Comprehension of small intestine physiology and function provides a framework for the understanding of several important disease pathways of the gastrointestinal system. This article reviews the development, anatomy and histology of the small bowel in addition to physiology and digestion of key nutrients.
Key points
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Embryologically, weeks 9 and 10 are critical time points with the potential for development of malrotation.
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Abnormalities in neural crest cell migration during the first trimester may lead to various neuropathies, one of the most common being Hirshsprung disease.
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The enteric nervous system plays a critical role in gut motility, secretion, and immune function.
Embryology
Development of Morphologic Structures
A review of the gut embryologic process provides a framework for understanding the function of the small bowel as well as the pathways that may lead to small intestinal disease. For the purpose of this review, the development of the small intestine is briefly examined with a focus on the major events outlined in Table 1 .
| Weeks | Major Developmental Milestones |
|---|---|
| 3 | Gastrulation: Early tubular gut formation; early formation of major digestive glands |
| 4 | Gut tube closes |
| 5 | Intestinal loop beginning to form |
| 7 | Herniation of intestinal loop |
| 8 | Intestine rotates in a counterclockwise direction and recanalizes; early innervation of parasympathetic neural precursors |
| 9 | Herniated gut returns into body cavity; epithelial cells differentiate |
| 11 | Small intestine begins to develop villi; goblet cells differentiate |
| 12 | Intestinal enzymes present |
| 20 | Peyer patches seen in small intestine |
Morphogenesis begins with gastrulation, the process of cell migration through the primitive streak, with eventual formation of the three fundamental germ layers of the embryo: ectoderm, mesoderm and endoderm. Although the small intestine is composed of cells that originate in all 3 layers, it is from the endoderm that the gastrointestinal (GI) tract initially develops and ultimately gives rise to the epithelium of the GI tract.
The intestinal lumen first takes the form of an elementary tube during the fourth week of embryogenesis when the cranial, lateral and caudal edges of the trilaminar embryonic disk fold under the dorsal axial structures and are brought together along the now ventral surface of the embryo. The process of tube formation is mediated by several genes, including GATA4, FOXA2, and SOX9. The assignment of biologic fate to small intestine cells, a process called specification, is triggered by CDXC. The acquisition of specialized features of the small intestine is dependent on interactions between the endoderm and mesoderm via the Hox signaling pathway. The resulting simple tubular structure consists of two blind ends on the cranial and caudal sides representing the foregut and hindgut, respectively. Between these two blind ends resides the future midgut. At this stage, the midgut remains largely open to the yolk sac, which has grown at a slower rate than the embryo. As development continues, the edges of the embryonic disc fuse together with the lateral margins of the midgut, forming a lumen, while the prior open connection to the yolk sac is reduced to a narrow tube called the vitelline duct.
In the fifth week, the midgut has elongated to such a degree that it is forced to fold, thus forming the primary intestinal loop; by the sixth week, this loop herniates through the umbilicus ( Fig. 1 ). Herniation of the bowel wall is necessary because the length of the gut increases faster than the length of the embryo and due to crowding by the proportionally larger liver and kidneys at this stage of development. The developing intestinal tract returns to the abdominal cavity between weeks 9 to 10 when the abdominal cavity is large enough to accommodate the intestinal tract. During the process of herniation, the intestinal loop rotates counterclockwise 90°, resulting in an ileum that lies in the right abdomen. As the intestinal loop returns into the abdominal cavity, it rotates an additional 180° counterclockwise, resulting in the final configuration of the gut in the abdominal cavity. This process is complete by week 11.
Formation of Villi
The villi of the small intestine form from simple epithelium during week 11. Villi and crypts develop in a coordinated manner, because villi formation is accompanied by invagination into the mesoderm, which eventually forms the intestinal crypts. This process is in part mediated by Shh and Ihh. Beginning during early development, and progressing through adulthood, the epithelial cells of the small intestine need to be constantly replaced due to frequent turnover. Stem cells located at the base of intestinal crypts are integral to this process. Stem cells generate progenitors for the epithelial cells lining the small intestine, a process mediated by several important signaling pathways including Wnt, Notch, and hedgehog. As these cells mature, they migrate up the villus, where they eventually interface with the intestinal lumen.
