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.[1]

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.[2] 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.[1]

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.[3] 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.[4] 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.[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 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, 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.[10]

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]

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.[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]