Anatomy and Physiology of the Small Intestine

Anatomy and Physiology of the Small Intestine Jacob Campbell 

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  James Berry 

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  Yu Liang

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he small intestine is the longest organ in the gastrointestinal (GI) tract. It is responsible for the absorption of nutrients, maintaining water and electrolyte balance, providing an immunologic barrier, and endocrine secretion.

EMBRYOLOGY During the fourth week of gestation, the flat embryonic endoderm folds and fuses in the midline to create the gut tube. The tube consists of the foregut, midgut, and hindgut. The midgut, which will give rise to the distal duodenum, jejunum, and ileum, is located in the middle of this tube and is open to the yolk sac. During development, the connection between the midgut and the yolk sac will close and become only a thin stalk known as the vitelline duct. A Meckel diverticulum is the persistent remnant of this structure. The endoderm will form the epithelial lining of the digestive tract, and the splanchnic mesoderm will give rise to the muscle, connective tissue, and peritoneal components of the gut wall. Throughout gestation, the small intestine will lengthen and rotate. By the fifth to seventh weeks, the midgut will have outgrown the capacity of the abdominal cavity, forcing it into a hairpin loop configuration and then herniating into the umbilical cord. As it herniates, the loop rotates 90 degrees counterclockwise. This rotation places the ileum in the left quadrant of the abdomen. Between the tenth and twelfth weeks, the midgut retracts back into the abdomen and will rotate an additional 180 degrees. By the end of the twelfth week, the midgut has rotated 270 degrees counterclockwise. The superior mesenteric artery is the axis of this rotation (Fig. 71.1). The rotation of the intestines is important for establishing the permanent location of the abdominal organs. The proximal jejunum is positioned on the left side of the abdomen and the remaining loops of intestine will be displaced to the right. Errors in midgut rotation result in congenital malrotation. Omphalocele results from mistakes in the midgut returning to the abdominal cavity. The location of the duodenum is affected by stomach rotation and pancreas development. As the stomach rotates during gestation, the duodenum will move to the right of the abdomen and up against the dorsal wall, and it will become retroperitoneal. The fusion of the ventral and dorsal pancreatic buds displaces the duodenum laterally creating the characteristic C-loop.1,2

CELL DIFFERENTIATION It is known that the gut develops along four different axes: (1) anterior-posterior, (2) dorsal-ventral, (3) left-right, and (4) radial. The development and differentiation of different regions of the gut are dependent on reciprocal

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interaction between the endoderm and the splanchnic mesoderm. In the initial stages of formation, the intestinal tract is lined by simple columnar endodermal epithelium that is surrounded by splanchnopleuric mesoderm. During the sixth week, the endodermal epithelium proliferates and occludes the lumen completely. Over the next 2 weeks, vacuoles will develop and coalesce to create a hollow tube. This process is known as recanalization. Duplication cysts and intestinal stenosis are the result of errors in recanalization. After this process is complete, the mucosal layer will develop villi as aggregates of mesoderm push through the epithelium. The submucosal connective tissue and smooth muscle layers arise from the mesodermal coating of the gut tube. During the creation of the villi, pitlike intestinal crypts form at the base of the villi. Epithelial stem cells reside within the crypt and undergo a high rate of mitosis, which gives rise to the epithelial cells for the entire intestine. The epithelial cells within each crypt are of monoclonal origin. The stem cell divides into daughter cells, leaving one daughter cell anchored in the crypt, whereas the other continues to divide and migrate up the side of the crypt and onto the villus. This division and migration is responsible for renewing the intestinal lining in a rapid manner. While in utero, the stem cells will differentiate into one of the four major epithelial cell types: Paneth, enteroendocrine, goblet, or enterocyte (the function of each cell will be discussed in a later section) (Fig. 71.2). At 12 weeks of gestation, cell differentiation has begun but maturation will continue during the fetal period and through the first months of life. The cells will not develop digestive function until exposed to food. The first stool, meconium, is actually lanugo, a mixture of vernix caseosa from the skin, desquamated cells from the gut, and bile.

ANATOMY The small intestine is approximately 7 meters in length, starting at the pylorus and ending at the ileocecal valve (ICV). It is divided into three sections: the duodenum, jejunum, and ileum. The majority of the duodenum is located in the retroperitoneum, whereas the jejunum and ileum are intraperitoneal structures. The lumen of the small intestine is a complex arrangement of structures that aid in nutrient absorption. Each structure is responsible for increasing the surface area of the intestine to enhance digestion and absorption of nutrients. The net result is a 600- to 1000-fold increase in surface area for a total of 250 to 400 m2. The epithelium of the small intestine is replaced every 3 to 6 days and can be influenced by a variety of factors. The rapid turnover and high mitotic rate of the cells makes the intestinal

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Anatomy and Physiology of the Small Intestine  CHAPTER 71 

ABSTRACT The small intestine is the longest organ in the gastrointestinal (GI) tract. It is responsible for the absorption of nutrients, maintaining water and electrolyte balance, providing an immunologic barrier, and endocrine secretion.

KEYWORDS Small bowel embryology; small bowel anatomy; small bowel blood supply; duodenum; digestion; absorption of nutrient and electrolyte; enterohepatic circulation; small bowel motility; small bowel immune defense

817.e1

818

SECTION II  Stomach and Small Intestine Superior mesenteric artery

Small intestine

Jejunum and ileum

Caecum 7 weeks

8 weeks

Caecum Jejunum

Ileum

Early 3rd month

Caecum descending inferiorly

Mesentery

Stomach

Superior mesenteric artery

Colon

Rectum Late 3rd month

FIGURE 71.1  During gestation the midgut outgrows the capacity of the abdominal cavity and herniates into the umbilicus, rotating 90 degrees counterclockwise. The midgut will rotate an additional 180 degrees as it retracts back into the abdomen around the 10th to 12th week of gestation for a total rotation of 270 degrees. (From Mitchell B. Embryology: An Illustrated Color Text. 2nd ed. Oxford: Churchill-Livingstone; 2005, Fig. 7.11, p. 45.)

lining susceptible to the effects of radiation and chemotherapy. The wall of the small intestine is made up of four main layers: the mucosa, submucosa, muscularis propria, and serosa. The innermost layer is the mucosa. It is composed of three separate layers: epithelium, lamina propria, and muscularis mucosae. The mucosa is the site of absorption of nutrients and water from the intestinal lumen. The submucosa is the strength layer of the bowel wall and is composed of dense connective tissue. When completing a bowel anastomosis, it is important to incorporate suture through this layer of tissue to ensure integrity of the anastomosis. Blood vessels and lymphatics, including Peyer patches and Brunner glands, are found in this layer of the bowel wall. The Meissner, or submucosal plexus, is also located in the submucosa and is an integral component of the enteric nervous system (ENS). It is responsible for regulating bowel motility and secretion in the mucosal layer. The muscularis propria is composed of two smooth muscle layers, an outer longitudinal layer, and an inner circular layer. The myenteric, or Auerbach plexus, is situated between these two muscle layers and, like the Meissner plexus, helps control bowel motility and secretion. The serosa is the outermost layer of the bowel wall and is a single layer of mesothelial cells (Fig. 71.3). Plicae circulares are transverse folds of mucosa and submucosa that aid in absorption of nutrients by increasing the surface area of the small intestine threefold. These folds are deep and visible on gross inspection and on radiographic imaging, even when the small intestine is distended. Villi are fingerlike projections of the mucosa that are present along the entire length of the small intestine. The villi are longest in the duodenum, where most of the digestion and absorption occurs, and shortest in the distal ileum. They increase the absorptive area 10-fold. The villus is coated with a single layer of columnar epithelial cells, called enterocytes. Between the enterocytes are goblet cells that secrete mucin. The mucin will lubricate and protect the intestinal wall as chyme and undigested food passes. Goblet cells become more prominent throughout the length of the small intestine. At the base of each villus are 0.3- to 0.5-mm invaginations of intestinal mucosa called intestinal crypts or crypts of Lieberkühn. Crypt cells are responsible for mitosis and secretion of fluid and electrolytes. Each crypt is monoclonal and contains only one stem cell type. The stem cell divides into daughter cells, leaving one daughter cell anchored in the crypt, whereas the other continues to divide and migrate up the side of the crypt and onto the villus. On the villus, the daughter cell may differentiate into a goblet cell, an enterocyte, or an enteroendocrine cell. The enterocyte will continue to mature as it migrates toward the apical end of the villus and take on increased digestive and absorptive ability. Enteroendocrine cells produce hormones that modulate the digestive process by altering secretion and motility. Other cells may migrate to the bottom of the crypt to become Paneth cells. The purpose of the Paneth cell is discussed in detail in the immunology section. Within each villus is a rich vascular supply from an arteriole and a venule that contribute to a network of

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

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Enterocyte

1400 cells/villus shed into lumen/day

4 days

Goblet cell

0 days

IIII

I I III I I

I I I I IIIIIIIII

IIIII

IIIIIII

Stem cell

II

II

Crypt

Stem cell

Enteroendocrine cell

II

Crypt

I I I I IIIIIII

III

I II I I I 1 day

II

I I I I II

I I II

II I

Villus

I II I I I I I I I I I I I I I I I I I I I

III

Villus

IIIIIIIIIIIIIIIIIII I I

2 days

I I I I I I I I I I I I I I I III I I I I

3 days

IIII I

IIIIII

II I I I I I I I I I I I I I I I

II II

III

I II

Paneth cell

FIGURE 71.2  Stem cells differentiate in utero into one of four major epithelial cell types: Paneth, enteroendocrine, goblet, or enterocyte. (From Carlson B. Human Embryology and Developmental Biology. 2nd ed. St Louis: Mosby; 2004, Fig. 14.10, p. 331.) Vascular network, longisection of villus Simple columnar epithelium with mucous cells 4 Mucous membrane

Lamina propria, smooth muscle cells, blood vessels

4

Central lymph capillary (lacteal) Openings of crypts (of Lieberkühn) Muscularis mucosae

3

3 Submucosa 2 Muscularis externa Subserous layer

Circular layer

2

Longitudinal layer

1

1 Serosa

FIGURE 71.3  There are four main layers of the small intestine. The outermost layer is the serosa followed by the subserosa. Next is the muscularis externa, which is made up of an outer longitudinal and an inner circular layer. The submucosa layer is next and the innermost layer is the mucous membrane, which consists of the intestinal villi. (From Sobotta J, Figge FHJ, Hild WJ. Atlas of Human Anatomy. New York: Hafner; 1974.)

capillaries. There is also a lacteal, a lymphatic capillary that runs the length of the villus. The lacteal can absorb larger particles containing lipids and lipid-soluble vitamins (Fig. 71.4). These particles are known as chylomicrons, which are generated by neighbor enterocytes as they absorb and process lipid.

