Digestive System

Overview of Gastrointestinal System Processes

In the previous chapter (Chapter 19), you learned how the kidneys influence the composition of the extracellular fluid by regulating the output of water and electrolytes. In this chapter, you will learn how the gastrointestinal system is necessary for the input of water, electrolytes, and nutrients. The renal and gastrointestinal systems share many similarities; both involve massive transport across epithelium, for example. However, there is one major difference between the two systems: The renal system is regulated to maintain normal composition of the extracellular fluid, whereas the gastrointestinal system is regulated to absorb all of the nutrients we consume, whether we need them or not. As we learn about the gastrointestinal system, we will revisit several cell components and functions (covered in Chapters 2–5), including biomolecules, enzyme activity, and transport mechanisms. The smooth muscle in the wall of the gastrointestinal tract is excited and contracts by mechanisms we have also encountered earlier in this book (in Chapter 12). We will apply what we learned about the nervous and endocrine systems to the enteric nervous system and the gastrointestinal hormones. We begin this chapter with an overview of the basic functions of the gastrointestinal system.

20.1 Overview of Gastrointestinal System Processes

Most of the nutrient molecules found in food are too large to be transported into the bloodstream intact. For this reason, these molecules must be chemically broken down to smaller molecules by enzymes in the lumen of the gastrointestinal tract, a process called digestion. This process is aided by the mechanical breakdown of food, which both enables it to move more easily through the tract and renders it more susceptible to the action of digestive enzymes. Once the larger nutrient molecules have been reduced to smaller digestive end-products, these molecules are transported into the bloodstream via a process called absorption. To aid in digestion and absorption, fluids containing enzymes and other substances are transported into the lumen of the gastrointestinal tract via a process called secretion. As these processes are occurring, the contents of the lumen are mixed and slowly propelled from one end of the tract to the other by the contractile activity of muscle located in the wall of the tract itself, which gives digestive organs the ability to move, called motility. The four basic processes of digestion, absorption, secretion, and motility are summarized in Figure 20.1.

In the next section, we explore the details of the gastrointestinal system in terms of how its anatomy relates to its function. In subsequent sections, we focus on the four basic digestive processes, including how they are regulated.

20.2 Functional Anatomy of the Gastrointestinal System

The gastrointestinal system (digestive system) comprises two major divisions: (1) the gastrointestinal tract (also known as the GI tract or digestive tract), which consists of several organs joined in series to form a passageway through which food and digestion products are conducted, and (2) accessory glands, a number of glands located outside the GI tract that secrete various fluids and enzymes into the lumen of the tract to aid the digestive process.

The Gastrointestinal Tract

The GI tract in vivo is essentially a hollow tube approximately 4.5 meters (15 feet) long that runs through the body and opens to the outside at either end. (When removed from the body, the GI tract is twice as long, 30 feet, due to the relaxation of smooth muscle found in the wall of the tract.) The tract begins at the mouth, where food enters, and ends at the anus, where unabsorbed material exits. These and the other organs of the GI tract—the pharynx, esophagus, stomach, small intestine, colon, and rectum—are shown in Figure 20.2 and discussed later in the chapter. Although each organ has its own unique structure and function, the wall of the GI tract maintains a relatively uniform structure throughout most of its length, which we examine next.

Generalized Structure of the Gastrointestinal Wall

The wall of most of the GI tract (exceptions being the mouth, pharynx, upper third of the esophagus, and external-most portion of the anus) has the same general features shown in Figure 20.3. Four distinct layers are found in the GI tract wall: (1) the mucosa, which lines the lumen of the GI tract; (2) the submucosa, an underlying layer of connective tissue; (3) the muscularis externa, a layer made up primarily of smooth muscle fibers; and (4) the serosa (or adventitia), an outer layer composed mostly of connective tissue.

The Mucosa: The mucosa is composed of three layers: (1) an innermost layer of cells called the mucous membrane, (2) a middle layer called the lamina propria, and (3) an outer layer of smooth muscle called the muscularis mucosae.

The mucous membrane is a layer of epithelial cells of various types (collectively referred to as enterocytes) that lines the inside of the GI tract, forming a continuous barrier separating the lumen from the body’s internal environment. Some enterocytes are classified as absorptive cells because they are specialized for absorption, the transport of nutrients and other materials from the lumen to the bloodstream. Other enterocytes are classified as exocrine cells because they secrete materials such as fluids and enzymes into the lumen (which is outside the body, as explained in Chapter 1). Exocrine cells include goblet cells, which secrete mucus (a sticky, viscous fluid containing glycoproteins called mucins) throughout the length of the GI tract; mucus forms a coating that protects the lining against abrasion and substances in the lumen that may attack tissue. Still other enterocytes are endocrine cells, which secrete hormones into the bloodstream. For example, G cells in the stomach mucous membrane secrete the hormone gastrin into the bloodstream. As we will see, gastrin and several other hormones play an important role in the regulation of digestive function.

The lamina propria is a layer of connective tissue underlying the mucous membrane. Contained within this layer are small blood vessels, nerves, and lymphatic vessels that communicate with larger nerves and vessels in still deeper tissue layers. The lamina propria also contains lymphoid tissue, including lymph nodules and Peyer’s patches, that is important in defending the body against bacteria, which are plentiful in the lumen of the intestines.

The muscularis mucosae is a thin layer of smooth muscle that serves primarily to contract the mucosa into folds, which stirs the lumenal contents and promotes contact with the mucosal surface. Within this layer are longitudinal muscle fibers, which run parallel to the tract’s long axis, and circular muscle fibers, which run around the tract’s circumference.

The Submucosa: The submucosa is a thick layer of connective tissue that provides the GI tract with much of its distensibility and elasticity, enabling it to tolerate a large degree of stretch without sustaining damage. This layer also contains many of the tract’s larger blood and lymphatic vessels. At its outer border is a network of nerve cells known as the submucosal plexus (Meissner’s plexus), which communicates with another nerve cell network in the muscularis externa called the myenteric plexus (Auerbach’s plexus) (see Figure 20.3); together these nerve plexuses make up the enteric nervous system (or intrinsic nervous system).

The enteric nervous system comprises an elaborate network of sensory neurons, motor neurons, and interneurons located within the wall of the GI tract. It is capable of regulating many GI functions independent of external influences. Input to the enteric nervous system comes from receptors located in the GI tract and autonomic neurons. Output from the enteric nervous system goes to effector cells (smooth muscle, exocrine glands, and endocrine glands) located within the GI tract and plays an important role in the control of digestive function.

The Muscularis Externa: The muscularis externa, which is largely responsible for the motility of the GI tract, contains two separate layers of smooth muscle: an inner layer of circular muscle and an outer layer of longitudinal muscle. The circular muscle layer consists of single-unit smooth muscle capable of generating spontaneous depolarizations, called slow-wave potentials. The circular muscle makes up the bulk of the muscularis externa. Contractions of the circular muscle layer decrease the diameter of the lumen of the GI tract. The longitudinal muscle layer consists of multi-unit smooth muscle that depends on neural input for contraction; contraction of the longitudinal muscle layer shortens the GI tract. Coordinated contractions of the circular and longitudinal muscles propel the lumenal contents through the GI tract and mix the contents with secretions that help digest food particles. Motility also promotes contact between the digestive end-products and the mucosal epithelium, thereby increasing the efficiency of absorption.

The Serosa: The serosa—the outermost layer of the GI tract wall—consists of an inner layer of fibrous connective tissue, which provides structural support, and an outer layer of epithelial tissue called the mesothelium, which secretes a watery lubricating fluid that makes it easier for organs to slide past one another. The mesothelium (along with a layer of underlying connective tissue) is continuous with the mesenteries, a system of clear, thin membranes that interconnects most of the abdominal organs and houses nerves and blood vessels running to them (Figure 20.4). The mesenteries help to anchor the organs in place and are continuous with the peritoneum, a membrane lining the inside of the abdominal cavity.

Functional Anatomy of Gastrointestinal Tract Organs

Now we turn our attention to the individual organs of the GI tract, progressing in order from the upper end of the tract to the lower end. We begin with the mouth, pharynx, and esophagus.

The Mouth, Pharynx, and Esophagus

The mouth or oral cavity is the beginning of the GI tract; it is where food enters and where the processes of mechanical breakdown and digestion begin (Figure 20.5). In the mouth, food is chewed (a process called mastication) to decrease the size of food particles and to mix them with a secretion called saliva. Saliva lubricates the food and contains an enzyme called salivary amylase, which begins the digestion of carbohydrates by breaking down starch and glycogen.

From the mouth, the food-saliva mixture is propelled by the tongue into the pharynx (commonly known as the throat), a common passageway for food and air. At the end of the pharynx, the passageways for food and air diverge. Whereas air enters the larynx and trachea via the glottis and proceeds toward the lungs, food enters the esophagus, which runs parallel and dorsal to the trachea. The esophagus is a muscular tube whose primary function is to conduct food from the pharynx to the stomach. Unlike the trachea, it is thin walled and pliant, so that it can easily stretch to accommodate food as it is swallowed; when food is not present, however, it is normally collapsed. The esophagus is unusual among the organs of the GI tract in that its wall contains both skeletal muscle (in the upper third of its length) and smooth muscle (in the bottom two thirds).

