateral plate mesoderm into two layers. The parietal (somatic) layer of lateral plate mesoderm is the more superior of the two and is in direct contact with the ectoderm and amniotic cavity. The more inferior layer is the visceral (splanchnic) layer of lateral plate mesoderm and is in contact with the underlying endoderm and secondary yolk sac. This separation is complete but not really dramatic by the 16th day. However, as this space enlarges, it pushes the visceral layer and endoderm medially, creating a notable separation by the 18th day. The visceral layers of lateral plate mesoderm and endoderm on each side grow closer to each other, pinching the endoderm on the left and right, creating a tube that is separate from the rest of the secondary yolk sac. As this proceeds, the yolk sac stretches away from the developing gut tube and remains connected to it via the vitelline duct at the midgut, which will form the small intestine and part of the large intestine. Aside from its connection to the vitelline duct and secondary yolk sac, the rest of the endoderm and accompanying visceral lateral plate mesoderm fuse to form a complete tube that stretches from the oropharyngeal membrane (developing mouth) to the cloacal membrane (eventual anus and urogenital openings). This tube is the early gastrointestinal tract, and it will give rise to all the organs of digestion as well as the respiratory and urogenital tracts. From cranial to caudal, it is divided into the foregut (esophagus, stomach, proximal duodenum, liver, spleen, pancreas), midgut (distal duodenum, jejunum, ileum, vermiform appendix, cecum, ascending and transverse colon), and hindgut (descending colon, sigmoid colon, and rectum). In addition to the vitelline duct, another pouch of endoderm stretches away from the developing gut tube, the allantois. This pouch, originally a caudal extension of the primary yolk sac, extends off of the developing hindgut, and as development proceeds, it extends into the connecting stalk, cranial to the cloacal membrane. It contributes to the wall of the urinary bladder, but that is not our focus at this time. Eventually both the vitelline duct and allantois will extend along-side each other into the umbilical cord, and aberrations of each structure are associated with malformations of the midgut and urinary bladder, respectively.
While the gut tube is forming from the endoderm and visceral lateral plate mesoderm, a similar process is occurring with the ectoderm and parietal lateral plate mesoderm, so that a left and right lateral fold will form and fuse anteriorly to become the body wall. The left and right lateral folds first extend toward the yolk sac and then turn medially. As this happens, these layers pull the amniotic sac, which had previously covered a small area, to surround the entire developing embryo. Cross sections of the developing embryo at 18 days will appear remarkably different, depending upon whether or not the cross section includes the secondary yolk sac and vitelline duct. A cross section that includes the yolk sac will show an incompletely fused gut tube at the midgut, with the vitelline duct leading away from, and opening into, a ballooned yolk sac. The lateral folds have not yet migrated anteriorly enough to form a complete body wall. However, a cross section in a more posterior plane will exclude the yolk sac and show a fused anterior body wall surrounding a circular gut tube. The gut tube remains anchored to the anterior body wall by the ventral mesentery, which will largely disappear, and the dorsal mesentery, which will remain and transmit the vessels and nerves that connect the gut tube to the rest of the body. The gut tube, with its surrounding visceral layer of lateral plate mesoderm, separates the right and left peritoneal cavities, “descendants” of the intraembryonic coelom to either side. When the ventral mesentery disappears, there will be a single peritoneal cavity. By this time, the amniotic cavity almost entirely covers the developing embryo, with only a narrow span of mesoderm separating the right and left lateral folds.
Before 1 month of development has passed, the heart has descended into the thoracic region, bringing along a mesodermal structure, the septum transversum, which will contribute to the diaphragm. The septum transversum narrows the peritoneal cavity considerably, leaving two small openings between the pericardial cavity in the thorax and the peritoneal cavity in the abdomen. These are the pericardioperitoneal canals and they are normally closed as the diaphragm receives a left and right pleuroperitoneal membrane from the body wall. Contributions from the dorsal mesentery of the esophagus and muscle from the body wall assist in closing these canals and creating the diaphragm by the ninth week. Later, the musculature of the diaphragm develops as a secondary ingrowth from the body wall. The phrenic innervation from the cervical spinal cord to the diaphragm originates when the transverse septum first develops at the cervical level of the embryo. As the septum shifts to a low thoracic level, the phrenic nerves elongate. The commonest developmental abnormality of the diaphragm is a faulty growth of the left pleuroperitoneal membrane, resulting in an opening through which abdominal viscera may herniate into the left pleural cavity.