Microvilli are tiny projections of the plasma membrane that line the apical border of the enterocyte. The microvilli are coated with a thick glycocalyx that aids in nutrient absorption and serves as a protective barrier. In addition, many enzymes necessary for digestion and absorption, collectively referred to as the brush border enzymes, are

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SECTION II  Stomach and Small Intestine Cell extrusion zone

Villous epithelium

Lamina propria Blood vessels Lymph vessels Nerves Smooth muscle Connective tissue Lymphocytes Plasma cells Eosinophils

Absorptive cells Goblet cells

Crypt epithelium

Paneth cells EnteroMitoses chromaffin Goblet cells cells Undifferentiated cells

Crypt lumen

Muscularis mucosae

FIGURE 71.4  Schematic representation of small intestinal mucosa. (From Townsend C, Beauchamp RD, Evers BM, et al., eds. Sabiston Textbook of Surgery. 18th ed. Philadelphia: Saunders; 2008. Modified from Keljo DJ, Gariepy CE. Anatomy, histology, embryology, and developmental anomalies of the small and large intestine. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathology/Diagnosis/Management. Philadelphia: Saunders; 2002:1646.)

released within this layer. These enzymes include nucleosidases, peptidases, and disaccharidases. Millions of microvilli make up the brush border and function to increase the surface area of the intestine another 20-fold. Brunner glands are acinotubular glands found mostly in the proximal two-thirds of the duodenum. They secrete an alkaline mucus-like substance that protects the duodenum from the acidic chyme produced by the stomach. The substance also lubricates the intestine and provides an alkaline environment essential for the activation of enzymes important for digestion and absorption. Many protective factors have been identified within Brunner gland secretions including human epidermal growth factor (beta urogastrone), an inhibitor of gastric acid secretion. Lysozyme and pancreatic secretory trypsin inhibitor (PSTI) have been identified in these secretions as well.3 Peyer patches are specialized aggregates of lymphoid follicles in the lamina propria. They are found along the antimesenteric border and are most abundant in the ileum. Peyer patches play an important role in mucosal immunity by recognizing and processing antigens. The germinal centers contain B lymphocytes, and T lymphocytes are in the interfollicular area. A specialized immune cell, the microfold cell or M cell, can be found in the epithelium overlying the lymphoid follicles. These cells are important in passive immunity by transporting antigens from the luminal surface to antigen-presenting cells into the lymphoid follicle.

DUODENUM The duodenum is the first section of the small intestine. It begins at the pylorus and ends at the ligament of Treitz and is approximately 25 cm in length. The duodenum is largely retroperitoneal and has an intimate anatomic relationship with the pancreas. It is divided into four sections: first (bulb), second (descending), third (transverse), and fourth (ascending). The first section, or the bulb, begins at the pylorus, which is demarcated by the prepyloric vein, and is approximately 5 cm in length. The posterior wall of this portion of the duodenum is in direct contact with the gastroduodenal artery (GDA), common bile duct, and portal vein. The superior border of the first segment of the duodenum is attached to the porta hepatis by the hepatoduodenal ligament, which envelops the portal triad. This portion of the duodenum begins the C-loop around the head of the pancreas (Fig. 71.5). The second, descending, section is retroperitoneal and is approximately 10 cm in length. This segment is anterior to the right kidney and ureter and the lateral border of the inferior vena cava. The medial border is in direct contact with the head of the pancreas. Evaluation of the posterior surface of the descending duodenum, the posterior surface of the pancreatic head, and the common bile duct requires medial rotation of the descending duodenum using the Kocher maneuver. The main

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

Posterior superior pancreaticoduodenal artery

Left gastric artery Minor papilla

Hepatic artery proper Gastroduodenal artery

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Right gastroomental artery

Supraduodenal artery

Major papilla

FIGURE 71.6  Endoscopic image of the major papilla and proximal minor papilla. Anterior superior pancreaticoduodenal artery Posterior inferior pancreaticoduodenal artery

Superior mesenteric artery Abdominal aorta Anterior inferior pancreaticoduodenal artery

FIGURE 71.5  Arterial supply to the duodenum. (From Drake RL, Vogl AW, Mitchel AWM. Gray’s Anatomy for Students. 2nd ed. Philadelphia: Churchill Livingstone; 2009, Fig. 4.64.)

pancreatic duct, the duct of Wirsung, and the common bile duct join and empty into the posteromedial wall of the midportion of the descending duodenum. This opening is known as the ampulla of Vater. The minor pancreatic duct, the duct of Santorini, may also empty into the duodenum as the minor papilla (Figs. 71.6 and 71.7). The third, transverse, section is also retroperitoneal and is bordered by the uncinate process of the pancreas superiorly and the hepatic flexure of the colon anteriorly. The relationship of the duodenum to the colon is important during mobilization of the hepatic flexure during colon resection. Care must be taken to avoid injury to the duodenum. The superior mesenteric vessels run anterior to the transverse duodenum. The right ureter, right gonadal vessels, inferior vena cava, and aorta are posterior to the transverse duodenum. The fourth portion of the duodenum courses in a cephalad direction to the left of the aorta and inferior to the neck of the pancreas. The end of the fourth portion is marked by the ligament of Treitz. The ligament serves as a point of fixation during intestinal rotation and runs from the right crus of the diaphragm and attaches to the intestinal wall at the duodenojejunal flexure.

JEJUNUM AND ILEUM The jejunum and ileum lie within the peritoneal cavity and are anchored to the retroperitoneum by a broad-based mesentery. The average length of the jejunum and ileum is 5 meters: 40% jejunum, 60% ileum. The jejunum begins at the ligament of Treitz and the ileum ends at the ICV. The jejunum is located centrally in the abdomen, whereas the ileum lies mostly in the hypogastric region and pelvic cavity. There is no clear anatomic landmark that marks the transition from the end of the jejunum to the beginning of the ileum; they are instead distinguished by other anatomic characteristics. The jejunum has a thicker mucosal lining, thicker wall, larger diameter, less fatty mesentery, and longer and straighter vasa recta. Another distinguishing feature is the plicae circulares, also known as the valvulae conniventes, in the mucosa. Plicae circulares are transverse folds of mucosa and submucosa that aid in absorption of nutrients by increasing the surface area of the small intestine. These folds are deep and are visible on gross inspection even when the small intestine is distended (Fig. 71.8). They are prominent in the proximal intestine and diminish throughout the length of the small intestine. The plicae circulares are also visible radiographically, thus differentiating the small intestine from the large intestine, which is devoid of this feature.

ILEOCECAL VALVE The ICV is a distinct feature of the small intestine and operates independently of the ileum or colon. It prevents the fecal contents in the colon from entering the small intestine and controls the flow of contents from the small intestine into the colon. The ability of the ICV to control the flow of digested contents may also help to prevent malabsorption and diarrhea. The valve is triggered by distention in the small intestine or the colon. If the ileum becomes distended, the valve will relax and allow the passage of contents from the small intestine into the

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SECTION II  Stomach and Small Intestine

Minor papilla

Dorsal duct Ventral duct

Major papilla

FIGURE 71.7  Magnetic resonance cholangiopancreatographic image demonstrating pancreas divisum with drainage of the dorsal duct through the minor papilla.

Peritoneum of mesentery (cut)

Ileal arteries and veins

Jejunal arteries and veins

Plicae circulares

Mucosal Peritoneum folds of mesentery (cut)

FIGURE 71.8  Plicae circulares are transverse folds of mucosa and submucosa that aid in absorption. These folds are deep and are visible on gross inspection. (From Gosling JA. Human Anatomy Color Atlas and Textbook. 5th ed. Philadelphia: Mosby; 2009, Fig. 4.64, p. 176.)