The movement of food from the pharynx to the esophagus is regulated by the upper esophageal sphincter (see Figure 20.5), a ring of skeletal muscle surrounding the esophagus at its upper end. (A sphincter is generally defined as a ring of muscle that surrounds an orifice and regulates the passage of material through it by altering its diameter.) At the esophagus’s lower end is the lower esophageal sphincter, a ring of smooth muscle that regulates the flow of food from the esophagus to the stomach. Both of these sphincters are normally closed; they open only when food is being swallowed. The lower esophageal sphincter prevents the contents of the stomach, which are acidic, from entering the esophagus. However, backflow of stomach contents into the esophagus (gastric reflux) can occasionally occur and produce heartburn, a burning sensation in the chest caused by irritation of the esophageal lining.

The Stomach

An important function of the stomach, a J-shaped sac located beneath the diaphragm, is to store food after it is swallowed and to release it into the small intestine. The lining of the stomach contains glands (called gastric glands) that secrete a watery fluid called gastric juice into the lumen. Contractile activity of smooth muscle in the stomach’s wall pulverizes food into smaller particles and mixes it with gastric juice, forming a mixture called chyme.

The stomach is divided into three major anatomical regions (see Figure 20.5): a domed upper portion called the fundus, which extends above the lower esophageal sphincter; a middle region called the body, which accounts for the bulk of the stomach’s volume; and a lower region called the antrum, which is narrower and smaller in volume. Contractions of the antrum propel chyme from the stomach into the small intestine, a process called gastric emptying. As chyme exits the stomach, it passes through a narrow passage called the pylorus on its way to the small intestine. The flow of chyme through the pylorus is regulated by a surrounding ring of smooth muscle called the pyloric sphincter, which opens and closes with each cycle of stomach contraction, such that chyme exits the stomach in spurts.

The stomach wall differs anatomically and functionally in the three regions of this organ. In the fundus, the wall is thin and easily expands to accommodate increases in volume following a meal. In the body of the stomach, the gastric mucosa folds longitudinally into rugae, which flatten as the stomach expands. These two anatomical specializations allow the stomach to expand approximately 20 times from its empty volume (50 mL) to its full volume (1000 mL). The antrum has the thickest muscle layer and produces the strong contractions responsible for gastric mixing and emptying. Both the fundus and the body contain gastric pits, which are populated by cells that secrete the products found in gastric juice.

Gastric pits contain a variety of secretory cells, including both exocrine and endocrine cells. In the neck, or upper region, of the pits, neck cells secrete mucus. Deeper in the pits are gastric glands, which contain the following cells: (1) chief cells, which secrete pepsinogen, the precursor for a proteolytic enzyme called pepsin; (2) parietal cells, which secrete both hydrogen ions (as HCl) to acidify the stomach contents and intrinsic factor, which is necessary for the absorption of vitamin B12; and (3) G cells, which secrete the hormone gastrin. Whereas parietal and chief cells secrete their products into the lumen of the stomach, G cells secrete gastrin into the bloodstream. The lumen of the stomach is the only locale in the GI tract where the contents are acidic. In fact, the pH of stomach contents can be as low as 2, which is equivalent to a 10 mM solution of hydrochloric acid! This acidity is necessary for converting pepsinogen into its active form, pepsin; it is also useful because it helps denature proteins in the food and kills many foodborne bacteria, thereby protecting the body against certain infections.

The stomach’s lining is protected against the potentially harmful effects of acid and pepsin by a surface covering of mucus and bicarbonate, called the gastric mucosal barrier. Neck cells in the gastric pits secrete mucus, whereas surface epithelial cells secrete both mucus and bicarbonate. If the gastric mucosal barrier is penetrated by acids, such as salicylic acid (aspirin), an ulcer can result (Clinical Connections: Ulcers).

The Small Intestine

From the stomach, chyme travels to the small intestine, a coiled tube about 2–3 cm in diameter and 2.5–3 meters long in vivo, that is the primary site for the digestion of all nutrients in food. The small intestine is also where most of the ingested nutrients, water, vitamins, and minerals (inorganic ions such as sodium, potassium, and calcium) are absorbed.

On the basis of subtle anatomical distinctions, the small intestine is divided into three major regions (Figure 20.6): an initial relatively short portion called the duodenum, which begins at the pylorus and extends for approximately 30 cm; a middle portion called the jejunum, which extends for about another 1 meter; and a terminal portion called the ileum, which extends approximately 1.5 meters and joins the colon. In the duodenum, chyme is mixed with a watery secretion from the pancreas called pancreatic juice, which contains a wide variety of digestive enzymes and is rich in bicarbonate. Bicarbonate neutralizes the acid in the chyme when it exits the stomach, which is necessary because the enzymes in pancreatic juice function at the normal pH of the small intestine (which is slightly basic) but not at an acidic pH. In addition to pancreatic juice, the duodenum receives bile, a fluid secreted by the liver that contains bicarbonate and bile salts, which aid in the digestion of fats, as described later.

As enzymes break down nutrients in the chyme, digestive end-products are released into solution and absorbed by cells in the mucosal epithelium. These simultaneous processes of digestion and absorption begin in the duodenum and continue to completion in the remainder of the small intestine. Unless an unusually large quantity of food has been ingested, absorption is typically completed within the first 20% of the small intestine’s length, or before the chyme has reached the ileum. Thus the small intestine has a large excess capacity for absorbing nutrients, indicating that its absorptive mechanisms are highly efficient.

The small intestine’s absorptive efficiency is attributable in part to the fact that the mucosal surface consists of finger-like projections called villi (singular: villus) that increase the surface area by roughly a factor of 10, compared to what the surface area would be if the inside of the small intestine was simply a smooth cylinder (see Figure 20.6). Each villus houses structures crucial to the absorption of nutrients, including a network of capillaries and a blind-ended lymphatic vessel called a lacteal. After nutrients are absorbed from the lumen of the intestine into the cells lining it, they are transported across the mucosal epithelium into the interstitial fluid on the other side. From there, most absorbed nutrients diffuse into the capillaries and then are carried away from the intestine in the general circulation. (Absorbed fats are an exception to this rule, as they diffuse into lacteals, as described shortly.)

Another factor that increases the absorptive efficiency of the small intestine is the presence of a brush border on the mucosal surface, which increases the surface area by a factor of 20. This brush border is made up of microvilli, which are located on the apical surface of epithelial cells and which number from 3000 to 6000 per cell. The brush border and villi are most prominent in the proximal portions of the small intestine (the duodenum, for instance), but become less pronounced as one progresses toward more distal portions of the small intestine. The epithelium of the brush border is designed for digestion and absorption. Several digestive enzymes and carrier proteins are located on the microvilli. Because of their location, these enzymes are called brush border enzymes. Other areas of the intestinal epithelium are designed for secretion.

Secretory cells of the small intestine are located in pits known as crypts of Lieberkühn (see Figure 20.6). These cells secrete copious amounts of bicarbonate-rich fluid, called succus entericus, into the lumen. This fluid is secreted mostly in the more proximal portions of the small intestine and is almost completely absorbed (along with fluid that is ingested) before the chyme reaches the colon.

Water-soluble materials that are absorbed from the intestines are carried by the bloodstream to the liver, which extracts certain nutrients for further processing. (Nutrients that remain in the blood are carried into the general circulation.) Blood from intestinal capillaries drains into the mesenteric veins and is carried to the liver by the hepatic portal vein (Figure 20.7). Blood delivered by the hepatic portal vein is deoxygenated, but a supply of oxygenated blood (which is necessary for the liver’s proper function) is delivered to the liver by the hepatic artery. Blood is carried from the liver to the general circulation by the hepatic vein, which drains into the inferior vena cava.

The Colon

The small intestine empties into the colon, which is larger in diameter (6 cm) than the small intestine, but considerably shorter (1.5 meters long). Like the small intestine, the colon is divided into regions on the basis of its anatomy (Figure 20.8). The four regions of the colon include the following segments: (1) the ascending colon, which runs upward on the right side of the body from the end of the small intestine toward the diaphragm; (2) the transverse colon, which runs across the abdominal cavity; (3) the descending colon, which runs downward on the left side; and (4) the sigmoid colon, an S-shaped segment leading to the rectum. The first three segments are specialized for absorbing water and ions from the chyme; the sigmoid colon serves primarily as a storage depot for whatever material remains in the lumen after absorption has occurred. Although the wall of the colon has the same fundamental structure as other parts of the GI tract, the longitudinal muscle layer of the muscularis externa is not continuous but is instead compressed into three relatively narrow bands called teniae coli, which run the colon’s length.

At the junction between the ileum and the colon, the flow of material is regulated by a ring of smooth muscle called the ileocecal sphincter (see Figure 20.8). Below this junction is a blind-ended bulb called the cecum, to which is attached the vermiform appendix, a wormlike appendage having no known function.

