The proper development of the midgut, which derives most of the small intestine and a significant portion of the large intestine, is crucial to the overall function of the human digestive tract. Midgut derived structures include the duodenum distal to the ampulla of Vater, the jejunum, ileum, cecum, ascending colon, and foremost two-thirds of the transverse colon. These structures are integral components of the digestive tract and are responsible for the digestion and absorption of many nutrients that humans consume through their diet. The embryological development of the midgut is a captivating process with the rapid growth of its derived structures outpacing the space available within the embryological abdominal cavity, forcing the midgut to herniate out from the abdomen and into the umbilical cord forming a loop. Different locations found along this loop will go on to derive structures located within the mature gastrointestinal tract.
Early on in embryologic development, specifically week three, a process referred to as gastrulation occurs. Gastrulation is the process in which the development of three distinct germ tissue layers forms. These layers include the endoderm, the mesoderm, and the ectoderm. Each one of these three layers contributes to an integral portion of the mature gastrointestinal tract. The endoderm derives the lining of the intestinal walls, including the associated glandular structures. The mesoderm derives the lamina propria and muscular portions of the intestines, as well as blood vessels and connective tissues. Finally, the ectoderm contributes to the enteric nervous system, otherwise known as the intrinsic “pacemaker” of the GI tract. This forms via migration of neural crest cells.
Following gastrulation, the development of the primitive gut tube begins as a hollow chamber of endodermis surrounded by mesodermal cells. The endodermal cells then extend and fold at the anterior and posterior aspects of the tube. This process yields the primitive gut tube, which joins adjacent to the embryologic yolk sac forming a closed tube. The primitive gut tube forms a blind-ending pouch that extends from the buccopharyngeal membrane to the cloacal membrane. The location of the midgut is between the foregut and hindgut in this primitive gut tube. Unlike the foregut and hindgut, it remains connected to the yolk sac via the vitelline duct. Through a series of complicated signaling pathways utilizing Sonic Hedgehog expression, interactions between epithelial and mesenchyme cell lines dictate the specific structure that will form along the primitive GI tract.
Differentiation continues, and starting around week six of gestation, the rapidly dividing and replicating midgut outgrows the abdominal cavity and herniates through the umbilical ring. The development of the midgut then continues outside of the abdominal cavity until roughly week ten of development. The cephalic portion of the intestinal loop develops into the distal duodenum, the jejunum, and a part of the ileum. The caudal limb becomes the remaining ileum, cecum and appendix, ascending, and proximal two-thirds of the transverse colon. The herniated intestinal loop continues to grow and rotates a total of 270 degrees around its primary blood supply, the superior mesenteric artery, during herniation, and return to the abdominal cavity. Upon return to the abdominal cavity, the segments of the midgut come to lie in temporary positions within the abdominal cavity. From here, the intestines migrate to their anatomically mature positioning. For example, the cecal bud, which derives the mature cecum, is the last part of the intestinal loop to return to the abdomen. It provisionally presides in the right upper quadrant, but eventually descends into the right iliac fossa, all the while the distal end of this bud forms the appendix. Any disruption in the positioning of the descent of the cecum can lead to mispositioning of the appendix.
The midgut derived small intestine starts with the duodenum distal to the ampulla of Vater and ends at the terminal ileum. These small-bowel segments serve as the chief sites for digestion and absorption. Contributions from the stomach like chyme, enzymes from the pancreas, and bile from the liver all meet in the duodenum for continued digestion and solubilization. Glands found in the submucosa of the duodenum known as Brunner’s glands are a diagnostic feature of the duodenum, and function to secrete alkaline secretions that assist in neutralizing acidic chyme from the stomach. The small intestine increases its surface area with microvilli, which sit atop absorptive cells or enterocytes. It is here in the glycocalyx of the microvilli, where enzymes like disaccharidases and dipeptidases exist. A genetic deficiency in the disaccharidase lactase leads to lactose intolerance, which can present in a patient with symptoms of abdominal bloating, diarrhea, and flatulence.