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

colon. If the colon becomes distended, however, the valve will close by increasing its tone to prevent the passage of contents from the colon into the ileum. The structure and neural control of the ICV are still being investigated. Recent work suggests that the valve forms from an intussusception of the ileum into the cecum and that the myenteric and submucosal plexuses are present within the valve along with interstitial cells of Cajal. Three muscle layers, an external circular, inner circular, and a longitudinal muscle layer, are continuous between the ileum and cecum, suggesting the mechanism for the propagation of motor activity from the ileum into the cecum.4

VASCULATURE ARTERIAL SUPPLY The small intestine is derived from the embryonic gut tube regions of the foregut and midgut. The celiac artery supplies the foregut and the superior mesenteric artery (SMA) supplies the midgut. The duodenum is both a foregut and midgut structure and thus receives dual blood supply. The jejunum and ileum are midgut structures and receive arterial blood from the SMA only (Fig. 71.9). The celiac trunk gives rise to the common hepatic artery, which divides into the proper hepatic artery and the GDA. The GDA supplies branches to the duodenum, stomach, and pancreas. The anterior superior and posterior superior pancreaticoduodenal arteries arise from the GDA and supply blood to the second and third portions of the duodenum as well as the pancreas. The SMA branches directly off of the aorta and supplies blood to the pancreas and to the second half of the duodenum to the mid transverse colon. The SMA gives rise to several branches that are important surgically. The posterior inferior and anterior inferior pancreaticoduodenal arteries anastomose with the superior pancreaticoduodenal arteries from the GDA to supply blood to the duodenum and pancreas. The intestinal arteries are branches from the SMA that create a unique network of arteries known as an arcade that supply the jejunum and ileum. Arterial branches known as vasa recta course from the arcade to the intestinal wall. These arteries then bifurcate and travel along the intestinal wall to provide adequate blood flow. The vasa recta represent another anatomic variant to help distinguish the jejunum from the ileum. The vasa recta of the jejunum are straight and long, whereas those supplying blood to the ileum are arborized and short (refer to Fig. 71.8). The ileocolic artery supplies blood to the ileum, cecum, right colon, and appendix.

VENOUS DRAINAGE The venous drainage of the small intestine mirrors the arterial supply. The duodenum empties into the pancreaticoduodenal, the right gastroepiploic, and the portal vein. The jejunum and ileum are drained by the superior mesenteric vein, which joins with the splenic vein to drain into the portal vein (Fig. 71.10).

LYMPHATICS There are several levels of lymphatic drainage of the small intestine that follow the vasculature. The lymph drains

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into the nodal chain adjacent to the bowel wall and then into the nodes of the mesenteric arcade. From there the lymphatic vessels follow along the trunk of the SMA and join with the two lumbar lymphatic trunks to drain into the cisterna chyli. The cisterna chyli is located below the level of the diaphragm at the end of the thoracic duct anterior to the lumbar spine and posterior to the aorta. Once lymph collects in this dilated sac, it will then pass through the aortic opening of the diaphragm and flow into the main thoracic duct. The thoracic duct runs parallel with the aorta and empties into the left subclavian vein where it joins the jugular vein (Fig. 71.11).

INNERVATION The innervation of the small intestine is composed of two separate systems that function independently. The autonomic nervous system (ANS) is derived from the central nervous system (CNS). The ENS is a specialized nervous system found only in the GI tract. This system is composed of neurons that lie within the bowel wall that respond to local and systemic stimulation. Parasympathetic and sympathetic nerve fibers connect the ENS to the CNS and can modulate the activity of the ENS in response to external stimuli. The ENS also functions independently, regulating its own function in response to intrinsic stimuli. There are also sensory neurons in the bowel wall that provide feedback to the ENS, the sympathetic system, the spinal cord, and the brainstem.

AUTONOMIC NERVOUS SYSTEM The ANS is composed of sympathetic and parasympathetic nerve fibers. The sympathetic innervation to the intestine is derived from nerve fibers located in the thoracolumbar spinal cord between segments T5 and L2. The paravertebral ganglia are located along either side of the vertebral column and span the length of the spinal cord. The prevertebral ganglia include the celiac, mesenteric, and hypogastric ganglia and are located along the aorta and its branches. The sympathetic innervation travels via preganglionic and postganglionic fibers. The sympathetic system secretes norepinephrine, which results in a direct inhibition of the smooth muscle. It also works indirectly by stimulating an inhibitory response from the ENS. Stimulation of the sympathetic system results in decreased intestinal motility, decreased secretion, and vasoconstriction. The parasympathetic system is composed of nerve fibers that leave the CNS via the cranial nerves and the sacral spinal nerves. The paired vagus nerve (cranial nerve X) provides parasympathetic innervation to the thoracic and abdominal viscera, which includes the pyloric sphincter and small intestine. The parasympathetic nervous system, like the sympathetic system, has preganglionic and postganglionic neurons. The length and location of these nerve fibers and neurons is a distinguishing feature between the parasympathetic and sympathetic systems. The preganglionic parasympathetic fibers are relatively long and often pass uninterrupted from the CNS to the viscera. In the small intestine, the postganglionic neurons are located within the bowel wall as part of the myenteric and submucosal plexuses. The postganglionic nerve fibers are very short because they have only a minimal distance

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SECTION II  Stomach and Small Intestine Common hepatic artery

Supraduodenal artery

Celiac trunk Splenic artery and vein

Gastroduodenal artery Posterior superior pancreaticoduodenal artery

Dorsal pancreatic artery

Right gastro-omental (gastroepiploic) artery

Inferior pancreatic artery Superior mesenteric artery and vein

Anterior superior pancreaticoduodenal artery Inferior pancreaticoduodenal arteries

(Common portion) Posterior

Middle colic artery (cut)

Anterior

Right colic artery Ileocolic artery

Superior mesenteric artery Anterior cecal artery Posterior cecal artery Appendicular artery

Jejunal and ileal (intestinal) arteries Anastomotic loops (arcades) Straight arteries (arteriae rectae)

FIGURE 71.9  Arterial anatomy of the small intestine. (Netter illustration from http://www.netterimages.com. Copyright Elsevier Inc. All rights reserved.)

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

Hepatic portal vein Left gastric vein Splenic vein Right gastric vein

Superior mesenteric vein

Middle colic vein (cut )

Jejunal and ileal (intestinal) veins Anastomotic loops

Right colic vein

Straight veins (venae rectae)

Ileocolic vein

Transverse colon (elevated) Transverse mesocolon

Superior mesenteric artery and vein

Jejunal and ileal (intestinal) vessels

Relations of superior mesenteric vein and artery in root of mesentery

FIGURE 71.10  Venous anatomy of the small intestine. (Netter illustration from http://www.netterimages.com. Copyright Elsevier Inc. All rights reserved.)

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SECTION II  Stomach and Small Intestine Right jugular trunk Right lymphatic duct Right subclavian trunk

Thoracic duct Left subclavian trunk

Celiac nodes Superior mesenteric nodes (central superior group) Thoracic duct

Cisterna chyli

Intestinal lymphatic trunk

Right and left lumbar lymphatic trunks

Superior mesenteric nodes (juxtaintestinal group)

FIGURE 71.11  Lymphatic anatomy of the small intestine. (Netter illustration from http://www.netterimages.com. Copyright Elsevier Inc. All rights reserved.)

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

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to travel to innervate the surrounding tissue. When the intestine is under the influence of parasympathetic stimulation, there is increased intestinal motility and secretion.

ENTERIC NERVOUS SYSTEM The ENS is an independently functioning system that can affect motility, secretion, vascular tone, and hormone release in the small intestine. The system, derived from the neural crest, is made up of more than 100 million neurons. The vagal neural crest is the source of the precursors that give rise to the ENS.5 Sacral neural crest cells also play a role in populating the distal gut; however their purpose is less well understood. Neural crest cells populate the gut via two main pathways: the RET/GFRα1/GDNF pathway and the EDNRB/Endothelin-3 pathway. This is significant because while loss-of-function mutations in the RET gene are associated with Hirschsprung disease, gainof-function mutations are associated with neuroendocrine neoplasms.6 The cell bodies lie within the bowel wall and reside within two named plexuses. The myenteric, or Auerbach, plexus is located between the longitudinal and circular muscle layers. The submucosal, or Meissner, plexus is located in the submucosa of the bowel wall between the circular muscle layer and mucosa. Once the myenteric plexus is populated with neural crest cells, they migrate inward to populate the submucosal plexus. This process is driven by netrins.7 The myenteric plexus runs the entire length of the intestinal wall and provides innervation to the muscular layers. Its main function is to control motor activity of the intestine. Stimulation of the myenteric plexus can result in excitatory or inhibitory effects. Excitatory effects include increased intestinal wall tone, increased intensity and rate of rhythmic contractions, and increased velocity of excitatory waves resulting in increased peristalsis. When inhibitory peptides are released, they act at the pyloric valve and ICV. The submucosal plexus provides innervation to intestinal glands, endocrine cells, and blood vessels. It works at a local level to control the secretion, absorption, and contraction within each segment of the intestine.8

SMALL INTESTINAL MOTILITY Small intestinal motility is regulated through a combination of myogenic, neural, and hormonal factors. Of these three, myogenic factors are the most important. Neural and hormonal factors act to modify myogenic-initiated motor patterns. Intestinal motor activity can persist even with complete blockade of neural signals. Intestinal motor activity exists in two phases: a fed state and a fasting, or interdigestive, state. During the fed state, food is moved along the intestine via segmentation and peristalsis. Segmentation is characterized by a pattern of pressure waves traveling short distances that serve to mix chyme and enhance its contact with the villous surfaces. The peristaltic pattern moves food along the intestine by a muscular contraction proximal to the food bolus and relaxation distal to the bolus.9 Motor activity continues during the interdigestive state via the migratory motor complex (MMC). The purpose of this activity is to propel undigested material through

Phase I

Phase II

Phase III

Phase IV

FIGURE 71.12  Diagrammatic representation of the four phases of the migratory motor complex. Amplitudes versus time are displayed.

the small intestine and into the colon. It also prevents reflux of bacteria from the colon into the terminal ileum. The MMC begins in the stomach and moves distal. Peristalsis occurs when these MMC electrical spikes are superimposed on intrinsic pacemaker potentials.10 There are three phases of the MMC. Phase I is characterized by an absence of motor activity, phase II consists of disorganized high-pressure waves that are accelerating in rate and occur intermittently, phase III is characterized by a continuous high rate of rhythmic contractions, and in phase IV the contractions once again become intermittent. This cycle repeats every 1.5 to 2 hours (Fig. 71.12).