On rare occasions, the opening of the appendix can become blocked and then inflamed, a condition known as appendicitis. If this condition persists, the appendix may rupture, spilling the lumenal contents into the abdominal cavity. Rupture is a dangerous situation because it almost always leads to peritonitis (inflammation of the peritoneum), which is fatal in most cases if left untreated. By the time chyme reaches the colon, it contains very few digestible nutrients because most of the materials present in the chyme have already been absorbed. What remains consists mainly of water, inorganic ions, indigestible material from food, and bacteria. The colon’s primary function is to reduce the volume of the chyme by absorbing most of the water remaining in it, thereby transforming it into a semisolid material called feces. The colon then stores the feces until it is ready to be eliminated from the body. Together, the cecum, colon, and rectum constitute what is often referred to as the large intestine.

More than 700 species of bacteria live in the lumen of the colon, forming what is called the intestinal flora. These bacteria have several functions, including the digestion of fiber and the production of vitamin K and vitamin B7 (biotin). By-products of bacterial metabolism include gases (flatus) such as nitrogen and carbon dioxide, and smaller amounts of hydrogen, methane, and hydrogen sulfide. Antibiotics may attack the intestinal flora as well as the invading pathogen, thereby causing intestinal discomfort. Food products containing bacteria, such as yogurt, can be consumed to supplement the intestinal flora.

The Rectum and Anus

Intermittently, the colon contracts strongly, pushing fecal material into the rectum. This material does not exit the body immediately because the movement of material through the anus is controlled by two sphincters: the internal anal sphincter, which is composed of smooth muscle, and the external anal sphincter, a ring of skeletal muscle that controls the opening to the outside. Relaxation of both sphincters, which are normally closed, allows fecal material to be eliminated from the body, a process called defecation.

The Accessory Glands

The accessory glands of the digestive system include the salivary glands, which secrete saliva; the pancreas, which secretes pancreatic juice; and the liver, which secretes bile. Although these accessory glands look very different superficially and perform different functions, they share many structural and functional similarities. Secretions of these glands are carried to the GI tract via ducts lined by epithelial cells, and within the body of a gland the ducts branch extensively, terminating in an enclosed space that is completely surrounded by a layer of specialized secretory epithelial cells (Figure 20.9). In the salivary glands and pancreas, these epithelial cells are arranged in ball-like clusters called acini (singular: acinus) (The arrangement of liver secretory cells is described later in this section.) The acinar cells secrete a fluid (referred to as the primary secretion) containing water, inorganic ions, and other solutes whose nature depends on the gland in question. As this fluid flows through the ducts, the epithelial cells lining the ducts secrete or absorb ions and/or water, thereby modifying the fluid’s composition.

The Salivary Glands

Saliva is produced by three pairs of major salivary glands (Figure 20.10): the parotid glands, located on both sides of the head at approximately ear level; the sublingual glands, located beneath the tongue on either side; and the submandibular glands, located on each side of the head beneath the lower jaw. Other smaller salivary glands are located in the wall of the mouth and pharynx.

Among the components of saliva are (1) bicarbonate, which makes the saliva alkaline and helps to neutralize acid; (2) mucus, which lubricates the food and protects the lining of the mouth from abrasion; (3) salivary amylase, a digestive enzyme that breaks down starch and glycogen; and (4) lysozyme, an enzyme that by destroying or lysing certain bacteria helps to prevent tooth decay.

The Pancreas

The pancreas, located behind and beneath the stomach (see Figure 20.2), is not only an exocrine organ of the digestive system but also an endocrine organ that secretes hormones important in the regulation of metabolism (see Chapter 21). The exocrine pancreas comprises the numerous acini and their associated ducts, whereas the endocrine pancreas consists of pancreatic islets scattered among the acini and ducts (Figure 20.11). Ducts from the acini converge to larger ducts, which eventually converge to the pancreatic duct, the main duct that carries pancreatic juice to the duodenum.

Pancreatic juice is rich in bicarbonate and also contains several digestive enzymes, including pancreatic amylase, which is similar to salivary amylase and breaks down starch and glycogen, and pancreatic lipases, which break down fats. Also present are a number of proteases, which break down proteins, and nucleases, which break down nucleic acids. Relative to its weight, the pancreas secretes more protein than any other tissue in the body, most of it in the form of digestive enzymes.

The Liver

The liver—the largest organ in the abdominal cavity—is amazingly versatile. Among its more important functions are the following:

1. Secretion of bile: As mentioned previously, the liver secretes bile, which contains bicarbonate, phospholipids, inorganic ions, and bile salts.

2. Metabolic processing of nutrients: Following a meal, the liver converts some of the absorbed glucose to glycogen, and some absorbed amino acids to fatty acids; the liver also synthesizes triglycerides and cholesterol and uses them to synthesize lipoprotein particles, which it then secretes into the bloodstream. During periods in which nutrients are not being absorbed, the liver converts glycogen to glucose and fatty acids to ketones. It also produces glucose by gluconeogenesis and synthesizes urea from ammonia, which is generated as a by-product of amino acid catabolism (see Chapter 3).

3. Removal of aged red blood cells from the blood: The liver contains macrophages that remove old red blood cells and bacteria from the blood. Hemoglobin from old red blood cells is then broken down by the liver; some components (such as iron) are saved for reuse, whereas others (such as bilirubin) are eliminated from the body.

   4. Elimination of wastes from the body: Bilirubin and other breakdown products of hemoglobin are secreted in the bile and eliminated from the body in the feces. (Bilirubin and similar breakdown products are referred to as bile pigments because in combination they impart a greenish color to the bile.) Other substances eliminated in the bile include excess cholesterol, insulin, foreign compounds such as drugs or poisons, and trace metals. The liver also chemically transforms many hydrophobic compounds (including toxins) into more hydrophilic forms so that they can be more readily dissolved in the plasma and eliminated by the kidneys.

   5. Synthesis of plasma proteins: The liver synthesizes most of the proteins that are present in the plasma, including albumin, steroid-binding and thyroid-hormone-binding proteins, clotting proteins, angiotensinogen, and thrombopoietin.

   6. Secretion and modification of hormones: The liver participates with the kidney in the activation of vitamin D, and it secretes insulin-like growth factors (discussed in Chapter 21). The liver also helps to clear many hormones from the body by metabolizing them.

   7. Storage of essential molecules: The liver stores certain vitamins (A, D, and B12) and metals (iron and copper).

   Because it manufactures and secretes bile, the liver is considered to be part of the biliary system, which comprises all structures involved in synthesizing or storing bile and delivering it to the GI tract (Figure 20.12). Bile is manufactured and secreted by the liver continually, but is released into the GI tract only when food is present. Between meals, the bile secreted by the liver is stored in a small muscular sac called the gallbladder, which is located immediately adjacent to and beneath the liver (Figure 20.12a). During meals, the gallbladder is stimulated to contract, which forces the stored bile into the common bile duct, which carries it to the duodenum. For people who have had their gallbladders removed, any secretion of bile by the liver goes directly to the GI tract.

   At their juncture with the duodenum, the common bile duct and the pancreatic duct converge to form a common passageway (called the ampulla of Vater) for the flow of bile and pancreatic juice (see Figure 20.11). The flow of these two fluids is regulated by a ring of smooth muscle called the sphincter of Oddi, which is normally closed but opens when food is present. Between meals, when the sphincter is closed, the bile secreted by the liver backs up in the common bile duct and “spills over” into the gallbladder, where it is stored and concentrated.

   The secretion of bile, like that of saliva and pancreatic juice, is a two-step process involving the formation of a primary secretion and its subsequent modification in ducts. However, the spongelike liver differs substantially in structure from the salivary glands and pancreas. The liver is a highly organized structure with right and left lobes.

   The functional unit of the liver is the liver lobule, consisting of liver cells called hepatocytes (Figure 20.12b). Each lobule is a roughly hexagonal-shaped structure with a central vein running through its middle. Along each of the six corners of the lobule runs a triad of vessels—a branch of the hepatic artery, a branch of the hepatic portal vein, and a branch of the hepatic duct (Figure 20.12c). The hepatic artery provides nutrient- and oxygen-rich blood to the liver, whereas the hepatic portal vein provides recently absorbed nutrients to the liver for processing. The branches of the hepatic artery and hepatic portal vein drain into liver sinusoids, blood-filled cavities that function much like veins except that exchange occurs within them. The sinusoids drain into branches of the hepatic vein. A single layer of hepatocytes forms the walls of the sinusoids and can take up necessary substrates from the blood to produce bile. On the side of the hepatocytes opposite the sinusoid are bile canaliculi. Hepatocytes synthesize bile from substrates taken up from the sinusoids and then secrete the bile into the bile canaliculi, which drain into bile ducts that eventually converge to form the common hepatic duct; this duct carries bile away from the liver to the gallbladder or small intestine. Also found in the walls of sinusoids are Kupffer cells, hepatic macrophages that phagocytose bacteria, old red blood cells, and other debris that may be in the blood passing through the liver.

   Digestion and Absorption of Nutrients and Water

   A typical recommended daily American diet consists of a mixture of carbohydrates (500 grams), proteins (125 grams), and lipids (50 grams). (To learn about the diet of athletes, see Understanding Exercise: The Role of Diet) Most of these nutrients are consumed as macromolecules that must be enzymatically broken down into smaller molecules before they can be absorbed, a process called chemical digestion or simply digestion. Digestion generally involves the hydrolysis of macromolecules to smaller subunits. In the next three subsections, we see how molecules in each of these major nutrient classes are digested and absorbed. Then we see how the digestive system handles vitamins, minerals, and water—components of food that are not digested but instead are simply absorbed in their original forms.