Caudal to the developing diaphragm is the foregut. The ventral and dorsal mesenteries remain in contact with the foregut, but the ventral mesentery disappears along the midgut and hindgut, leaving the developing gut tube suspended in the abdominal cavity. From the dorsal aorta, the celiac trunk supplies blood to the foregut, and its branches will supply all of the foregut organs as they develop. Extensions of the foregut stretch into the ventral and dorsal mesenteries to create the hepatic diverticulum and dorsal pancreatic bud, respectively. The hepatic diverticulum will form the liver and gallbladder but will also give rise to a ventral pancreatic bud, which will fuse with the dorsal pancreatic bud to form the entire pancreas. The ventral mesentery remains in contact with the developing liver, eventually forming the falciform ligament. The further development of this region will be covered in the sections related to the specific foregut organs, the esophagus, stomach, duodenum, liver, gallbladder, and pancreas.
During the sixth week the midgut has begun to elongate substantially and runs out of room within the peritoneal cavity. It moves into the umbilical cord, creating a physiologic umbilical herniation, which is a normal event in the development of the gastrointestinal system. The vitelline duct has narrowed but still connects the midgut to the secondary yolk sac, and this connection is one of the reasons that the physiologic herniation occurs, pulling the midgut into the umbilical cord. The vitelline duct will typically disappear roughly 10 weeks into development as the midgut starts returning to the peritoneal cavity. The superior mesenteric artery is derived from the vitelline artery and supplies all the developing midgut structures and, eventually, all organs of the midgut. The further development of this region will be covered in the sections related to the small and large intestines.
Development of the hindgut is intimately connected with the urinary and reproductive systems. All three systems initially empty into a common chamber, the cloaca, which is separated from the amniotic cavity by a cloacal membrane. The allantois extends from the cranial end of the cloaca and stretches into the umbilical cord alongside the vitelline duct. Between 4 and 7 weeks, the mesoderm located between the allantois and the vitelline duct/midgut, called the urorectal septum, extends caudally and separates the hindgut from the rest of the cloaca, which will hereafter be called the urogenital sinus. By the end of 7 weeks, the urorectal septum has totally partitioned the digestive and urogenital systems, leaving a urogenital membrane and anal membrane on the external surface of the body in the place of the cloacal membrane. The inferior mesenteric artery will supply all the hindgut organs. The further development of this region will be covered in the sections related to the large intestine and anal regions.
Although the foregut began as a simple, midline, tubular structure lined by epithelium derived from endoderm, it twists, expands, and elongates to create the adult relationships between each abdominal organ. Fusing and expansion of the dorsal mesenteries are key in this process. The portion of the foregut that will become the stomach first starts to expand in the sagittal plane, ballooning outward on its anterior and posterior surfaces. However, the expansion of the posterior surface quickly outpaces the other side and the stomach begins to bend. The enlarged expansion of the posterior side will become the stomach’s greater curvature, and the anterior side will become the lesser curvature. As this is happening, the presumptive stomach rotates so that the posterior side shifts toward the left of the body while the anterior right side shifts to the right. The rotation and expansion of the posterior side are what give the stomach its characteristic shape, with the esophagus entering just to the right of the fundus and greater curvature, and the outlet of the stomach, the pyloric region, shifting to the right and slightly superior to the greater curvature. This moves the stomach from a superior/inferior axis to more of a right/left axis within the abdomen. The inner, circular layer of muscle at the terminus of the stomach enlarges significantly to form the pyloric sphincter.
The rotation and expansion of the stomach do not occur in isolation. The foregut is attached to the posterior body wall by a dorsal (posterior) mesentery, called the dorsal mesogastrium, in which the spleen and dorsal part of the pancreas will develop. The section of this mesentery between the developing spleen and the stomach will become the greater omentum. Anteriorly it is connected to the liver, and thereafter, to the anterior body wall by a ventral (anterior) mesentery. The section of the ventral mesentery that attaches the liver to the anterior body wall will become the falciform ligament, and the section between the liver, stomach, and duodenum will form the lesser omentum. As the stomach’s posterior surface expands and rotates to the left, the attached mesentery follows, laying the spleen along the left side of the abdominal cavity. The dorsal mesentery between the stomach and spleen expands, folding onto itself and creating a large pocket between the two folds.
The pocket thus formed is called the omental bursa. Continued rotation and expansion of the greater curvature bring this double-layered “apron” to extend inferiorly from the stomach, falling anterior to the transverse colon and small intestine. The motion of the developing stomach and growth of the liver shift the stomach to the left and the liver to the right side of the abdomen. This also brings the omental bursa to lie anterior to the pancreas, inferior to the inferior surface of the liver, and posterior to the stomach and lesser omentum, which can be subdivided into the hepatogastric and hepatoduodenal ligaments. Occasionally the omental bursa can extend superiorly and posteriorly to the liver as the superior recess of the omental bursa. In its mature form, the omental bursa is isolated from the rest of the abdominal cavity, except for a small opening called the omental foramen located immediately posterior to the right edge of the hepatoduodenal ligament.