AUTONOMIC NERVOUS SYSTEM CONTROL OF MOTILITY Sympathetic control of the small bowel synapses on the ENS and directly innervates smooth muscle, endocrine, and secretory cells. When the sympathetic system is stimulated, digestive and secretory functions are inhibited. Studies suggest that sympathetic tone primarily acts to lower propulsive force. α-Adrenoreceptors, with α1 being most important, have been well demonstrated to inhibit intestinal motility in humans and animals.11,12 Neostigmine

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SECTION II  Stomach and Small Intestine

promotes intestinal motility by inhibiting acetylcholinesterase at the neuromuscular junction. Reglan (metoclopramide) will increase upper GI motility by sensitizing tissue to acetylcholine. Parasympathetic innervation is mediated by preganglionic nerve fibers that synapse on neurons within the ENS. The postganglionic neurons can be cholinergic or peptidergic. Peptidergic neurons release peptides such as substance P, motilin, and vasoactive intestinal peptide (VIP). As with the sympathetic system, the parasympathetic system has both efferent and afferent fibers that relay information back and forth between the small intestine and the CNS. The vagus nerve, which is responsible for parasympathetic innervation to the small intestine, is a mixed nerve with approximately 75% afferent and 25% efferent fibers.

Segmentation

Concentric muscular contractions Peristalsis Food bolus

Receptive relaxation ahead of bolus

ENTERIC NERVOUS SYSTEM CONTROL OF SMALL INTESTINAL MOTILITY The ENS has an independent role in motility and also helps in the execution of sympathetic and parasympathetic signals. The ENS receives sensory information from mechanoreceptors and chemoreceptors within the bowel wall and then responds via direct innervation of smooth muscle, secretory, and endocrine cells. Segmentation intestinal motor activity involves reciprocal neural inhibition and disinhibition of adjacent segments of bowel, and it is likely that this pattern is preprogrammed into the enteric neural circuitry with the steady burst-type activity as the pacemaker. In humans, opiates cause a continuous pattern of segmentation that is nonpropulsive and constipating. The peristaltic reflex is triggered by distention. The peristaltic reflex consists of a reciprocal action that propels chyme along the small intestine. Immediately behind the bolus, longitudinal muscle relaxes and lengthens, whereas circular muscle contracts. Ahead of the bolus, the longitudinal muscle contracts, expanding the lumen, and circular muscle relaxes (Fig. 71.13). The precise sequential nature of this motor pattern compared to segmentation suggests that the neural pattern required for this is more complex. The contraction is thought to be mediated by acetylcholine and substance P, whereas the relaxation is mediated by VIP and nitric oxide. Several lines of evidence suggest serotonin and substance P are involved in initiating and maintaining peristalsis.13 Infusion of partially digested triglycerides into the ileum has an inhibitory effect on jejunal motility and increases small intestinal transit time, the ileal brake reflex. This allows more time for nutrient absorption when the absorptive capacity of the more proximal small intestine is limited by accelerated transit or mucosal disease. Peptide YY released from ileal endocrine cells has been suggested as a possible effector of this reflex, and was found experimentally to be significantly correlated with lowering of jejunal peristalsis.14

HORMONAL CONTROL OF SMALL INTESTINE MOTILITY Multiple hormones have a role in modifying motor activity in the small intestine. All act through modification of the electrical and contractile patterns. The pacemaker activity of the small intestine is consistent with a pacemaker focus

FIGURE 71.13  Mechanisms of peristalsis. The peristaltic pattern moves food along the intestine by a muscular contraction proximal to the food bolus and relaxation distal to the bolus. (Modified from http://leavingbio.net/Human%20Nutrition/ Human%20Nutrition_files/image018.jpg.)

TABLE 71.1  Hormonal Control of Small Intestinal Motility Hormone

Actions

PROMOTILITY Gastrin CCK Motilin VIP

Increased contraction rate Smooth muscle contraction; increased mixing of intestinal contents, increased intestinal transit Increased intestinal transit Duodenal contractions; increased motility

ANTIMOTILITY Secretin Glucagon

Reduced contractility, more pronounced in duodenum Inhibitory effect globally

CCK, Cholecystokinin; VIP, vasoactive intestinal peptide.

in the proximal duodenum. The periodic rate of the proximal pacemaker operates at a higher frequency than do pacemaker cells more distally, and thereby override and drive distal pacemaker activity at this higher rate. Distally in the distal jejunum and ileum, there is a declining ability to overdrive pacemaker activity at a higher rate, setting up a gradient of gradual distal slowing of pacemaker activity. How GI hormones modulate the intrinsic small intestinal pacemaker has been a subject of much study. The pharmacodynamics of many GI hormones, including gastrin, cholecystokinin (CCK), and secretin, are similar in that they show a rapid rise up to a peak level within approximately 20 to 40 minutes and thereafter a fall (Table 71.1).

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

Most experimental evidence is in agreement that gastrin increases the number of contractions of the small intestine. Its effect on intestinal transit time is less clear; however, findings from a study of serum levels of GI hormones on patients with functional bowel diseases clearly demonstrated that gastrin peak levels and total response were impaired in those patients with constipation-predominant symptoms.15 CCK increases action potentials in smooth muscle occurring in line with pacemaker potentials. Overall this increases mixing of intraluminal contents and speeds propulsion through the small intestine. However, there is one region of the small intestine where this does not hold true; in the region of the sphincter of Oddi, CCK relaxes intestinal smooth muscle.16 The effect of motilin is similar to the effects of gastrin and CCK. Motilin increases small bowel action potentials without increasing the rate of pacemaker activity; however, its stimulatory activity is greatest proximally and diminishes beyond the duodenum progressively. Motilin does accelerate small intestinal transit through an increase of small bowel propulsive contractions, but its potency is only about half of that of CCK. Vasoactive intestinal peptide has been shown to cause duodenal muscle contraction in some experiments, but its overall effect is unclear. Small doses appear to cause a muscular reaction, whereas larger doses result in a biphasic response, where an initial relaxation is followed by increased muscle tone and sustained contractions. Experimental evidence is consistent with VIP having a stimulatory effect on motility. In contrast to motilin, secretin reduces contractility and action potentials in the small bowel without having a significant effect on the duodenal pacemaker. This inhibitory effect on contractility is greatest proximally and steadily decreases distally. Secretin also opposes the action of CCK and can prevent CCK-induced contractions, but this can be overcome by large amounts of CCK. Glucagon has generally been found to have an inhibitory effect on small intestinal motility; however, it does stimulate small intestinal action potentials in low doses.16,17 Prostaglandin E1 has also been found to speed GI motility. Oral ingestion has led to rapid development of abdominal colic and diarrhea.18 Hormonal Effects on Integrated Patterns of Small Bowel Motility Motilin is believed to be the initiating factor of the MMC motor pattern, with CCK and gastrin opposing it. Plasma motilin levels have been found to be elevated during the initiation of bursts of action potentials and contractions in the stomach and duodenum, with levels falling as the bursts travel distally through the small intestine. Exogenous CCK disrupts the initiation and propagation of this motor pattern, whereas secretin delays the initiation of burst-type electrical activity and reduces the number of action potentials without affecting the distal propagation of electrical activity (Fig. 71.14).16 Serotonin is stored in the small intestine and secreted from it in large amounts, both prandially and postprandially. There are serotonin receptors on neurons, endothelial cells, and smooth muscle cells. Serotonin has an important

829

CCK Motilin Secretin Glucagon Promotility Hydrogen sulfide

VIP Gastrin Serotonin Ghrelin

FIGURE 71.14  Hormonal effects on integrated patterns of small bowel motility. The green arrow indicates promotility and the red arrow indicates inhibition of motility. CCK, Cholecystokinin; VIP, vasoactive intestinal peptide.

physiologic effect during digestion by causing intestinal hyperemia, motility, and secretion. In patients with irritable bowel syndrome, modulation of serotonin levels with selective serotonin receptor agonists or antagonists has been demonstrated to successfully treat patients with constipation and diarrhea-predominant disease.19,20 Ghrelin, a protein with 50% homology to motilin, stimulates the MMC and causes increased motility in the small intestine.21,22

FACTORS AFFECTING SMALL BOWEL MOTILITY Systemic Disease It is well recognized that certain patients with digestive diseases have altered small intestinal motility. It was recognized in 1977 that patients with small intestinal bacterial overgrowth also had small intestinal dysmotility.23 A high proportion of patients with irritable bowel syndrome were initially identified as having small intestinal bacterial overgrowth; however, this is controversial because of the low sensitivity of the lactulose breath test that was used for diagnosis. Disordered small intestine motility has been demonstrated in patients with liver disease and portal hypertension, and in patients with nonalcoholic steatohepatitis (NASH). A subsequent study identified small intestinal bacterial overgrowth in approximately one-third of cirrhotic patients. NASH patients in a separate study were found to have a higher baseline level of hydrogen by the lactulose breath test. Abnormal small intestinal motility has also been demonstrated in patients with chronic renal failure.24 Colonic Distention Patients with functional bowel disorders have an association between disordered upper GI motility and colorectal dysfunction. This may reflect inappropriate activation of visceral reflexes. In one human study, rectal distention during the fasting state increased the incidence of the MMC and decreased duodenal contractility, whereas in the fed state the effect on decreasing motility was even more profound and the rate of small intestinal transit was significantly slowed.25

830

SECTION II  Stomach and Small Intestine

Obesity Obesity has also been suggested as a factor that modulates the rate of small bowel transit. Considering that the rate of small intestinal transit plays a critical role in determining the rate of food intake, satiety, digestion, and absorption of nutrients, it has been questioned whether there is an association between obesity and small intestinal dysmotility. This, however, has not been thoroughly studied. There are reports that obese patients have a dysfunctional MMC, with the result that contractile action of the small intestine is more prominent in the fasting state in obese subjects. A significantly enhanced level of contractility in the small intestine is seen in obese patients, which is consistent with a neutrally mediated etiology. Such increased contractility may lead to more rapid nutrient absorption and loss of postprandial satiety.26,27 Circadian Rhythm Disruption Circadian rhythms drive cell proliferation as well as motor and secretory activity in the GI tract and liver. Disruption of the sleep-wake cycle has been demonstrated to result in many GI pathologies including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and peptic ulcer disease (PUD). Circadian disruption also accelerates aging and promotes tumorgenesis in the GI tract. Treatment with melatonin has shown a protective effect on GI mucosa and improves symptoms in patients with functional GI disorders.10

SMALL INTESTINAL SECRETION The small intestine has a multitude of tightly regulated secretory functions, and their disruption is prominent in certain GI disease states. Secretion may be through passive or active transport. Passive transport is driven by an existing electrochemical gradient, whereas active transport is an energy-requiring process that acts against a gradient. Small intestinal secretions include mucin, bicarbonate, and water.