The small intestine also contains gland-like structures known as crypts of Lieberkuhn. These structures form by invaginations of the mucosal surface of the intestine between adjacent microvilli and house, a necessary cell type known as Paneth cells. These cells have been investigated and found to synthesize and expel proteins and peptides that aid in the host defense against invasive microorganisms. Intestinal stem cells also reside at the base of these crypts. Each segment of the small intestine contains goblet cells, which are responsible for the production of mucus. The quantity of goblet cells increases as one moves distally through the small intestine. A diagnostic feature of the ileum is grouped lymphoid follicles known as Peyer’s patches. These patches contain immune cells known as M cells that can transfer luminal antigens to mediating immune cells below. They play a significant role in the mucosal immunity of the ileum. Neurons of the enteric plexus, which control gut motility, are located between circular and longitudinal muscular layers and in the submucosa of the small and large intestines.
The structures of the large intestine that derive from the midgut are the cecum, ascending colon, and the proximal two-thirds of the transverse colon. The large bowel functions to reabsorb water and electrolytes and to store and dispose of undigested food products. The cellular makeup of the midgut derived large bowel is like that of the small intestine and includes crypts of Lieberkuhn, goblet cells, and enterocytes, but lacks the microvilli present in the small bowel. The large bowel contains muscle bands that run longitudinally on its outer surface, known as teniae-coli. When these bands of muscle contract, saclike dilations of the colon referred to as haustra form. The vermiform appendix attaches to the cecum at the connection of the small and large intestines. The appendix contains the same layers as the large intestine, which includes the mucosa, submucosa, muscularis propria, and serosa. The appendix also has a large number of lymphatic nodules and has implications as an essential component of the immune interaction with bacteria found in the intestines.
The complexity of midgut development takes place with the help of the simultaneous development of the enteric plexus. Nitric oxide assists in the movement of the midgut during this embryological period. Without nitric oxide, the developing midgut experiences a dampened response to neuronal signals, which leads to a reduced frequency of contractions and potentially abnormal development.
Multiple signaling pathways participate in the complex development of the midgut. The signaling protein nodal is responsible for differentiation into either mesoderm or endoderm. Higher-level exposures to nodal go on to form endoderm, while lower-level exposures favor mesoderm. Nodal has also shown to be necessary during A-P patterning. A-P patterning helps differentiate structures derived from the foregut, midgut, and hindgut. The microvilli that line the intestinal walls develop molecularly through coordination by the endoderm and mesoderm using Hedgehog signals.
The midgut functions as the deriving source of gastrointestinal structures that help the body digest and absorb nutrients consumed through diet. The mature midgut derived structures play roles in the digestive, immune, enteric nervous, and endocrine systems.
A multifaceted process involving biomechanical and molecular inputs contribute to the complex mechanism behind the developing midgut. The primitive gut tube forms following the initiation of gastrulation around week 3 of embryologic development, and it continues to develop with patterning along the tube’s A-P axis. This process of anterior-posterior patterning divides the primitive gut tube into distinct sections, which will function as individual segments of the future mature, functioning bowel . Interactions between the three primitive germ layers have demonstrated to be integral in the development of the midgut, with the interactive process shown by the communication between the developing mesenchyme and endoderm. These two tissue layers have shown to demonstrate integral functions on the final positioning and morphology of distinct cell lines that make up midgut structures; this cross-talk continues throughout life and contributes to stem cell maintenance within the intestinal crypts of the mature intestinal tract .
Through a Sonic Hedgehog gradient that starts in the endoderm and distributes throughout the mesoderm, this signaling cascade allows for the vilification of the intestines and further development of the inner muscular layers that are found within the bowel walls . The final resting positioning of midgut derived gastrointestinal structures is completed following intestinal looping and return to the embryologic abdominal cavity, involving many similar biomechanical and molecular mechanisms and signaling cascades.
