Introduction

The midgut is the middle segment of the early gut tube that ultimately produces most of the small intestine and a significant portion of the large intestine. The proper development of the midgut is crucial to the overall function of the human digestive tract. Early in development, the incipient embryonic gut is an endodermal-derived tube divided based on its arterial supply into three segments: the foregut, midgut, and hindgut. Each segment of the primordial gut gives rise to different parts of the adult gastrointestinal tract and outgrowth organs.

Midgut-derived organs are supplied by the superior mesenteric artery and include the duodenum distal to the entrance of the bile duct, the jejunum, ileum, cecum, appendix, ascending colon, and proximal two-thirds of the transverse colon. These organs are integral components of the digestive tract and collectively contribute to the digestion and absorption of nutrients, water, and salts that humans consume through their diet. The midgut development is a captivating process involving the rapid growth of the gut segment that outpaces the space available within the developing abdominal cavity. This forces the midgut to herniate outside of the abdominal cavity at the future site of the umbilicus and into the umbilical cord. Later in development, the segments along the midgut loop will derive structures of the mature gastrointestinal tract.[1]

Development

Early in embryonic development, just three weeks post-fertilization, gastrulation occurs. Gastrulation is the process that results in the development of three distinct germ layers. These layers include the endoderm, mesoderm, and ectoderm. Each of these three tissue layers contributes to an integral portion of the mature gastrointestinal tract. Endoderm produces the lining of the intestinal walls, including the associated glandular structures.[2] Mesoderm produces the lamina propria, muscular portions of the intestines, blood vessels, and connective tissues. Finally, the ectoderm produces the enteric nervous system, a partially autonomous nervous system also known as the intrinsic “pacemaker” of the GI tract. The enteric nervous system forms via the migration of ectodermally derived neural crest cells.[1]

Following gastrulation, primitive gut tube development begins as a hollow chamber of endoderm is then surrounded by mesodermal cells. The endodermal cells extend and fold at the anterior and posterior aspects of the tube. This process yields the primitive gut tube, which joins adjacent to the embryonic yolk sac to form a closed tube.[3] The primitive gut tube forms a blind-ending pouch that extends from the buccopharyngeal membrane to the cloacal membrane. The midgut is situated between the foregut and hindgut in this primitive gut tube. Unlike the foregut and hindgut, the midgut continues to communicate with the yolk sac via the vitelline, omphaloenteric, or omphalomesenteric duct. Through a series of complicated signaling pathways involving Sonic Hedgehog expression, interactions between epithelial and mesenchymal cell lines order the structures that form along the primitive GI tract.

Gut differentiation continues, and at about six weeks post-fertilization, the rapidly dividing and replicating midgut outgrows the abdominal cavity and herniates through the umbilical ring as a u-shaped midgut loop with a cranial and caudal limb and the vitelline duct as its apex. The development of the midgut then continues external to the abdominal cavity and embryo until roughly week ten of development. The cranial limb of the midgut loop produces the distal duodenum, the jejunum, and a proximal portion of the ileum. The caudal limb forms the remaining ileum, cecum, appendix, ascending colon, and proximal two-thirds of the transverse colon. The herniated midgut loop continues to elongate and rotates counter-clockwise when viewed anteriorly with the superior mesenteric artery as its axis for rotations. The midgut rotates 270 degrees around its primary blood supply, the superior mesenteric artery, during herniation and subsequent hernial reduction as it returns to the abdominal cavity.[4] 

Upon re-entering the abdominal cavity, the midgut segments lie in temporary positions within the abdominal cavity, with the cranial limb entering first and settling into the center and the caudal limb wrapping around it. From this point, the differential growth of segments of the midgut results in their repositioning to typical adult positions. For example, the cecal bud producing the mature cecum settles to a position inferior to the liver within the right upper quadrant. Eventually, differential growth allows the cecum to descend to a position at the right iliac fossa, and the distal end of the cecal bud forms the appendix. Any disruption or peritoneal fusion during the developmental descent of the cecum may lead to atypical positioning of the cecum and appendix in the adult.

Cellular

The midgut-derived small intestine extends from the duodenum just distal to the major duodenal papilla, the entrance of the common bile and major pancreatic ducts, and the ampulla of Vater and continues for the remainder of the small intestine. These small-bowel segments serve as the chief sites for digestion and nutrient 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 neutralize 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 abdominal bloating, diarrhea, and flatulence symptoms.[5]

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.[6] These cells have been investigated and found to synthesize and expel proteins and peptides that aid in the host's defense against invasive microorganisms.[7] 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.[8] 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.[9] 

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, including the mucosa, submucosa, muscularis externa or 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.[10]

Biochemical

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.[11]

Molecular Level

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 been shown to be necessary during A-P patterning.[2] 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.[1]

Function

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.

Mechanism

A multifaceted process involving biomechanical and molecular inputs contributes to the complex mechanisms underlying 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 anterior-posterior patterning process divides the primitive gut tube into distinct sections, which will function as individual segments of the future mature, functioning bowel.[12] Interactions between the three primitive germ layers have been demonstrated to be integral in midgut development, with the interactive process shown by the communication between the developing mesenchyme and endoderm. These two tissue layers have demonstrated integral functions in 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.[13]

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.[14][15] 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.

Testing

Many testing options are available for the various developmental anomalies in utero. Antenatal ultrasound can detect polyhydramnios, an excess of amniotic fluid commonly associated with intestinal atresia. The "double-bubble" sign found on prenatal ultrasound gives specific evidence toward diagnosing duodenal atresia, which may be in the organ's foregut- or midgut-derived segment. This ultrasonographic sign is from discontinuous segments of the bowel due to the abnormal development of the intestine. Atresia in more distal parts of the midgut is diagnosable with fetal MRI.[16]

Ultrasound is also the testing modality of choice for diagnosing gastroschisis and omphalocele, both conditions involving extraperitoneal abdominal organs. 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.[17] Meckel diverticulum is often first diagnosed incidentally on imaging but can be visualized with a Meckel radionuclide scan if there is high suspicion.[18] This condition occurs as a remnant of the vitelline or omphaloenteric duct, which is an open channel between the apex of the midgut loop and the yolk sac that fails to fully degenerate and close. 

Pathophysiology

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 often caused by a failure of the intestine to fully recanalize, leaving a non-patent lumen, and correlates with various conditions, including 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 often due to a disruption in the blood supply of the mesenteric vessels, leading to bowel discontinuity and ischemic necrosis.[19]

Midgut volvulus is a condition that infants can be predisposed to by intestinal malrotation during GI tract development. 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.[20]

The vitelline duct, or omphaloenteric duct, omphalomesenteric duct, or yolk stalk, is a tubular structure that allows communication between the midgut and the fetal yolk sac. This channel typically separates and disappears 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 diverticulum. Meckel diverticulum occurs when the vitelline duct is not entirely obliterated, and the remnant forms an outpouching of the ileum. Meckel diverticulum is the most common congenital anomaly of the gastrointestinal tract. It is usually located 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.[21] 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, leading to ulceration and bleeding.[18]

Intussusception is the telescoping or invagination of one segment of the 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 diverticulum. Associations with recent viral infections leading to hypertrophy of ileal lymphoid follicles and the rotavirus vaccine have also been implicated.[22] 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 the midgut fails 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.[23] A congenital umbilical hernia can arise when the umbilical ring fails to close following the herniation of the midgut.

Clinical Significance

The midgut development 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 embryonic development of the midgut helps in a deeper understanding of the basis of many congenital gastrointestinal conditions.