MUCIN SECRETION The mucin layer, produced by goblet cells, is a vital part of the innate immunity of the GI tract. Its production is regulated by immune mediators: leukotrienes, interferon, interleukin (IL)-9, IL-13.28 The mucin layer in the stomach and duodenum is approximately 80 to 280 µm thick and creates a pH gradient that protects the mucosa (Fig. 71.15). The mucin also creates an antimicrobial barrier. The mucin glycoproteins are toxic to many bacteria and the mucin lattice provides an anchor for immunoglobulin A (IgA) and antimicrobial peptides.28 Other protective measures include the production of potent vasodilators, nitric oxide, and prostaglandins, as well as angiogenic growth factors to help maintain adequate blood flow to the intestinal mucosa.29,30 Along with mucin, intestinal bicarbonate is the first line of defense against mucosal damage by acid and pepsin. The duodenum secretes the highest rate of bicarbonate per unit of area. Duodenal

Lumen [H] Mucin layer pH Gradient

Mucin granules

Goblet cell

Enterocyte

FIGURE 71.15  Mucin secretion in the proximal small intestine. Mucin combined with bicarbonate secretion establishes a pH gradient that protects the mucosal surface from damage by acidic luminal contents.

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

H2O

Lumen

HCO 3

Cl

Cl

HCO 3

831

HCO 3

H2O

Aquaporin

CFTR

CFTR

Ion conductive pathway

Pi

cAMP, cGMP

Cl

H2O

Aquaporin

HCO 3

Na/K/2 Cl

Basal surface

Na

Na/HCO 3 symporter

FIGURE 71.16  Movement of water and bicarbonate through small intestinal enterocytes by transcellular and paracellular methods. cAMP, Cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; cGMP, cyclic guanosine monophosphate.

bicarbonate production is estimated to neutralize approximately 40% of the total postprandial acid load to ensure that the pH in duodenal mucus is maintained at neutral under all conditions of gastric acidities. The precise mechanism that senses duodenal acid remains unknown. Duodenal bicarbonate secretion is driven by the cystic fibrosis transmembrane conductance regulator (CFTR) and by an apical anion conductive pathway (Fig. 71.16). The CFTR transport process requires energy, and the action of carbonic anhydrase is also required for efficient HCO3− transport. Duodenal HCO3− secretion is under paracrine, hormonal, and neural control of the ENS and CNS. Despite their proximity to the stomach, these two organs achieve secretory control in important and different ways. Duodenal bicarbonate secretion markedly increases in response to the presence of duodenal acid. This is mediated by both neural reflexes and prostaglandin activity. The neural effectors are believed to include VIP and acetylcholine. The peptides guanylin and uroguanylin have an important role in the local control of bicarbonate secretion. These endogenous proteins are secreted by enterochromaffin cells of the duodenum. They both markedly increase HCO3− secretion by increasing cellular cyclic guanosine

monophosphate (cGMP) and thereby driving the action of CFTR. Uroguanylin is most abundant in the proximal small intestine, and its release is stimulated by low pH in the duodenum. Dopamine also controls HCO3− secretion. D1, but not D2, receptor stimulation has been demonstrated to lead to HCO3− secretion in both animal models and human studies. The action of the sympathetic nervous system is also important in modulating duodenal HCO3− secretion. Overall, the sympathetic nervous system appears to have a potent inhibitory effect on HCO3− secretion by the duodenum, which likely influences the ability of the mucosal lining to protect itself from acid-mediated injury.29

WATER SECRETION IN THE SMALL INTESTINE Although the small intestine has a net absorptive balance of water transit, it concurrently secretes water to solubilize and dilute intraluminal nutrients and maintain intraluminal fluidity. The movement of water is both transcellular and paracellular. It is generally accepted, although not conclusively proven, that water movement into the lumen is dependent on a Cl− gradient established by CFTR.31 Recent studies in mice have further supported the role of CFTR in establishing this anion gradient.32 Certain disease states

832

SECTION II  Stomach and Small Intestine

associated with abnormal chloride transport provide evidence for this hypothesis. Patients with cystic fibrosis, in which there is a defect in the CFTR protein rendering it hypo- or nonfunctional, have inspissated secretions. Although the most well-known morbidity is pulmonary, these patients also have defects in bicarbonate secretion from the pancreas and suffer from hard, dehydrated stools. Water passively equilibrates across osmotic gradients in two ways. Water molecules easily move in a paracellular route through intercellular tight junctions, whereas water channels, called aquaporins, facilitate transcellular water movement. Information from infections with Vibrio cholerae, the causative agent in cholera, has shown that water permeability and secretion are influenced not only by ion channels in enterocytes but also through tight junctions.31,33,34 A multitude of effectors are important for the regulation of water secretion. Hormonal factors are required, as well as signaling by the ENS. The two most important hormonal effectors are serotonin and VIP. Serotonin has also been found to trigger VIP release.35

REGULATION OF SECRETION The ENS is involved in regulation of secretion. Cholera toxin has been found to cause release of serotonin from enterochromaffin cells and to stimulate increased levels of cyclic adenosine monophosphate (cAMP). Substance P has also been long known to be a powerful secretagogue. Substance P causes increased blood flow, water exchange, and intestinal motility. l-Tryptophan, the metabolic precursor of serotonin, also stimulates secretion. Histamine affects H2 receptors in the small intestine that are known to control secretion. Prostaglandins are also involved, specifically prostaglandin (PG)E1 and PGE2. Several other molecules, including CCK, guanylins, and galanin, are all prosecretory. Peptide YY is the major antisecretory hormone. It has a range of effects, including slowing motility to lengthen contact time of intraluminal contents with the absorptive epithelial lining, and has been associated with the ileal brake, the primary inhibitory feedback mechanism that slows transit of a meal through the gut.36 It also inhibits gastric and pancreatic secretions as well as chloride secretion. A more recently discovered neuropeptide called antisecretory factor is another potent effector and can be induced by certain types of partially hydrolyzed complex carbohydrates. This has important clinical application in patients with inflammatory bowel disease. In trials where patients are given cereal made with partially hydrolyzed complex carbohydrates, the antisecretory factor synthesis is triggered and most patients report subjective improvement (Table 71.2, Fig. 71.17).34,35,37–39 Small intestinal secretion and absorption must be tightly regulated because any derangement in this tight balance may have major physiologic consequences, as in the case of cholera infection. The degree of regulation is highlighted by the handling of nitric oxide (NO) in the small intestine. It behaves chemically as a free radical but its effects persist for only seconds. This makes for an ideal mechanism of regulation by nervous or hormonal signaling because its action can be quickly switched on and off.

TABLE 71.2  Hormonal Control of Small Intestinal Secretion Hormone

Effects

PROSECRETORY Serotonin

VIP

Cholera toxin Pituitary adenylate cyclase–activating protein Substance P L-Tryptophan PGE1 and PGE2 Cholecystokinin Guanylins Galanin

Increased Ca2+ influx, cAMP and cGMP generation, opening of Cl− channels Increased Ca2+ influx, cAMP and cGMP generation, opening of Cl− channels Increased serotonin levels, increased cAMP levels Homology to VIP; receptors in ileum

Opens water channels; affects CFTR Metabolic precursor of serotonin Prosecretory Prosecretory Prosecretory Prosecretory

ANTISECRETORY Neuropeptide Y (peptide YY) Antisecretory factor

Increased absorptive time, decreased gastric and pancreatic secretions Antisecretory globally in small intestine

cAMP, Cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; PGE1, prostaglandin E1; PGE2, prostaglandin E2; VIP, vasoactive intestinal peptide.