   Carbohydrates

   Most carbohydrates in the diet are in the form of polysaccharides, such as starch and cellulose from plants and plant products (pasta and breads, for example) and glycogen from animals and animal products. Although all polysaccharides are polymers of glucose, they differ in structure. Cellulose cannot be digested, because it is not a substrate of digestive enzymes. Furthermore, the intestinal flora break down some cellulose into absorbable units, although the amount transformed in this way is negligible. Therefore, most cellulose passes through the intestinal tract and is eliminated from the body in feces. Cellulose is a major component of what nutritionists call dietary fiber and is considered an important part of the diet because it aids in intestinal motility. Other consumed carbohydrates include disaccharides such as sucrose (table sugar) and lactose (milk sugar), and to a lesser extent, monosaccharides such as glucose and fructose. The absorbable forms of carbohydrates are monosaccharides. Thus most consumed carbohydrates must be digested before they can be absorbed.

   Digestion of Carbohydrates to Monosaccharides: Polysaccharides are digested by amylases located in saliva and pancreatic juice; thus digestion begins in the mouth. Salivary amylase can digest polysaccharides for only a short time, however, before it is inactivated by the acidic environment of the stomach. Pancreatic amylase continues the digestion of polysaccharides in the small intestine.

   Amylases are limited in their ability to digest polysaccharides because they cannot break bonds at branch points or between glucose monomers at the end of polysaccharide chains. Thus salivary and pancreatic amylases reduce starch or glycogen to either maltose (disaccharides consisting of two glucose monomers) or short, branched polysaccharides called limit dextrins (Figure 20.13).

   Digestion of carbohydrates to monosaccharides is completed by a variety of brush border enzymes bound to the apical membranes of absorptive cells lining the small intestine. These enzymes include dextrinase and glucoamylase, which break down limit dextrins and straight-chain glucose polymers to glucose monomers; sucrase, which hydrolyzes sucrose to glucose and fructose; lactase, which hydrolyzes lactose to glucose and galactose; and maltase, which hydrolyzes maltose to two glucose molecules. (To see what happens when one of these enzymes is deficient, see Clinical Connections: Lactose Intolerance, p. 612.) These enzymes are in close proximity to other membrane-bound proteins that transport the monosaccharides into the epithelial cells, the first step of absorption. To illustrate the action of brush border enzymes, the digestion and absorption of maltose is shown in Figure 20.14.

   Absorption of Carbohydrates: Once carbohydrates have been digested to monosaccharides, they are absorbed by carrier-mediated transport across epithelial cells lining intestinal villi. Glucose and galactose enter the epithelial cells via cotransport with sodium across the apical membrane and then cross the basolateral membrane by facilitated diffusion (see Figure 20.14). The same cotransporter on the apical membrane is used for both monosaccharides. Fructose is absorbed by facilitated diffusion, so no energy is required. Following transport across the epithelium, these molecules then diffuse into capillaries and travel to the liver for processing.

   Proteins

   Proteins enter the GI tract through ingestion, secretion (mucins and enzymes, for example), and the turnover of enterocytes, which are sloughed into the lumen of the GI tract. Proteins must be digested to tripeptides, dipeptides, and amino acids prior to absorption. Two types of enzymes digest proteins: (1) endopeptidases, which split polypeptides at interior peptide bonds, thereby producing smaller peptides, and (2) exopeptidases, which cleave off amino acids from one end of the polypeptide, thereby producing amino acids. To protect the secretory cells from the proteolytic action of these enzymes, the enzymes are stored in these cells in an inactive form, called zymogens. The zymogens are sequestered in vesicles called zymogen granules and are secreted by exocytosis. Once they are secreted into the lumen of the GI tract, other enzymes convert zymogens into active enzymes by proteolytic activation (cleaving of amino acids off a precursor to form the active protein).

   Digestion of Proteins to Small Peptides and Amino Acids: The digestion of proteins begins in the stomach with the action of pepsin, an endopeptidase. Pepsinogen, the precursor for pepsin, is secreted by chief cells of the stomach (Figure 20.15). Pepsinogen is partially activated by interaction with hydrogen ions secreted by the parietal cells of the stomach. The partially active pepsinogen can then fully activate other pepsinogens by proteolytic activation. At that point, pepsin can start digestion of proteins in the lumen of the stomach, but it cannot complete their digestion to individual amino acids because its actions are limited to splitting bonds between certain amino acids only. In addition, after gastric emptying, pepsin becomes inactive in the alkaline lumen of the small intestine.

   The pancreas secretes several zymogens into the duodenum, including trypsinogen, chymotrypsinogen, and procarboxypeptidase. Enterokinase, a brush border enzyme, proteolytically activates trypsinogen by converting it to trypsin (Figure 20.16). Trypsin then activates other zymogens through proteolytic activation, including chymotrypsin and carboxypeptidase. Like pepsin, trypsin and chymotrypsin are endopeptidases that break peptide bonds between certain amino acids only, which limits their ability to fully digest proteins. Carboxypeptidase and a brush border enzyme, aminopeptidase, are exopeptidases that finish protein digestion by cleaving amino acids from the carboxyl and amino ends of a polypeptide chain, respectively. The final digestion products include amino acids, dipeptides, and tripeptides.

   Absorption of Amino Acids and Small Peptides: Once proteins are digested, amino acids are actively transported into intestinal epithelial cells by cotransport with sodium across the apical membrane. There are at least four distinct amino acid carriers that can transport the 20 amino acids. Dipeptides and tripeptides are also actively transported across the apical membrane, but their transporters are distinct from those used for amino acids. Once inside epithelial cells, the dipeptides and tripeptides are broken down by intracellular proteases to amino acids. Amino acids are then transported across the basolateral membrane by facilitated diffusion and diffuse into the blood.

   Lipids

   Lipids consumed in the diet are primarily triglycerides (90%), with some phospholipids and cholesterol being part of dietary intake. Other lipids enter the GI tract through secretions, such as bile. The digestion of lipids follows the same basic pattern as that for carbohydrates and proteins—large molecules are broken down by enzymes to smaller molecules before they are absorbed. However, carbohydrates and proteins are water soluble, whereas lipids are water insoluble. Therefore, the mechanism of lipid absorption is markedly different from what we have seen so far. In this section, we place particular emphasis on the digestion and absorption of triglycerides.

   Digestion of Triglycerides: Lipids are digested by a class of enzymes called lipases. Digestion of lipids begins in the mouth with lingual lipase, an enzyme found in saliva. This process continues in the stomach with lingual lipase, which remains active in the acidic stomach environment, and gastric lipase, an enzyme secreted into the gastric lumen. Most digestion of lipids, however, does not take place until the lipids reach the small intestine, where the chyme is mixed with pancreatic lipases.

   Because lipids are hydrophobic, ingested fats do not mix readily with the rest of the stomach contents; instead, they coalesce to form large droplets that float on top of the chyme. As these fats leave the stomach, they do so as large globules that are practically indigestible because lipases are water-soluble (like other digestive enzymes) and can act only on molecules near a globule’s surface. Thus the vast majority of the lipid molecules in these globules cannot be reached by the enzymes.

   The Action of Bile Salts: Efficient digestion of lipids is made possible by the action of bile, which first comes into contact with fat globules in the duodenum. The bile does not actually digest lipids, because it contains no enzymes; it simply facilitates the action of lipases by breaking fat globules down into smaller droplets, a process called emulsification. By increasing the total surface area of the droplets, emulsification increases the amount of lipid that is exposed to water and, therefore, is susceptible to enzymatic digestion.

   The emulsification of fats is due primarily to the action of bile salts, cholesterol derivatives synthesized by hepatocytes and secreted in the bile. Although cholesterol itself is very hydrophobic because it is composed almost entirely of nonpolar hydrocarbons, bile salts possess a number of oxygen-containing polar groups (such as hydroxyl groups [¬OH] and carboxyl groups [¬COOH]) that are hydrophilic (Figure 20.17a). Because all of these polar groups are located on one side of the molecule (the opposite side is nonpolar), bile salts are amphipathic.

   When bile salts come into contact with a fat globule, their hydrophobic sides face inward (toward the hydrophobic droplet), and their hydrophilic sides face outward (toward the water), as shown in Figure 20.18. In so doing, bile salts endow the droplets with a polar “coating” that allows them to mix more readily with water and break down into smaller droplets.

   The Action of Pancreatic Lipase: As fat is being emulsified in the duodenum, it also mixes with pancreatic lipase. For pancreatic lipase to interact with the hydrophobic fat globule, it must bind with colipase, a peptide secreted in pancreatic juice. A colipase molecule binds to a lipase molecule in a one-to-one fashion, allowing the lipase to interact with the fat globule and digest outer layers of lipids (Figure 20.19).

   Lipases act on triglycerides to break the bonds linking fatty acids to the two carbons on either end of the glycerol backbone. As a result, the end-products of triglyceride digestion are two free fatty acids and a monoglyceride (a glycerol molecule to which a single fatty acid is attached). Some of these dissolved end-products are quickly absorbed into epithelial cells lining the small intestine; others remain in the chyme, aggregating with bile salts, cholesterol, and other lipid-soluble substances into small particles called micelles, which readily exchange lipids with the surrounding solution. As more dissolved lipids are absorbed, the micelles release more products to be absorbed.