Development of the Enteric Nervous System
Neural crest cells are the source of the enteric nervous system (ENS). The vagal neural crest supplies ganglia to the intestine, and its innervation is completed by week 13 of development. Disturbances of this process can result in genetic abnormalities, such as Hirschsprung disease and intestinal neuronal dysplasia.
Embryology
Development of Morphologic Structures
A review of the gut embryologic process provides a framework for understanding the function of the small bowel as well as the pathways that may lead to small intestinal disease. For the purpose of this review, the development of the small intestine is briefly examined with a focus on the major events outlined in Table 1 .
| Weeks | Major Developmental Milestones |
|---|---|
| 3 | Gastrulation: Early tubular gut formation; early formation of major digestive glands |
| 4 | Gut tube closes |
| 5 | Intestinal loop beginning to form |
| 7 | Herniation of intestinal loop |
| 8 | Intestine rotates in a counterclockwise direction and recanalizes; early innervation of parasympathetic neural precursors |
| 9 | Herniated gut returns into body cavity; epithelial cells differentiate |
| 11 | Small intestine begins to develop villi; goblet cells differentiate |
| 12 | Intestinal enzymes present |
| 20 | Peyer patches seen in small intestine |
Morphogenesis begins with gastrulation, the process of cell migration through the primitive streak, with eventual formation of the three fundamental germ layers of the embryo: ectoderm, mesoderm and endoderm. Although the small intestine is composed of cells that originate in all 3 layers, it is from the endoderm that the gastrointestinal (GI) tract initially develops and ultimately gives rise to the epithelium of the GI tract.
The intestinal lumen first takes the form of an elementary tube during the fourth week of embryogenesis when the cranial, lateral and caudal edges of the trilaminar embryonic disk fold under the dorsal axial structures and are brought together along the now ventral surface of the embryo. The process of tube formation is mediated by several genes, including GATA4, FOXA2, and SOX9. The assignment of biologic fate to small intestine cells, a process called specification, is triggered by CDXC. The acquisition of specialized features of the small intestine is dependent on interactions between the endoderm and mesoderm via the Hox signaling pathway. The resulting simple tubular structure consists of two blind ends on the cranial and caudal sides representing the foregut and hindgut, respectively. Between these two blind ends resides the future midgut. At this stage, the midgut remains largely open to the yolk sac, which has grown at a slower rate than the embryo. As development continues, the edges of the embryonic disc fuse together with the lateral margins of the midgut, forming a lumen, while the prior open connection to the yolk sac is reduced to a narrow tube called the vitelline duct.
In the fifth week, the midgut has elongated to such a degree that it is forced to fold, thus forming the primary intestinal loop; by the sixth week, this loop herniates through the umbilicus ( Fig. 1 ). Herniation of the bowel wall is necessary because the length of the gut increases faster than the length of the embryo and due to crowding by the proportionally larger liver and kidneys at this stage of development. The developing intestinal tract returns to the abdominal cavity between weeks 9 to 10 when the abdominal cavity is large enough to accommodate the intestinal tract. During the process of herniation, the intestinal loop rotates counterclockwise 90°, resulting in an ileum that lies in the right abdomen. As the intestinal loop returns into the abdominal cavity, it rotates an additional 180° counterclockwise, resulting in the final configuration of the gut in the abdominal cavity. This process is complete by week 11.
Formation of Villi
The villi of the small intestine form from simple epithelium during week 11. Villi and crypts develop in a coordinated manner, because villi formation is accompanied by invagination into the mesoderm, which eventually forms the intestinal crypts. This process is in part mediated by Shh and Ihh. Beginning during early development, and progressing through adulthood, the epithelial cells of the small intestine need to be constantly replaced due to frequent turnover. Stem cells located at the base of intestinal crypts are integral to this process. Stem cells generate progenitors for the epithelial cells lining the small intestine, a process mediated by several important signaling pathways including Wnt, Notch, and hedgehog. As these cells mature, they migrate up the villus, where they eventually interface with the intestinal lumen.