Control of NO synthesis is arguably the point where multiple signaling pathways converge, including neurohormones, cytokines, and cyclic nucleotides. Evidence indicates that a careful balance of NO synthesis in the small intestine may be responsible for the overall preabsorptive state. Experimental manipulation of levels of l-arginine, the biochemical precursor of NO, shows its effect on secretion. Low luminal levels of l-arginine are associated with increased absorption of water, glucose, and electrolytes, whereas higher levels cause reduced exchanges of fluid. Cathartics such as magnesium sulfate and bisacodyl cause increases in NO synthesis, in addition to osmotic effects. Decreased luminal levels of NO due to scavenging or sequestration may be responsible for the antisecretory effects of soluble and poorly soluble fibers, as well as bismuth subsalicylate and kaolin. NO is also closely associated with cyclic nucleotide metabolism.31

SMALL INTESTINAL MUCOSAL IMMUNITY The small intestine provides the largest immune barrier between the epithelial surface of the body and the body interior. It comes into heavy and constant contact with foreign proteins, viruses, bacteria, and bacterial toxins as well as harmful chemical compounds from the environment. Accordingly, the mucosal surfaces of the body have an immune complement to match. Taken together, the mucosa-associated lymphoid tissues (MALT) include approximately 80% of all immune cells in a healthy human being, with the majority, or 70% of the overall total number

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

Prosecretory Substance P VIP 5-Hydroxytryptamine Bacterial enterotoxins CCK, guanylins Secretory interleukins

833

Antisecretory Neuropeptide Y (substance P) Antisecretory factor GLP-2 5-HT receptor antagonists Sigma receptor agonists Ca-calmodulin antagonists Enkephalins

Enterocyte

FIGURE 71.17  Regulators of small intestinal secretion. CCK, Cholecystokinin; GLP-2, glucagon-like peptide 2; 5-HT, 5-hydroxytrpyamine; VIP, vasoactive intestinal peptide. (Modified from Wapnir RA, Teichberg S. Regulation mechanisms of intestinal secretion: implications in nutrient absorption. J Nutr Biochem. 2002;13:190.)

of immunocytes, belonging to the gut-associated lymphoid tissues (GALT). The mucosal immune system of the small intestine has three main functions: (1) protect mucosal surfaces against colonization or invasion by harmful microbes; (2) provide a barrier to undigested foreign antigens including those from ingested material and those produced by nonpathogenic commensal flora; and (3) prevent the development of immune responses to these antigens, which may be potentially harmful to the host. Most of the other areas of the body under immune surveillance are sterile. The mucosal surfaces, however, are surrounded by a milieu of foreign material at all times. Thus MALT must select appropriate effector mechanisms and the intensity of response to foreign antigens to avoid self-harm from the response.40 The mucosal immune system of the small intestine is composed of multiple elements of innate and adaptive immunity. IgA secretion may be the best recognized component of mucosal immunity. It is diverse and includes specialized antigen-presenting cells, mucosal macrophages, antibacterial proteins released from the epithelium, and specialized B and T cells (Fig. 71.18).

PANETH CELLS Paneth cells provide strong innate mucosal immunity by the exocytosis of bactericidal granules in response to inflammatory signals (Fig. 71.19). Paneth cells originate from crypt stem cells. After differentiation, they migrate down into the crypt of Lieberkühn and reside adjacent to the stem cells. The Paneth cell also produces proepidermal growth factor and signal molecules essential for the maintenance of crypt stem cell activity.41 The Paneth

cell has an average life span of 20 days. Their distribution in the small intestine is heterogeneous and increases distally, resulting in a high concentration in the terminal ileum. Their appearance elsewhere in the large intestine is considered Paneth cell metaplasia and is a recognized feature of inflammatory bowel disease (IBD). The granules of Paneth cells contain several antimicrobial proteins including lysozyme, α-defensins, and phospholipase. Lysozyme inhibits bacterial growth by attacking and hydrolyzing glycosidic bonds found in bacterial cell wall peptidoglycans. It is found in cytoplasmic granules and is directly exocytosed in response to bacteria. The α-defensins comprise the majority of the secretory granules from the Paneth cell. Their function is to attack intraluminal bacterial and fungal pathogens. In humans, there are only two α-defensins: HD5 and HD6. Recombinant HD5 is effective against Candida albicans and several species of bacteria. HD5 disrupts the cell membrane of target microbes. HD6 self-assembles to form fibrils and nanonets that entangle bacteria. In vivo studies have shown that HD5 plays an important role in shaping the composition of the gut flora. Studies in humans have shown that a reduced expression of HD5/6 is a central feature of ileal Crohn disease. This link is thought to be due to a weakened mucosal defense and an altered group of commensal bacteria.42 Secretory phospholipase A2 type IIA (sPLA2-IIA) is another important product released by Paneth cells, macrophages, and vascular smooth muscle cells. Luminal sPLA2-IIA degrades bacterial membrane phospholipids, stimulates leukocytes, and modifies circulating phospholipids. Its expression is markedly increased by proinflammatory signals such as bacterial lipopolysaccharide, IL-1,

834

SECTION II  Stomach and Small Intestine Dietary antigen Immunologic Barrier Secretory IgA and IgM lymphocytes

Nonimmunologic Barrier Digestive enzymes, mucus, peristalsis, intestinal flora

Secretory immunoglobulin in bile

M cell overlying Peyer patch Secretory immunoglobulin transported across epithelial cell Dendritic Macrophage cell B cell

Liver

Portal vein

Lamina propria lymphocytes

T cell Peyer patch lymphocytes

Plasma cell producing secretory immunoglobulin

Lymphocyte network Hepatic vein

Systemic circulation Mesenteric lymph node Spleen, peripheral lymph nodes

FIGURE 71.18  Schematic representation of the small intestine immunologic defenses. (From Townsend C, Beauchamp RD, Evers BM, et al, eds. Sabiston’s Textbook of Surgery. 18th ed. Philadelphia: Saunders; 2008, Fig. 48.11; Modified from Duerr RH, Shanahan F. Food allergy. In: Targan SR, Shanahan F, eds. Immunology and Immunopathology of the Liver and Gastrointestinal Tract. New York: Igaku-Shoin; 1990, p. 510.)

tumor necrosis factor-α (TNF-α), and interferon (IFN)-γ. sPLA2-IIA knockout mice, a model of human familial adenomatous polyposis coli (FAP), are more susceptible to colorectal tumorigenesis. This suggests that sPLA2-IIA is involved in intestinal tumor suppression.43,44 Paneth cells also express TNF-α, the pleiotropic inflammatory mediator, in an inducible fashion. Its specific function in Paneth cells is unknown. There is some evidence to suggest that it plays a role in crypt regeneration and is induced following damage to Paneth or crypt cell populations. Interestingly, transgenic mice with constitutive TNF-α expression will develop lesions that resemble Crohn disease and rheumatoid arthritis. Antibodies against TNF-α (Infliximab) are a very effective treatment for Crohn disease and rheumatoid arthritis. Nucleotide oligomerization domain 2 (NOD2), a part of an intracellular signaling molecule, binds peptidoglycan from bacteria and activates the inflammatory cascade. It may be regarded as an intracellular sensor of microbial patterns similar to Toll-like receptors. NOD2 was the first gene identified to be correlated with a risk of developing Crohn disease. Individuals with homozygous NOD2 mutation have an increased risk of developing Crohn disease by 40-fold. The possibility that Crohn disease pathogenesis

is related to disordered mucosal defense highlights the importance of interrelation among physiologic processes of the small intestine.45–47

MICROFOLD CELLS Microfold (M) cells are specialized cells that form an essential part of the host mucosal defense by sampling intraluminal contents for pathogens and foreign antigens. They are located in the follicle-associated epithelium surrounding Peyer patches, and in isolated follicles, the appendix, and extraintestinal MALT. M cells are so named because of the presence of microfolds on the apical surface. M cells originate from stem cells in intestinal crypts, and share a common precursor with enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. M cells have a characteristic morphology of the basolateral surface. They possess a marked concavity that allows close contact with antigen-presenting cells.28 The function of M cells is transcellular transport. They internalize substances from the intestinal lumen and transport them across the epithelial barrier to the basal membrane, where interaction with immune cells can take place. M cells have been demonstrated to transport a variety of particulates, from inert substances such as latex

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

beads to microorganisms. The precise method by which M cells internalize various molecules and microbes varies with the size, pH, chemical nature, and presence or absence of a specific M cell receptor to the material. Although internalized substances traverse the M cell cytoplasm, they do not undergo major processing. The avidity of M cells for foreign molecules and organisms and their rapid transepithelial transport may be exploited by a variety of pathogens, which target M cells for host invasion. Many of these pathogens use M cells preferentially or even almost exclusively. Foremost among them, and most studied, are Salmonella. M cells comprise the major route of entry for this pathogen, and its uptake is associated with extensive damage to the follicular area, leading to unrestricted invasion and ulcer formation. Yersinia, Shigella, Vibrio cholerae, the pathogenic strain of Escherichia (O157:H7), poliovirus, human immunodeficiency virus 1 (HIV-1), and prion disease all exploit M cells for ease of entry. Additionally, some pathogens can increase M cell density by promoting M cell differentiation.48,49

INTESTINAL MACROPHAGES Macrophages are ubiquitous in the body and play a prominent role in the immune response. Functionally,

835

mucosal macrophages have important effects on bacterial clearance, maintaining homeostasis, and protective immunity. The small intestine is replete with resident macrophages that can be found in the lamina propria and within Peyer patches. Small-intestine macrophages are derived from the common bone marrow myeloid precursor that produces monocytes, macrophages, and dendritic cells (DCs). The small-intestine macrophages differ from circulating macrophages by expressing surface markers unique to their role in mucosal defense (Table 71.3). It is known that mediators in the mucosal environment are capable of modifying and conditioning DCs in the intestine as well as giving regulatory T cells gut-homing properties, and it is suspected that the same is true in the development of mucosal macrophages. Intestinal macrophages are strongly phagocytic like their hematopoietic counterparts. Their position adjacent to the lamina propria makes them well suited to encounter luminal bacteria that have crossed the intestinal epithelial barrier. Intestinal macrophages may also encounter pathogens that have been transferred by epithelial cells. Mucosal macrophages prevent pathologic inflammation in the intestine. They are highly phagocytic and exhibit strong bactericidal activity to clear out bacteria without activating the inflammatory pathway. Mucosal macrophages do not secrete proinflammatory signals such as IL-12, IL-23, TNF-α, or IL-1. They do not express or upregulate costimulatory molecules such as cluster of differentiation (CD)40, CD80, or CD86. Additionally, mucosal macrophages constitutively release antiinflammatory cytokine IL-10. Deletion or inhibition of IL-10 results in spontaneous colitis in mice. Finally, they produce the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) to suppress the expression of proinflammatory genes.50,51

DENDRITIC CELLS IN THE SMALL INTESTINE

FIGURE 71.19  Histologic representation of a Paneth cell. (From Gartner LP. Color Textbook of Histology. 3rd ed. Philadelphia: Saunders; 2007, Fig. 17.18, p. 404.)