   Because of the continued action of pancreatic lipase and the release of fatty acids and monoglycerides into solution, fat droplets shrink during their transit through the small intestine, disappearing by the time chyme reaches the colon. In the ileum, the bulk of the bile salts that were secreted into the duodenum (approximately 95%) are absorbed into the circulation; these bile salts are eventually recycled by the liver and secreted again in the bile via a pathway referred to as the enterohepatic circulation.

   Absorption of Lipids: The first step in the absorption of lipids is the entry of fatty acids and monoglycerides into absorptive intestinal epithelial cells (enterocytes), which occurs by simple diffusion. Inside the cells, these molecules enter the smooth endoplasmic reticulum, where they are acted upon by enzymes that reassemble them into triglycerides (Figure 20.21). (Other end-products of lipid digestion are also reassembled in a similar fashion.) These lipids are then packaged by the Golgi apparatus into large particles called chylomicrons, which belong to a general class of particles known as lipoproteins (see Discovery: Lipoproteins and Plasma Cholesterol, p. 616).

   Following their synthesis, chylomicrons are secreted by exocytosis across the basolateral membrane and into the interstitial fluid (see Figure 20.21). After reaching the interstitial fluid, they enter the lymphatic system via the lacteals, which, like other lymphatic capillaries, have openings in their walls that are large enough to allow such particles to pass through. (Chylomicrons cannot enter the bloodstream directly because they are too large to cross capillary walls.) The flow of lymphatic fluid eventually carries the chylomicrons to the bloodstream, where much of the lipid contained within them is released to cells for use, including cells in adipose tissue.

   Water-soluble vitamins are absorbed by special transport proteins, with some requiring active transport, and others facilitated diffusion. One water-soluble vitamin, vitamin B12, cannot be absorbed by itself; it can be absorbed only when bound to intrinsic factor, which is secreted into the lumen of the stomach by parietal cells. Intrinsic factor binds to vitamin B12 to form a complex that is subsequently absorbed in the ileum. Because vitamin B12 is necessary for the synthesis of hemoglobin, its deficiency leads to a particular form of anemia called pernicious anemia, which can result from a lack of vitamin B12 in the diet or a lack of intrinsic factor.

   Absorption of Minerals

   Absorption of Sodium and Chloride: Most sodium enters the GI tract through secretions (80%), although some is ingested daily. The precise mechanism for sodium absorption varies between regions of the intestine. In the duodenum and jejunum, the epithelium is “leaky,” similar to the epithelium in the proximal tubules of the kidney. Thus, as some water is absorbed by paracellular transport, it brings with it dissolved solutes by a process called solvent drag. Active transport of sodium occurs in the jejunum, ileum, and colon, with the ileum and colon having “tight” epithelium. Active absorption depends on the action of a basolateral Na+/K+ pump, which keeps sodium levels inside enterocytes low. Sodium enters enterocytes across the apical membrane by a variety of mechanisms, including cotransport with other molecules and ions (cotransport is more important in the proximal intestine, where most solutes are absorbed), and countertransport with hydrogen ions.

   Absorption of sodium is generally coupled to chloride absorption to maintain electroneutrality. In the leaky jejunum, chloride simply follows the positively charged sodium. In the ileum and colon, chloride is actively absorbed by countertransport with bicarbonate across the apical membrane and by facilitated diffusion across the basolateral membrane. The bicarbonate transported into the lumen buffers hydrogen ions secreted into the lumen and forms carbonic acid in the lumen. Carbonic anhydrase, located in the lumen of the intestinal tract, catalyzes the breakdown of carbonic acid to water and carbon dioxide.

   Absorption of Potassium: Potassium is passively absorbed in the small intestine, but it may be absorbed or secreted in the colon, depending on electrochemical gradients. When the concentration in the lumen is approximately 25 mM or less, potassium is secreted. When the lumenal concentration is greater than 25 mM, potassium is absorbed. Because increased volume of water in the chyme (which occurs in diarrhea) results in a low concentration of potassium in the chyme, less potassium is absorbed. Severe diarrhea, therefore, can cause hypokalemia.

   Absorption and Secretion of Bicarbonate: In the jejunum, bicarbonate ions are passively absorbed. As stated previously, hydrogen ions in the lumen interact with bicarbonate ions that are in the lumen (from the pancreatic juice) to form carbonic acid, which then dissociates to carbon dioxide and water. Some of the carbon dioxide diffuses into the enterocyte and reacts with water inside the cell to form carbonic acid. The intracellular carbonic acid dissociates to hydrogen ions and bicarbonate. The hydrogen ions are secreted in exchange for sodium, and the bicarbonate is transported across the basolateral membrane and then diffuses into the bloodstream. In the ileum and colon, bicarbonate is secreted in exchange for chloride ions. The bicarbonate buffers the contents of the intestine.

   Regulated Absorption of Calcium: Unlike most substances consumed, the absorption of calcium is regulated based on the body’s needs. Calcium is actively absorbed in the duodenum and jejunum via two steps: (1) Calcium binds to a brush border protein, called calcium-binding protein, and is then taken into the cell by an unknown mechanism; and (2) calcium is transported out of the cell by a Ca2+ pump on the basolateral membrane. Calcium absorption is enhanced by the hormone 1,25(OH)2D3 which increases the amount of calcium-binding protein.

   Absorption of Iron: The absorption of iron, like that of calcium and vitamin B12, requires the aid of a protein. In this case, the protein is transferrin, which is secreted by enterocytes into the lumen of the small intestine. In the lumen, transferrin binds to iron ions to form a complex, which then binds to a receptor on the apical membrane. Both the receptor and the complex are taken into the cell by receptor-mediated endocytosis, and the iron is either stored in the enterocyte as ferritin or transported across the basolateral membrane to the blood, where it is carried by another form of transferrin. The absorption of iron from enterocytes is closely matched to the body’s needs. As plasma levels of iron decrease, ferritin releases more iron, which then crosses the apical membrane and enters the blood.

   Absorption of Water: Although we consume only some 2 liters of water per day, secretions from the stomach, intestine, and accessory glands result in another 7 liters of water entering the GI tract. Therefore, absorption of water is critical to maintain normal fluid balance. The absorption of water is passive and is driven by an osmotic gradient across the mucosal epithelium—a gradient created by the transport of solutes from the lumen to the interstitial fluid. One of these solutes, sodium, is especially important in the creation of this gradient: It is the most abundant of all solutes in the lumen and in the interstitial fluid and, therefore, makes the largest contribution to the osmotic pressure. Approximately 95% of the water that is initially present in the duodenum is typically absorbed by the time chyme reaches the colon.

   General Principles of Gastrointestinal Regulation

   The GI system is unlike the other organ systems we have studied in that, for the most part, it does not act to maintain constancy of conditions in the body’s internal environment—at least not directly—because generally the amount of material absorbed by the GI tract is not determined by conditions inside the body. Most of the nutrients ingested are absorbed completely, so virtually nothing with nutritive value is eliminated in the feces.

   Although GI functions are not regulated according to the conditions in the internal environment, they are influenced by an impressive array of neural and hormonal regulatory mechanisms, many of which involve negative feedback control. Many of these mechanisms work to control conditions in the lumen of the GI tract to maximize absorption. Now we take a brief look at general principles pertaining to the regulation of GI function.

   Neural and Endocrine Pathways of Gastrointestinal Control

   Regulation of gastrointestinal function involves the autonomic nervous system, enteric nervous system, and GI hormones secreted from the stomach and small intestine. The enteric nervous system consists of its own sensory neurons, motor neurons, and interneurons. Influences of the autonomic nervous system on GI functions are generally indirect, mediated via communication to the enteric nervous system.

   The function of GI organs is influenced by stimuli arising from within the GI tract, such as the presence or absence of food or changes in the acidity of the lumenal contents. Conditions in the lumen of the tract are monitored by three types of receptor neurons located within the GI tract wall: mechanoreceptors, which detect the degree of distension of the wall; chemoreceptors, which monitor the concentrations in the lumen of specific substances such as hydrogen ions and fats; and osmoreceptors, which monitor the osmolarity of the lumenal contents. Afferents from these receptors project to both the enteric nervous system and the central nervous system (CNS).

   The enteric nervous system and CNS exert their control over GI function via neurons projecting to various types of effector cells in GI organs, usually smooth muscle cells or secretory cells (which may be exocrine or endocrine). Neural input to smooth muscle cells controls GI motility, whereas input to secretory cells regulates the release of chemicals. Whereas exocrine cells secrete their product into the lumen of the GI tract, endocrine cells secrete their product, hormones, into the bloodstream, where the hormones circulate and eventually return to the GI system to exert their effects. The actions of four GI hormones are well established—gastrin, secreted by the stomach, and cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic peptide (GIP), secreted by cells in the duodenum and jejunum and referred to collectively as enterogastrones.