Development of the Enteric Nervous System
Neural crest cells are the source of the enteric nervous system (ENS). The vagal neural crest supplies ganglia to the intestine, and its innervation is completed by week 13 of development. Disturbances of this process can result in genetic abnormalities, such as Hirschsprung disease and intestinal neuronal dysplasia.
Anatomy
Macroscopic Features
At the most basic level, the small intestine is a 6- to 7-m-long hollow tube that begins at the pylorus and ends at the ileocecal valve. The most proximal portion of the intestine is the duodenum, which is traditionally divided into 4 sections ( Fig. 2 ). The duodenum starts at the pylorus with the duodenal bulb; superficially this corresponds to just above the level of the umbilicus. The first part of the duodenum is the only portion that is not retroperitoneal and is instead connected to the liver by a part of the lesser omentum called the hepatoduodenal ligament. The duodenum then quickly travels into the retroperitoneal space and descends as it sweeps around the head of the pancreas. The descending portion of the duodenum is the site of the major and minor duodenal papilla. The major duodenal papilla serves as the common entrance for the bile and pancreatic ducts, whereas the minor duodenal papilla is the entrance for the accessory pancreatic ducts. The duodenum then returns to the peritoneal cavity at the level of the L2 vertebra, where it is fixed to the retroperitoneum by a suspensory ligament called the ligament of Treitz, marking the transition from duodenum to jejunum.
The jejunum resides primarily in the left upper quadrant of the abdomen, is approximately 2.5 m in length, and is suspended in the peritoneal cavity by a thin mesentery attached to the posterior abdominal wall, which allows for relatively free movement. Examination of the luminal surface of the jejunum reveals plicae circulares, which represent circular mucosal and submucosa folds that serve to increase surface area. Plicae circulares are particularly numerous in the proximal jejunum but also exist in the duodenum and decrease as one moves distally in the small bowel and are totally absent by the terminal ileum. Lymphoid follicles can be visualized in the small intestine, particularly in children. They are most numerous in the ileum and are called Peyer patches.
The jejunum transitions to the ileum without an anatomic delineation and is primarily found in the right lower abdomen and pelvis. The jejunum is distinguished from the ileum by its thicker lumen and more prominent mucosal folds. The small bowel ends at the ileocecal valve, which is composed of 2 semilunar lips that protrude into the cecum and serve as a barrier to retrograde flow of colonic contents into the small intestine. The function of the valve relies on the angulation between the ileum and cecum, which is created by the superior and inferior ileocecal ligaments. The mesentery is a double-layered fold of peritoneum with fat, blood vessels and the lymphatic system residing within these layers. Its superior attachment is at the duodenal-jejunum junction, and its posterior attachment is near the ileocecal junction at the upper border of the right sacro-iliac joint.
Histology
The small intestine is composed of 4 layers: mucosa, submucosa, muscularis propria, and adventitia (serosa).
Mucosa
The lumen-facing surface of the small intestine is lined by the mucosa, which is composed of 3 distinct layers: epithelium, laminal propria, and muscularis mucosae. The predominant cell type of the epithelium is absorptive cells called enterocytes. Each enterocyte has approximately 3000 microvilli at its luminal surface, which appear as a striated brush border on the surface of the villi. The villi, microvilli and plicae circulares together increase the absorptive surface of the small intestine by 600-fold.
The epithelial cells lining the lumen are organized in a crypt-villi axis and are constantly proliferating and differentiating. Fueling this proliferation are intestinal stem cells located in the crypt base. As the cells differentiate, they migrate in a vertical direction to the apical portion of the villus. These cells differentiate into 1 of 7 different cell types (absorptive enterocytes, enteroendocrine cells, Paneth cell, goblet cells, tuft cell, cup cells, and M cells). These terminally differentiated cells serve many roles, as outlined in Table 2 .
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