DCs in the small intestine play an important and interconnected role in promoting a tolerogenic environment to commensal bacteria while still allowing for robust immune activation due to pathogens. They exist in several areas, notably in Peyer patches of the small intestine, in isolated lymphoid follicles, and in mesenteric lymph nodes. On encountering foreign material, the Peyer patches and lamina propria DCs migrate to mesenteric lymph nodes, where they present antigen to T cells. The origin of DCs in the small intestine appears to be from a monocyte precursor. The basic subtypes of DCs in small intestinal GALT are similar to other lymphoid organs in the body with a population of conventional DCs and plasmacytoid DCs. Retinoic acid produced by DCs appears important in maintaining homeostasis in the

TABLE 71.3  Differences Between Circulating and Small Intestinal Macrophages Type of Macrophage

Toll-Like Receptor

CD14 (LPS Recognition)

FcαR (IgA Recognition)

FcγR1 and FcγRIII (IgG Recognition)

Complement Receptors CR 3, CR 4

Small intestine macrophage Circulating macrophage

+ or Absent ++++

Absent +++

Absent +

Absent +

Absent +

Ig, Immunoglobulin; LPS, lipopolysaccharide.

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SECTION II  Stomach and Small Intestine

small intestine immune environment. NO also appears to have a role as a transmitter in the pathways influenced by DCs. NO is important in DC migration within MALT.

Starch Amylase

T CELLS IN THE SMALL INTESTINE T cells circulate in the small intestine and have important distinct properties and differences from the T cells circulating in other areas of the body. T cells have specific tropism, which is imprinted by DCs. T cells are found in different anatomic levels of the small intestine. There are, broadly speaking, two populations: intraepithelial lymphocytes and lamina propria lymphocytes. Lamina propria T lymphocytes consist of a largely equal percentage of CD4+ and CD8+ cells. Intraepithelial T lymphocytes are primarily CD8+ and are composed of two populations: CD8 αβ cells with the αβ T-cell receptor (TCR), and a smaller CD8 αα population. These relatively less numerous CD8 αα cells are only rarely found in other tissues and are thought to be resident in the small intestine.52

IMMUNOGLOBULIN A IN THE SMALL INTESTINE IgA is the most prevalent immunoglobulin in the human body. IgA synthesis and secretion by the gut is likely one of the most recognized features of small intestinal mucosal immunity. In steady-state conditions, approximately 40 to 60 mg/kg/day of IgA are produced and it is estimated that about 80% of all IgA is produced in the gut. Human IgA consists of two forms: IgA1 and IgA2. IgA1 is the predominant form in the small intestine, and IgA2 is prevalent in the colon. IgA production only takes place in MALT. The majority of B cells that produce it are found in the lamina propria but migrate to Peyer-patch germinal centers for IgA synthesis. However, there is also extrafollicular IgA synthesis that has been reported in isolated lymphoid follicles as well as in the lamina propria. IgA has a variety of functions. In general, low-affinity IgA antibodies produced by T-cell–independent pathways function in immune exclusion, or containing commensal bacteria in the intestinal lumen. High-affinity antibodies resulting from T-cell–dependent production are thought to prevent pathogenic microbes from colonizing or invading the epithelial lining. However, neither of these is absolute. IgA mediates transcytosis of certain antigens across M cells and intestinal epithelial cells; this controlled entry may be critical in initiating immune responses. In addition, depending on the type of IgA bound to antigen, an antiinflammatory or proinflammatory response is driven. IgA also has a role in maintaining intestinal homeostasis. IgA interaction with commensal bacteria can prevent their internalization and also regulate their surface expression of inflammatory signals, promoting host tolerance. IgA antibodies to commensal bacteria can limit the inflammatory response of intestinal epithelial cells. IgA can shape the overall composition of intestinal bacteria.52–55

DIGESTION AND ABSORPTION The small intestine is the site of absorption of nutrients, water, and vitamins from food. Although digestion of proteins and carbohydrates has begun by the time food

Lactose

Maltose

-Limit dextrins

Maltotriose

Maltase

-Dextrinase

Sucrase

Lactase

Glucose

Trehalase

Trehalose

Sucrase Sucrose

FIGURE 71.20  Carbohydrate digestion. The oligosaccharides (starch) and disaccharides (lactose, trehalose) are digested via hydrolytic cleavage to monosaccharides by saccharidases located in the brush border.

reaches the duodenum, the small intestine is completely responsible for fat digestion. This process of digestion and absorption usually takes 3 to 6 hours.

CARBOHYDRATE DIGESTION Carbohydrates constitute the majority of the human diet. Complex starches, disaccharides, and monosaccharides (simple sugars) are the sources of digestible carbohydrates. Starch is the most abundant form of carbohydrate consumed and exists as amylose or amylopectin. Amylose is a linear polymer of glucose, and amylopectin is a branched form of amylose. Sucrose and lactose are commonly consumed disaccharides. Sucrose is a glucose-fructose dimer and lactose is a glucose-galactose dimer. Glucose, galactose, and fructose are monosaccharides and when ingested do not require any further digestion for absorption. Starches and disaccharides must be broken down into monosaccharides before they can be absorbed in the small intestine. Digestion of starch begins immediately in the mouth via salivary amylase. This period of digestion is short as salivary amylase is quickly inactivated by gastric acid. The majority of carbohydrate digestion takes place in the small intestine with the help of pancreatic amylase. Amylase breaks the starches down into short-chain sugars called oligosaccharides. The most common oligosaccharides are maltotriose, maltose, and α-limit dextrins, which are digested via hydrolytic cleavage to monosaccharides by saccharidases located in the brush border. The family of saccharidases includes lactase, maltase, sucraseisomaltase, and trehalase. They break down the short-chain sugars into glucose, galactose, and fructose (Fig. 71.20). The absorption of monosaccharides requires active transport. A low intracellular Na+ concentration provides the gradient for active transport from the intestinal lumen into the enterocyte. The transport of glucose and galactose

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

transmembrane H+ gradient. Amino acids require active transport that is Na+ dependent. Once in the cell, dipeptides and tripeptides are broken down into amino acids by cytosolic peptidases. Amino acids, specifically glutamine, can be used by the cell for energy. Other amino acids will be used for protein synthesis or will pass into the portal circulation. The majority of protein absorption occurs in the jejunum (Fig. 71.22).

can be the rate-limiting step in absorption because they compete for the same sodium-coupled carrier. Fructose is absorbed via carrier-mediated facilitated diffusion. The enterocyte can use the monosaccharides for energy or transport them into the venous system.

PROTEIN DIGESTION There are three main sources of protein: dietary, endogenous secretions, and desquamated cells. Protein digestion begins in the stomach via pepsin and continues in the small intestine. Pancreatic fluid is also necessary for protein digestion (Fig. 71.21). Proteases secreted by the pancreas enter the duodenum in inactive states as proenzymes. The proenzymes are activated by brush border enzymes. The two main classes of enzymes are endopeptidase and exopeptidase. The endopeptidase cleaves internal bonds, whereas the exopeptidase cleaves bonds on the carboxyl terminal. One of the most important proenzymes is trypsinogen. Once released into the duodenum, trypsinogen is converted to the active enzyme trypsin by the endopeptidase, enterokinase. Once active, trypsin converts several other proenzymes into their active forms (chymotrypsinogen to chymotrypsin, proelastase to elastase, and procarboxypeptidase to carboxypeptidase). In addition, trypsin can activate trypsinogen molecules. Proteins are broken down in the intestinal lumen by the proteases into short oligopeptides and amino acids. The brush border enzymes, peptidases, further hydrolyze the oligopeptides into free amino acids, dipeptides, and tripeptides, which can all be absorbed by enterocytes. Dipeptides and tripeptides are more easily absorbed by the enterocyte because they are transported via a

FAT DIGESTION Fats are ingested as triglycerides, phospholipids, cholesterol, and cholesterol esters. Triglycerides make up 90% of ingested fat in the Western diet. It is composed of three fatty acids and one glycerol. Pancreatic enzymes are integral in the digestive process of fat. Fat digestion also requires bile from the liver for emulsification, which is the process by which large fat globules are broken down into smaller sizes that are easier targets for water-soluble enzymes. Bile salts and lecithin are amphiphilic and are important in the breakdown of large fat molecules into small molecules. The fat-soluble portion absorbs into the fat globules, leaving the water-soluble end projecting outward to dissolve in the aqueous solution in the intestinal lumen. Once they become part of the aqueous solution in the lumen, the fat globules are more susceptible to fragmentation by mechanical agitation and enzymatic cleavage. Pancreatic lipase breaks down the triglycerides into free fatty acids and 2-monoglycerides. The fat components are transported to the brush border for absorption via micelles. Micelles are composed of bile salts and lecithin that are oriented with their fat-soluble end forming a sterol nucleus and the water-soluble end projecting outward. Digested fats

Enterokinase

Trypsin Chymotrypsin Carboxypeptidase Elastase Amylase Lipase Colipase Cholesterol ester Hydrolase Phospholipase A 2

837

Trypsinogen Chymotrypsinogen Procarboxypeptidase Proelastase Cholesterol esterhydrolase Pancreatic lipase Colipase Phospholipase A 2 Amylase CCK Secretin

FIGURE 71.21  Protein digestion in the small intestine requires enzymes secreted from the pancreas. These enzymes are secreted as proenzymes and are activated by brush border enzymes in the small intestine. CCK, Cholecystokinin.