   Short and Long Reflex Pathways

   Neural and hormonal control of GI function is summarized in Figure 20.22, which shows that a stimulus in the lumen of the GI tract can trigger a response without any involvement of the CNS. In this case, signals may travel from receptors to the intrinsic nerve plexuses and then directly to the effectors, following what is called a short reflex pathway; alternatively, signals may follow a long reflex pathway, traveling from receptors to the CNS and then to the intrinsic nerve plexuses, which relay information to the effectors. (In some cases the CNS may relay signals directly to the effectors.)

   As a general rule, long reflex pathways involve either the sympathetic nervous system or the parasympathetic nervous system, or both. Increased parasympathetic activity usually enhances GI activity, which is manifested as an increase in muscle activity or product secretion; conversely, sympathetic activity generally has the opposite effect, promoting a reduction in GI activity. (There are some exceptions to this rule, however.)

   Phases of Gastrointestinal Control

   A given region of the GI tract can respond to stimuli arising either within that region or in more remote regions. For example, the rate of stomach acid secretion is influenced both by the degree of acidity of the stomach contents (secretion decreases with increasing acidity) and by the level of acidity in the duodenum. The function of GI organs can also be affected by stimuli arising from outside the GI tract; for instance, stomach acid secretion is influenced by the smell of food.

   Control of GI function by stimuli arising in the head (such as the smell, taste, or thought of food) is referred to as cephalic-phase control, which is always affected by input from the CNS. Control of GI function by stimuli arising in the stomach or the small intestine is referred to as gastric-phase control or intestinal-phase control, respectively. Gastric-phase and intestinal-phase stimuli exert their effects via long or short reflex pathways or by altering the secretion of GI hormones.

   Regulation of Food Intake

   Physiological regulation of food intake generally involves the hypothalamus and can occur over either the short term or the long term. Eating a meal because you are hungry and then stopping because your hunger has disappeared is an example of short-term regulation; increases in your daily food consumption over the weeks after you begin an exercise program is an example of long-term regulation. One factor that is important in long-term regulation is leptin, a hormone secreted by adipose tissue (Figure 20.23).

   Adipocytes secrete leptin at levels proportional to the amount of adipose tissue. When the dietary intake of calories in nutrients exceeds the body’s demands, fat is deposited in adipose tissue. This action promotes the release of leptin, which then acts on appetite-control centers in the arcuate nucleus of the hypothalamus to reduce the sensation of hunger. Physiological signals that have hunger-suppressing effects, such as leptin, are referred to as satiety signals. Leptin stimulates the release of other satiety factors from the arcuate nucleus, including alpha melanocyte stimulating hormone (aMSH) and cocaine and amphetamine related transcript (CART), which coordinate responses to reduce fat stores. In addition to inducing satiety to reduce food intake, aMSH and CART increase sympathetic activity and stimulate the release of the anterior pituitary tropic hormones known as thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH), thereby promoting a general increase in the body’s metabolic rate and reducing fat storage. Some people are born with congenital deficiencies in leptin. These individuals tend to eat excessively and nondiscriminatively—a condition called hyperphagia—which results in severe obesity. Administration of leptin over time can reverse their severe hunger, with the treated patients then losing weight quickly. However, administration of leptin in obese individuals without a genetic defect in leptin has little effect on their obesity.

   Opposing the actions of satiety factors are orexigenic factors, including neuropeptide Y (NPY) and agouti-related peptide (AgRP), both of which are released from the arcuate nucleus and act on the lateral hypothalamus to promote eating behavior and decrease metabolism. Orexigenic factors achieve this effect by increasing parasympathetic activity, decreasing sympathetic activity, and inhibiting the secretion of ACTH and TSH.

   Food intake is also influenced by a number of other physiological variables that are important in short-term regulation. The absorption of nutrients from a typical meal, for example, stimulates pancreatic islet cells to release the hormone insulin, which acts on the hypothalamus to induce satiety. Another hunger-suppressing hormone, CCK, is released in response to the presence of food in the duodenum. Neural signals from certain mechanoreceptors and chemoreceptors in the wall of the GI tract signal the presence of food or digestion products in the lumen, and these signals also suppress hunger.

   Just as there are short-term satiety factors, so there are also short-term orexigenic factors, including the gastric hormone ghrelin, which is released from the stomach when it is empty. Ghrelin promotes the release of NPY and AgRP, which then promote feeding behavior. The removal of ghrelin-secreting cells during gastric bypass surgeries may contribute significantly to the effectiveness of this procedure in producing weight loss.

   People become obese when they consume, on a regular basis, more calories than their bodies use. Most of the excess calories are stored as triglycerides in adipose tissue. Four major factors contribute to the development of obesity: genetic factors, environmental factors, excessive food intake, and insufficient exercise. Regardless of its cause, obesity predisposes a person to many diseases, including atherosclerosis, heart disease, liver disease, and type 2 diabetes mellitus.

   Even though food intake is necessary to supply nutrients to the body, food intake is strongly affected by unrelated factors, including psychosocial influences. From your own experience, you likely know that even when you are not particularly hungry, you can be persuaded to eat when you see an appealing dish, when you have a rare opportunity to eat a favorite food, or when you are with a group of friends who are eating.

   Gastrointestinal Secretion and Its Regulation

   So far, we have learned that several substances are secreted into the lumen of the GI tract. In this section, we look at the mechanisms of exocrine secretion, including how these mechanisms are regulated.

   Saliva Secretion

   The secretion of saliva is controlled by neural input to the salivary glands via both branches of the autonomic nervous system. Unlike most tissues that are dually innervated by the autonomic nervous system, saliva secretion is stimulated by both parasympathetic and sympathetic neurons. However, parasympathetic activity stimulates copious secretion of a watery saliva, whereas sympathetic activity stimulates minute secretion of a protein-rich, viscous saliva. (A nervous person giving a presentation often suffers from “dry mouth” even though saliva production is increased with the increased activity of the sympathetic nervous system.)

   Saliva secretion is regulated by the salivary center in the medulla oblongata, which controls autonomic output to the salivary glands. Information pertaining to the taste of food is relayed to the salivary center by chemoreceptors in taste buds. The presence of food in the mouth stimulates these receptors, resulting in activation of the parasympathetic nervous system and increased saliva secretion. Activity of the salivary center is also affected by input from the cerebral cortex, which relays information pertaining to the sight and smell of food and other cephalic-phase stimuli.

   Acid and Pepsinogen Secretion in the Stomach

   The mechanism of acid secretion in the stomach is in some ways reminiscent of the mechanism of hydrogen ion secretion in the renal tubules. The acid secreted by the stomach is generated inside parietal cells by the carbonic anhydrase (CA)-catalyzed reaction, converting the reaction of carbon dioxide and water into hydrogen ions and bicarbonate (Figure 20.24). A proton pump that uses ATP transports hydrogen ions out of the parietal cell and into the lumen of the stomach in exchange for potassium ions, which move from the lumen into the cell. Bicarbonate ions exit the parietal cell across the basolateral membrane in exchange for chloride ions, which then move into the lumen through channels in the apical membrane. The net result is that hydrogen and chloride ions are transported into the lumen while bicarbonate is transported into the interstitial fluid.

   The secretion of acid by parietal cells is stimulated by parasympathetic nervous activity, gastrin, and histamine, which is secreted by cells in the stomach lining and acts as a paracrine agent. Acid secretion is controlled by cephalic-phase, gastric-phase, and intestinal-phase stimuli and is generally stimulated when food is present in the stomach and suppressed when the food leaves. Because the stimuli that affect acid secretion also tend to affect the secretion of pepsinogen in the same manner, the secretion of pepsinogen generally rises and falls in parallel with changes in acid secretion.

   As shown in Figure 20.25a, cephalic-phase stimuli arising either from the sight, taste, and smell of food or from the acts of chewing and swallowing trigger increased activity in parasympathetic nerves to the stomach, which in turn stimulates both parietal cells and chief cells to secrete acid and pepsinogen, respectively, and G cells to secrete gastrin. The gastrin enters the bloodstream and stimulates the parietal and chief cells, reinforcing the effects of parasympathetic input.

   Once food reaches the stomach, gastric-phase stimuli come into play (Figure 20.25b). The presence of proteins and protein digestion products in the lumen stimulates chemoreceptors in the wall of the stomach, whereas the presence of food distends the stomach, which activates mechanoreceptors. As a result, signals are relayed to parietal cells and chief cells via short reflex and long reflex pathways, triggering the release of acid and pepsinogen; signals are also sent to G cells, triggering the release of gastrin. In addition, the proteins present in the lumen exert a direct effect on G cells that stimulates them to secrete gastrin.

   As food leaves the stomach, both gastric-phase and intestinal-phase stimuli work to reduce acid and pepsinogen secretion. The exit of food from the stomach reduces the degree of distension and lowers the concentration of proteins and protein digestion products in the lumen, causing a withdrawal of the stimuli that previously stimulated gastric secretion. The exit of proteins also tends to increase gastric acidity (because proteins normally buffer some of the secreted hydrogen ions); the greater acidity acts directly on G cells to suppress gastrin secretion, thereby causing the withdrawal of another stimulus for acid secretion.