There are many testing options available for the various developmental anomalies that can present in utero. Antenatal ultrasound can detect polyhydramnios, which is commonly associated with intestinal atresia. The “double-bubble” sign found on prenatal ultrasound gives specific evidence toward a diagnosis of duodenal atresia. This ultrasonographic sign is from discontinuous segments of the bowel due to the underdevelopment of the intestine. Atresia in more distal parts of the midgut is diagnosable with fetal MRI.
Ultrasound is also the testing modality of choice for diagnosing gastroschisis as well as omphalocele. Ultrasound has proven very efficient in finding most omphaloceles within the first trimester. Prenatal serum studies in the mother will also show increased serum alpha-fetoprotein. Meckel’s diverticulum is often first diagnosed incidentally on imaging but can be visualized with a Meckel radionuclide scan if there is high suspicion.
The midgut is subject to a variety of potential pathologies during embryologic development. Intestinal atresia can present with bilious vomiting early in the life of the newborn. Duodenal atresia is generally thought to be due to a failure of the intestine to recanalize, leaving a non-patent lumen and correlates with Down syndrome. A double bubble sign on a radiograph will be present due to the dilated stomach and proximal duodenum. Jejunal and ileal atresia is due to a disruption in the blood supply of the mesenteric vessels, leading to bowel discontinuity and ischemic necrosis.
Midgut volvulus is a condition that infants can be predisposed to by intestinal malrotation during the development of the GI tract. Malrotation can happen anywhere along the bowel and increases the likelihood that the child will advance to acquiring a midgut volvulus, which is the intestines winding upon one another; this condition can include disruption of blood flow to the involved segments of the bowel leading to necrosis.
The vitelline duct, or omphalomesenteric duct, is a tubular structure that allows communication between the midgut and the fetal yolk sac. This structure separates typically and is wiped out spontaneously during weeks 5-9 in fetal development. Pathologies associated with abnormal separation and obliteration of the vitelline duct include vitelline cyst, vitelline fistula, and Meckel’s diverticulum. Meckel’s diverticulum occurs when the vitelline duct does not get entirely obliterated, and the remnant forms an outpouching of the ileum. The most common congenital anomaly of the gastrointestinal tract and is usually within two feet of the ileocecal valve is roughly two inches long, is twice as common in males, and occurs in approximately 2% of newborn babies. It is a true diverticulum because it contains all the layers of the small intestine. Still, it can also possess ectopic tissue from the pancreas or gastric mucosa, which can lead to ulceration and bleeding.
Intussusception is the telescoping or invagination of one segment of bowel into another. It most commonly appears at the junction of the ileum and cecum. Intussusception is most often due to a lead point such as a malignancy or Meckel’s diverticulum. Associations with recent viral infection leading to hypertrophy of ileal lymphoid follicles and the rotavirus vaccine have also been implicated. Patients will present with intermittent severe abdominal pain, red currant jelly stools, and an ultrasonographic finding known as a “target sign.”
Gastroschisis and omphalocele are conditions that can occur when there is a failure of the midgut to return to the peritoneal cavity after its herniation and rotation around week six of gestation. The critical difference between gastroschisis and omphalocele is that an omphalocele is herniated bowel covered by the amnion. In contrast, in gastroschisis, the viscera are not covered and have direct exposure to amniotic fluid. Omphalocele is due to an abdominal wall defect. In comparison, gastroschisis is thought to be due to herniated bowel not being able to return to the abdominal cavity correctly. A congenital umbilical hernia can arise when there is a failure of the umbilical ring to close following the herniation of the midgut.
The development of the midgut is a multifaceted process requiring regulatory genes and signaling pathways. The interaction among embryologic tissues and growth factors involved in this process of midgut differentiation is subject to a variety of insults that can be the source of specific pathologies diagnosed either in utero or postpartum. A sound understanding of the embryological development of the midgut helps in a deeper understanding of the basis of many congenital gastrointestinal conditions.
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