838

SECTION II  Stomach and Small Intestine INTESTINAL LUMEN

Amino acid

Dipeptides and tripeptides

Na

Transmembrane H gradient

Cytosolic peptidase

Protein digestion

Amino acid Dipeptides and tripeptides

FIGURE 71.22  Protein digestion. Amino acids

require Na+-dependent active transport. Dipeptides and tripeptides diffuse via transmembrane H+ gradient and are subsequently degraded to amino acids by cytosolic peptidase.

Duodenal enterocyte

Mixed micelle

Bile salts remain in intestinal lumen FA MG MG FA FA MG

MG

MG FA

FA MG

FA

MG FA FA MG

CoA

FA

Phospholipids

Cholesterol

Fat-soluble vitamins TG

Apoproteins

TG

TG

Golgi

Chylomicron

CoA

FA

Smooth endoplasmic reticulum

Bile salt FA

TG

Enterocyte

Fatty acid

MG

Monoglyceride

TG

Triglyceride

Lymphatic circulation

FIGURE 71.23  Lipid digestion. Mixed micelles carry fatty acids and monoglycerides to the brush border, where they are absorbed into the enterocyte. Bile salts are recycled via enterohepatic circulation. The fatty acids and monoglycerides are processed by the smooth endoplasmic reticulum to form triglycerides. In the Golgi complex, triglycerides are combined with fat-soluble vitamins and apoproteins to form chylomicrons, which are transported in the lymphatic circulation.

are easily absorbed into the micelles for transport to the brush border (Fig. 71.23). Once at the brush border, the micelle will break down, allowing the fatty acids and monoglycerides to enter the cell and the bile salts to remain in the intestinal lumen, where they will join with new monoglycerides and fatty acids to repeat the same transport process. Once in the

cell, the monoglycerides and fatty acids will be transported to the smooth endoplasmic reticulum (sER) via cytosolic carrier proteins. In the sER, triglycerides reform and are transported to the Golgi apparatus to be packaged for exocytosis. In the Golgi, the triglycerides will be combined with cholesterol, phospholipids, and apoproteins to become a chylomicron. The core of the chylomicron contains the

Anatomy and Physiology of the Small Intestine  CHAPTER 71 

triglycerides, cholesterol, phospholipids, and fat-soluble vitamins, making it hydrophobic. Phospholipids and apoproteins line the chylomicron’s surface. The chylomicrons are then packaged into secretory vesicles and exit the cell and enter the central lacteal via exocytosis. Once in the lacteal, the chylomicrons are part of the lymphatic circulation. Short- and medium-chain fatty acids may be absorbed directly into the portal blood. This is only a small portion, however, and the majority of fat is absorbed as chylomicrons and is transported in the intestinal lymphatics to the thoracic duct. Cholesterol is also absorbed in the small intestine as very-low-density lipoproteins (VLDLs). The VLDL particle contains a high ratio of cholesterol to triglyceride and is taken up into the lymphatic system.

839

TABLE 71.4  Vitamins and Method of Intestinal Absorption Vitamin

Method of Absorption

Fat soluble: A, D, E, K Vitamin C (ascorbic acid) Biotin Nicotinic acid Folic acid B2 (riboflavin) B1 (thiamine) B6 (pyridoxine) B12 (cobalamin)

Chylomicrons Na+-dependent brush border carriers Na+-dependent brush border carriers Passive diffusion Na+-independent brush border carriers Na+-dependent brush border carriers Na+-independent brush border carriers Passive diffusion Translocation with intrinsic factor

ENTEROHEPATIC CIRCULATION The majority of fat is absorbed in the duodenum and proximal jejunum. The bile salts involved in fat absorption are actively absorbed in the ileum and passively absorbed in the jejunum.56 The average bile salt pool in humans is 2 to 3 g. Approximately 95% of bile salts are reabsorbed into the portal circulation for transport back to the liver. Once in the liver, the bile salts are resecreted and stored in the gallbladder until the next meal stimulates their release. This process of absorption from the intestine with transport back to the liver and resecretion from the gallbladder is known as enterohepatic circulation. This process occurs about six times in a 24-hour period. Bile salts can be absorbed passively or actively. Bile salts that are unconjugated easily diffuse into the circulation in the jejunum. Conjugated bile salts are absorbed in the terminal ileum by an Na+-dependent active transport system. Regardless of the mechanism, the majority of the bile salts are recycled back to the liver via the portal circulation. A minimal amount, less than 0.5 g, of bile salts is not reabsorbed and passes into the colon for excretion. A small amount of bile salt in the colon is not clinically significant; however, a large amount may produce diarrhea. Patients who have undergone an ileal resection lose the ability to reabsorb conjugated bile salts, and the high concentration of bile salts in the colon may impair sodium and water absorption, causing diarrhea. Cholestyramine is a bile salt–binding resin that can be used to treat patients with this condition.

VITAMIN ABSORPTION The small intestine is the site of absorption of both watersoluble and fat-soluble vitamins. The fat-soluble vitamins A, D, E, and K are transported and absorbed similarly to dietary fats. They are taken up by micelles and transported into the enterocyte, where they are packaged into chylomicrons and then taken up into the lymphatic system. The water-soluble vitamins are absorbed in the jejunum and ileum by active or passive transport (Table 71.4). Vitamin B12 (cobalamin) is absorbed in a unique fashion. First, intrinsic factor, secreted from gastric parietal cells, couples with vitamin B12. The complex then binds to a membrane receptor at the terminal ileum and is absorbed. Once in the cell, the complex dissociates and vitamin B12 enters the portal circulation. Diseases that alter the availability of intrinsic factor or membrane receptor in the

terminal ileum can cause vitamin B12 deficiency. Proximal or total gastrectomy, gastric bypass, and distal ileal resection can all result in vitamin B12 deficiency.

WATER AND ELECTROLYTE ABSORPTION On average, 8 to 10 L of fluid will flow through the small intestine in a 24-hour period. The sources of water are dietary intake, salivary fluid, and gastric, biliary, pancreatic, and intestinal secretions. The small intestine is the greatest site of water and electrolyte absorption, and less than a liter of fluid is presented to the colon for absorption. The colon will absorb the rest of the water, allowing only a small amount to be excreted in the stool. Water is absorbed in the small intestine by passive diffusion or as a result of osmotic pressure differences due to electrolyte absorption. The absorption of water is tightly regulated by the absorption of electrolytes. Water will follow the flow of electrolytes to maintain an isotonic environment between the tissue and intestinal lumen. In the proximal small intestine, water freely flows into the cell through permeable tight junctions between enterocytes. The tight junctions become less permeable in the distal intestine, where water requires active transport to enter the cell. This process usually requires coupling with electrolytes. Electrolyte absorption occurs by active transport or coupling. Sodium, chloride, bicarbonate, calcium, and iron are all absorbed in the small intestine. Potassium, magnesium, phosphate, and other ions are also absorbed through the intestinal mucosa. Sodium enters the enterocyte via solute-coupling or electroneutral sodium chloride absorption and is then released into the circulation by an Na+/K+-ATPase pump. Solutes such as glucose, amino acids, short-chain peptides, and bile acids are absorbed via cotransport with Na+. Na+ enters the cell with the solute and then exits at the basolateral membrane via the Na+/K+-ATPase pump. This in turn creates an electrochemical gradient across the cell that allows for the accumulation of solutes (Fig. 71.24). The absorption of Cl − is also facilitated by this gradient. The absorption of Na+ leaves the luminal contents electronegative and the cell and paracellular space electropositive. The negatively charged Cl− ions can then freely diffuse across the cell. Most of the Cl− absorption occurs in the duodenum and jejunum. Bicarbonate is absorbed in the duodenum and jejunum. A large portion of the bicarbonate found in the intestinal

840

SECTION II  Stomach and Small Intestine

functions can result in debilitating disease states and even death. There is much that is known about the mechanisms by which these disease states occur, but further understanding of the molecular and genetic organization of the small intestine will serve to enhance clinical care.

INTESTINAL LUMEN Solute

Na Na B

A

ACKNOWLEDGMENT

H

The authors would like to thank Andrea M. Abbott, Leonard Armstrong, and Eric H. Jensen for their contributions to the previous version of this chapter.

Enterocyte

REFERENCES K

K

Na Transport A: Cotransport B: Exchange C: NaK-ATPase

C Na Na Na

FIGURE 71.24  Sodium transport in the enterocyte via the three primary mechanisms of cotransport, exchange, and Na+/ K+-ATPase.

chyme is a result of pancreatic secretion and bile. The process of bicarbonate absorption involves two indirect steps. First, H+ ions are secreted into the lumen in exchange for Na+ entering the cell. The H+ in the intestinal lumen combines with the bicarbonate ions to form carbonic acid (H2CO3). The carbonic acid dissociates into carbon dioxide (CO2) and water (H2O). The H2O remains in the intestinal lumen and the CO2 is taken up into the circulation and then exhaled. Calcium is actively absorbed in the duodenum and jejunum. The absorption of calcium is dependent on parathyroid hormone and vitamin D. Parathyroid hormone activates vitamin D by stimulating the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, which is the active form of vitamin D. 1,25-Dihydroxycholecalciferol increases the availability of calcium-binding protein located in the brush border. Calcium will bind to this specific protein and be absorbed into the cell. Calcium ions move out of the cell into the circulation by facilitated diffusion. In the presence of activated vitamin D, approximately 35% of ingested calcium is absorbed in the small intestine. The absorption of iron from dietary sources takes place in the duodenum in the presence of bile. Bile contains apotransferrin, a molecule that binds with free iron, hemoglobin, and myoglobin. Once bound to the iron product, the apotransferrin becomes transferrin. Transferrin molecules, with their iron product, bind to membrane receptors on the intestinal epithelium and are absorbed into the cell via pinocytosis. Once in the cell, the transferrin and iron product will pass into the circulation as plasma transferrin. The small intestine is responsible for many functions that are necessary for human life. Disorders of these

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