   The reduction in gastric secretion that occurs during gastric emptying is also triggered by signals arising from the entry of food into the duodenum. As chyme leaves the stomach, the osmolarity of the duodenal content rises, the concentrations of fats and acid in the content rise, and the duodenum becomes more distended. These changes stimulate chemoreceptors, osmoreceptors, and mechanoreceptors, which relay signals via long reflex and short reflex pathways to parietal and chief cells in the stomach, inducing a decrease in acid and pepsinogen secretion. In addition, signals relayed to the endocrine cells in the small intestine increase the secretion of CCK, secretin, and GIP, all of which suppress the secretory activity of parietal and chief cells.

   Secretion of Pancreatic Juice and Bile

   The secretion of pancreatic juice begins in the pancreatic acini, where cells produce a relatively small volume of fluid containing water, electrolytes, and digestive enzymes. As this fluid flows through the ducts leading from the acini, duct cells secrete a larger volume of bicarbonate-rich fluid that is added to it. Even though both components of the pancreatic juice—enzyme-rich fluid and bicarbonate-rich fluid—are secreted together during a meal, the regulatory mechanisms that control their secretions are somewhat separate, and for this reason the composition of the pancreatic juice can vary.

   The secretion of pancreatic juice is influenced by cephalic-phase, gastric-phase, and intestinal-phase stimuli, although the last predominate. The strongest influences on pancreatic secretion are the hormones CCK and secretin, which are released in response to the presence of food in the duodenum. CCK acts primarily on acinar cells to stimulate enzyme secretion, whereas secretin acts primarily on duct cells to stimulate the secretion of bicarbonate-rich fluid. Although CCK by itself is only a weak stimulus for bicarbonate secretion, its effect becomes stronger when secretin is present. Likewise, secretin by itself exerts only a weak stimulatory effect on enzyme secretion, but this effect becomes much stronger when CCK is present. Put another way, when CCK and secretin are both present, these hormones amplify each other’s effects, a phenomenon known as potentiation.

   The release of secretin and the subsequent secretion of bicarbonate-rich fluid are strongly affected by the acidity of the duodenal contents. The flow of chyme from the stomach into the duodenum raises the acidity of the duodenal contents, which stimulates chemoreceptors in the wall. As a result, signals are relayed via short and long reflex pathways to endocrine cells in the duodenum and jejunum, which then release secretin in response. The resulting rise in plasma secretin levels acts on pancreatic duct cells to stimulate the secretion of bicarbonate-rich fluid, which combines with hydrogen ions in the duodenum to lower the acidity of the contents. This reduction of acidity is necessary for the proper activity of pancreatic and other enzymes that work in the small intestine.

   The secretion of CCK is regulated primarily by the concentrations of protein digestion products and fat in the duodenum, which increase as chyme leaves the stomach. The increased levels of these products activate chemoreceptors, which relay signals via short reflex and long reflex pathways to endocrine cells, triggering the release of CCK, which acts on acinar cells to stimulate enzyme secretion. Later, once digestion products have left the duodenum, these signals are turned off, so CCK secretion falls.

   CCK and secretin are also responsible for regulating the entry of bile into the duodenum. In response to increased acidity in the duodenum, secretin acts on the liver to stimulate bile secretion; the presence of protein digestion products and fat in the duodenum stimulates the secretion of CCK, which by promoting gallbladder contraction and relaxation of the sphincter of Oddi, allows bile to flow into the duodenum.

   Rates of Fluid Movement in the Digestive System

   The volume of fluid that moves into and out of the digestive system each day is impressive, amounting to several times the normal plasma volume. The liver and pancreas combined secrete into the GI tract an average of 2 liters of fluid per day, and the salivary glands secrete another 1.5 liters. An additional 3.5 liters is secreted by glands in the wall of the stomach and small intestine, and approximately 2 liters enters the GI tract via ingested water. The great majority of the secreted and ingested fluid—some 8.5 liters each day—is absorbed by the small intestine; the colon also absorbs some fluid.

   Gastrointestinal Motility and Its Regulation

   The GI tract is capable of generating finely tuned patterns of motion that both propel forward and mix the lumenal contents. In fact, it is largely because of this motility that digestion and absorption are so efficient. In this section, we examine the various patterns of motility in digestive organs, and we see how motility is regulated. We begin with the basis of GI motility: electrical activity in smooth muscle.

   Electrical Activity in Gastrointestinal Smooth Muscle

   GI smooth muscle is arranged in layers at two levels. In the muscularis mucosae is a thin layer of longitudinal muscle fibers and circular muscle fibers that function to mix lumenal contents. In the muscularis externa are two separate layers of smooth muscle: an inner circular layer and an outer longitudinal layer. The inner circular layer is capable of generating slow, spontaneous, graded depolarizations known as slow waves, which when large enough to bring the membrane potential to threshold are accompanied by action potentials. When action potentials are generated, they tend to occur in bursts coinciding with the peaks of the slow waves. Extensive electrical coupling between smooth muscle cells, due to the presence of gap junctions, allows propagation of this electrical activity (both slow waves and action potentials) to nearby nonpacemaker cells. The frequency of slow waves varies from region to region along the length of the tract because muscle cells in different regions are driven by different sets of pacemaker cells.

   In any given region of the GI tract, circular muscle slow waves occur at regular intervals at a fairly constant frequency. This pattern, which is referred to as the basic electrical rhythm (BER), is affected by neural activity and hormones. In general, parasympathetic activity is excitatory and tends to promote increased contractile force; sympathetic activity has the opposite effect. These influences reflect changes in the pattern of slow-wave activity.

   Neural activity and hormonal signals generally affect the amplitude of slow waves rather than their frequency. Excitatory stimuli shift the membrane potential upward, so that it still increases and decreases with each slow wave, but at a higher (more positive) average value; inhibitory stimuli shift the membrane potential downward. An upward shift in the membrane potential may trigger either the sudden appearance of action potentials (if none are occurring initially) or an increase in action potential frequency, both of which generally result in increases in circular muscle contractile force. Downward shifts in the membrane potential tend to reduce action potential frequency and contractile force.

   Although contractile activity is related to the pattern of electrical activity in circular smooth muscle, the nature of the relationship depends on the location of the muscle. In the stomach, smooth muscle generates force in a graded fashion that varies according to the degree of depolarization; that is, action potentials are not required for contraction to occur. Larger depolarizations trigger stronger contractions, and if the depolarizations are large enough to trigger action potentials, the force of contraction increases further. In contrast, smooth muscle contraction in the intestines requires action potentials, and stronger contractions occur with a higher frequency of action potentials.

   Peristalsis and Segmentation

   The basic electrical rhythm sets up a wave of contraction in the muscularis externa that travels longitudinally down the intestinal tract. These waves, called peristalsis, propel the contents forward at a rate dependent on the basic electrical rhythm. Peristalsis is caused by the coordinated activity between the circular and longitudinal muscle layers in adjoining segments of the GI tract. In the proximal GI segment, the circular muscle contracts while the longitudinal muscle relaxes. This effect decreases the diameter of the tract. In the distal GI segment, the circular muscle relaxes while the longitudinal muscle contracts, causing an increase in the diameter of the tract that prepares it to receive the contents from the proximal segment. Activity in the distal segment actually precedes activity in the proximal segment as it prepares for the arrival of contents.

   In the small intestine, the muscularis externa is also capable of segmentation, alternating contractions between intestinal segments that mix the chyme. In segmentation, while one segment of circular muscle in the intestine contracts, segments on either side relax, thereby allowing contents to move in both directions from the contraction (as opposed to the unilateral propulsion of contents during peristalsis). The result is that chyme is shuttled back and forth, mixing the contents and bringing digestive products into close contact with the mucosa.

   Chewing and Swallowing

   Chewing is like breathing, in that it is controlled both consciously and unconsciously; we can control the rate and force of chewing motions voluntarily, or we can chew without even thinking about it. Unconscious chewing is orchestrated by a chewing reflex that is activated by the presence of food in the mouth as follows: When food is not present in the mouth, the muscles that hold the lower jaw closed are tonically active and constantly exert force. However, the presence of food in the mouth stimulates pressure receptors and triggers inhibition of the jaw-closing muscles, allowing the jaw to drop in response to the pull of gravity.

   Opening of the jaw relieves the pressure of food against the receptors, which removes the inhibitory stimulus from the jaw-closing muscles, allowing them to close the jaw once again. When this happens, however, the pressure is restored, which triggers inhibition of the jaw-closing muscles and allows the jaw to open, and so on. Thus the operation of this reflex induces the alternating opening and closing motion of the jaw that constitutes chewing.

   Chewing and the associated tongue movements both reduce the food mass to smaller particles and ensure that food is mixed thoroughly with saliva, transforming the food into a semisolid mass called a bolus. When the bolus becomes soft and moist enough to swallow, the tongue propels it to the back of the mouth and into the pharynx, where it stimulates mechanoreceptors that initiate the swallowing reflex, a series of muscle contractions coordinated by the swallowing center in the medulla. The swallowing reflex involves the following series of steps:

   1. As the bolus begins to descend from the pharynx, it presses downward on the epiglottis (a flap of tissue guarding the glottis), causing it to cover the glottis and preventing the bolus from entering the larynx and trachea. Closure of the glottis is aided by muscles of the neck, which raise the larynx. Reflex mechanisms also inhibit inspiratory muscles, which suppresses breathing motions.

   2. The upper esophageal sphincter relaxes, enabling the entry of the bolus into the esophagus. Once the bolus passes through, the sphincter closes again.

   3. Entry of the bolus into the esophagus stimulates stretch receptors, triggering peristalsis. The peristaltic wave propels the bolus toward the stomach, which it reaches in about 9 seconds.

   4. Upon arrival of the bolus at the lower end of the esophagus, the lower esophageal sphincter relaxes momentarily to allow the bolus to enter the stomach.

   5. In the event that the initial or primary peristaltic wave is unsuccessful in delivering the bolus to the stomach, it is followed by additional secondary waves initiated by stimulation of mechanoreceptors in the esophagus.

   Prior to the arrival of the bolus, the stomach makes preparations to accommodate it through a process called receptive relaxation. In this process, the swallowing center in the medulla triggers relaxation of smooth muscles in the upper portion of the stomach, which increases its volume.

   Gastric Motility

   Following ingestion of a meal, the muscles of the stomach accomplish two tasks: mixing of the chyme to ensure that food and gastric juice are thoroughly combined, and regulation of gastric emptying such that chyme enters the small intestine at an appropriate rate. Both of these tasks are achieved by peristaltic waves in the stomach, which are coordinated by the enteric nervous system.

   Gastric Motility Patterns: Peristaltic waves travel downward from the upper body of the stomach to the pylorus, normally at a rate of about three per minute. Each wave begins as a weak contraction but progressively increases in force as it advances toward the pylorus. Because the pyloric sphincter is closed, the wave of contraction does not push the bulk of the chyme forward; instead, most of it is forced to flow backward, which mixes it.

   However, as peristaltic waves increase in strength, they force the pyloric sphincter open as chyme is propelled forward, spurting into the duodenum. The rate of gastric emptying depends on several factors, including the composition of the chyme, the volume of chyme in the stomach, and the force of gastric contractions. In general, emptying is faster when the volume of chyme is larger and gastric contractions are stronger. However, only liquid and small particles in the chyme can move through the pyloric sphincter. Liquids enter the duodenum approximately 3 minutes after ingestion. Smaller particles (less than 1 mm in diameter) follow 20–30 minutes later. In contrast, large particles may stay in the stomach up to 9 hours before they are broken down to a size that can move through the pyloric sphincter.

   During periods of fasting, peristaltic contractions eventually cease, and the stomach becomes quiescent for an hour or two, after which time another pattern of activity appears. First, the antrum begins to undergo a series of intense contractions (called a migrating motility complex) that are accompanied by relaxation of the pyloric sphincter. After a while, these contractions stop and the stomach goes into another period of quiescence, which is followed by another burst of contractions, and so on. This pattern of activity sweeps the stomach of its contents, including any particles that might have been too large to pass through the pyloric sphincter.

   Regulation of Gastric Motility: Control of gastric motility is achieved primarily through changes in the force of smooth muscle contractions. (Changes in frequency do occur but are relatively minor.) The force of gastric contraction increases in response to gastrin and decreases in response to CCK, secretin, and GIP. (In fact, GIP was originally called gastric inhibitory peptide because of its inhibitory influence on gastric motility.)

   The control of gastric motility is similar to the control of gastric secretion, in that motility is influenced by cephalic-phase, gastric-phase, and intestinal-phase stimuli. Effective cephalic-phase stimuli include pain, fear, and depression, which normally inhibit gastric motility, and anger and aggression, which stimulate it. Gastric-phase stimuli (including distension of the stomach) and intestinal-phase stimuli (including distension of the duodenum and changes in lumenal acidity, osmolarity, and fat concentration) regulate gastric emptying such that chyme exits the stomach at a rate that is well matched to the small intestine’s ability to process it. Specifically, if gastric emptying exceeds the rate at which the small intestine can process contents, then distension of the duodenum occurs, and increases in lumenal acidity, osmolarity, and fat concentration all occur, thereby decreasing gastric motility and thus gastric emptying.

   Vomiting

   On occasion, certain conditions can cause the contents of the stomach and sometimes of lower portions of the GI tract to be forcefully expelled through the mouth, a phenomenon known as vomiting. Vomiting can be triggered by a variety of stimuli, including illness (such as influenza), strong emotional states, severe pain, severe distension of the stomach or small intestine, rotational motion of the head (as in motion sickness), or the ingestion of certain substances (such as copper sulfate). Substances that stimulate vomiting are known as emetics. Given that many emetics are poisonous, vomiting acts as a protective mechanism that removes these substances from the GI tract before substantial quantities can be absorbed into the blood.

   Vomiting involves a complex sequence of events (called the vomiting reflex) that is coordinated by a region in the medulla called the vomiting center. Prior to the actual act of vomiting, a person usually experiences a sensation of nausea, the skin becomes pallid, and heart rate and sweating increase. Eventually, a series of deep inspirations are followed by closure of the glottis. Abdominal muscles begin to contract strongly, causing the abdominal wall to move inward as the inspiratory movements cause the diaphragm to move downward. This combination of motions raises the abdominal pressure substantially and effectively squeezes the stomach, raising the pressure inside. Finally, the lower esophageal sphincter relaxes, allowing stomach contents to enter the esophagus. If contractions are not strong enough to eject this material into and out of the mouth, it returns to the stomach; this can occur several times before abdominal contractions become strong enough to push the material through the upper esophageal sphincter and out through the mouth.

   Motility of the Small Intestine

   Like the stomach, the small intestine exhibits different patterns of motility depending on whether food is present or absent. Motility patterns also differ in the muscularis externa and muscularis mucosae.

   Motility Patterns in the Small Intestine: When chyme is present in the small intestine, brief periods of peristalsis that propel the chyme forward are interspersed with relatively longer periods of segmentation that mix the chyme. During fasting, peristalsis and segmentation cease and are replaced by migrating motility complexes that periodically move through the intestine, sweeping it of its contents.

   Segmentation, peristalsis, and migrating motility complexes result from the contractile activity of the external muscle layers, but the innermost layer (the thin muscularis mucosae) also undergoes regular contractions when food is present. These contractions mix chyme near the surface of the mucosa and may exert a “massaging” effect on the lacteals, which helps propel the lymphatic fluid forward.

   Regulation of Motility of the Small Intestine: Contractions of the small intestine are influenced both by distension and by input from extrinsic nerves and hormones. During intestinal phase control, moderate distension of the intestine triggers an increase in contractile force, a response mediated by both short and long reflex pathways that tends to relieve the distension by propelling the intestinal contents onward. During gastric-phase control, gastrin both stimulates motility in the ileum and promotes relaxation of the ileocecal sphincter to increase the rate at which these contents move from the small to large intestine, thereby making room for more chyme to enter the duodenum.

   The small intestine also exhibits a number of specialized reflexes that are orchestrated by the CNS and come into play only in certain situations. In the intestino-intestinal reflex, severe distension or injury to any portion of the small intestine inhibits contractile activity throughout the rest of the intestine, which helps protect the injured part from further stretching and additional injury. In the ileogastric reflex, distension of the ileum causes inhibition of gastric motility, which decreases the rate at which chyme enters the duodenum. In the gastroileal reflex, the presence of chyme in the stomach triggers increased motility in the ileum.

   Motility of the Colon

   In the colon, contractile activity serves to mix the chyme, to expose it to the mucosal surface (which facilitates the absorption of minerals and water), and to propel the lumenal contents toward the rectum for storage and eventual elimination.

   Motility Patterns in the Colon: The more proximal portions of the colon exhibit a pattern of motility called haustration, which is similar to segmentation in the small intestine, except that the segments (haustra) are delineated by permanent folds in the intestinal wall and are regular in appearance. Haustration is also significantly slower than segmentation; its contractions occur at a rate of about two per hour.

   About three or four times a day, a different pattern of activity begins. This activity, called mass movement, is like a peristaltic wave, except that after a given portion of the intestine contracts, it remains contracted for a longer time before relaxing. These waves of contraction propel the lumenal contents forward rapidly and sweep the colon clean.

   Regulation of Motility of the Colon: Like the small intestine, the colon exhibits specialized reflexes that act only in certain circumstances. In the colonocolonic reflex, distension of one part of the colon induces relaxation of the remaining parts. In the gastrocolic reflex, the presence of a meal in the stomach triggers an increase in colonic motility and an increase in the frequency of mass movements.

   Defecation

   The elimination of feces from the body is controlled both unconsciously by a defecation reflex and voluntarily. The defecation reflex is triggered by distension of the rectum, which occurs as fecal material begins to enter the rectum from the colon, usually during mass movements of the colon. This distension stimulates stretch receptors and initiates several events. First, smooth muscle in the wall of the rectum is stimulated to contract, which raises the pressure inside. Peristaltic contractions of the sigmoid colon are also stimulated, which propels more fecal material into the rectum, further raising the pressure. At the same time, the internal anal sphincter relaxes while the external anal sphincter contracts, preventing the material from exiting the body. If the colonic contractions are strong enough to raise the pressure in the rectum to a certain critical level, the external anal sphincter relaxes, allowing defecation to proceed. In adults and children who are toilet trained, defecation may be postponed by voluntary contraction of the external anal sphincter. Constipation, caused by insufficient defecation, can lead to increased pressure in the colon, which can cause diverticula.