Vander et al.: Human 17. The Digestion and © The McGraw ...sibotesting.com/.../11/Digestion-and-Absorption... · The Digestion and Absorption of Food CHAPTER SEVENTEEN 557 TABLE

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

III. Coordinated Body Functions

17. The Digestion and Absorption of Food

© The McGraw−Hill Companies, 2001

chapter

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553

Regulation of GastrointestinalProcessesBasic Principles

Mouth, Pharynx, and Esophagus

Stomach

Pancreatic Secretions

Bile Secretion

Small Intestine

Large Intestine

Overview: Functions of theGastrointestinal Organs

Structure of the GastrointestinalTract Wall

Digestion and AbsorptionCarbohydrate

Protein

Fat

Vitamins

Water and Minerals

Pathophysiology of theGastrointestinal TractUlcers

Vomiting

Gallstones

Lactose Intolerance

Constipation and Diarrhea

SUMMARY

KEY TERMS

REVIEW QUESTIONS

CLINICAL TERMS

THOUGHT QUESTIONS

C H A P T E R 17

The Digestion and Absorption of Food





T relevant to understanding some of the tract’s properties. For

example, the large intestine is inhabited by billions of

bacteria, most of which are harmless and even beneficial in

this location. However, if the same bacteria enter the internal

environment, as may happen, for example, in the case of a

ruptured appendix, they may cause a severe infection.

Most food enters the gastrointestinal tract as large

particles containing macromolecules, such as proteins and

polysaccharides, which are unable to cross the intestinal

epithelium. Before ingested food can be absorbed, therefore,

it must be dissolved and broken down into small molecules.

This dissolving and breaking-down process—digestion—is

accomplished by the action of hydrochloric acid in the

stomach, bile from the liver, and a variety of digestive

enzymes that are released by the system’s exocrine glands.

Each of these substances is released into the lumen of the

GI tract by the process of secretion.

The molecules produced by digestion then move from

the lumen of the gastrointestinal tract across a layer of

epithelial cells and enter the blood or lymph. This process is

called absorption.

While digestion, secretion, and absorption are taking

place, contractions of smooth muscles in the gastrointestinal

tract wall serve two functions; they mix the luminal contents

with the various secretions, and they move the contents

through the tract from mouth to anus. These contractions are

referred to as the motility of the gastrointestinal tract.

The functions of the gastrointestinal system can be

described in terms of these four processes—digestion,

secretion, absorption, and motility (Figure 17–2)—and the

mechanisms controlling them.

The gastrointestinal system is designed to maximize

absorption, and within fairly wide limits it will absorb as much

of any particular substance as is ingested. With a few

important exceptions (to be described later), therefore, the

gastrointestinal system does not regulate the amount of

nutrients absorbed or their concentrations in the internal

environment. The regulation of the plasma concentration of

the absorbed nutrients is primarily the function of the kidneys

(Chapter 16) and a number of endocrine glands (Chapter 18).

Small amounts of certain metabolic end products are

excreted via the gastrointestinal tract, primarily by way of the

bile, but the elimination of most of the body’s waste products

is achieved by the lungs and kidneys. The material—feces—

leaving the system at the end of the gastrointestinal tract

consists almost entirely of bacteria and ingested material that

was neither digested nor absorbed—that is, material that was

never actually part of the internal environment.

The gastrointestinal (GI) system (Figure 17–1) includes the

gastrointestinal tract (mouth, pharynx, esophagus, stomach,

small intestine, and large intestine) plus the accessory organs

(salivary glands, liver, gallbladder, and pancreas) that are not

part of the tract but secrete substances into it via connecting

ducts. The overall function of the gastrointestinal system is to

process ingested foods into molecular forms that are then

transferred, along with salts and water to the body’s internal

environment, where they can be distributed to cells by the

circulatory system.

The adult gastrointestinal tract is a tube approximately

15 ft long, running through the body from mouth to anus.

The lumen of the tract, like the hole in a doughnut, is

continuous with the external environment, which means that

its contents are technically outside the body. This fact is

Mouth

Sublingual salivary gland

Submandibularsalivary gland

Trachea

Liver

Gallbladder

Parotidsalivarygland

Pharynx

Esophagus

Stomach

Pancreas

Smallintestine

Largeintestine

Colon

Cecum

Rectum

Anus

FIGURE 17–1Anatomy of the gastrointestinal system. The liver overlies thegallbladder and a portion of the stomach, and the stomachoverlies part of the pancreas.

554





Overview: Functions of theGastrointestinal OrgansFigure 17–3 presents an overview of the secretions andfunctions of the gastrointestinal organs. The gastroin-testinal tract begins with the mouth, and digestionstarts there with chewing, which breaks up large piecesof food into smaller particles that can be swallowed.Saliva, secreted by three pairs of salivary glands (seeFigure 17–1) located in the head, drains into the mouththrough a series of short ducts. Saliva, which containsmucus, moistens and lubricates the food particles be-fore swallowing. It also contains the enzyme amylase,which partially digests polysaccharides. A third func-tion of saliva is to dissolve some of the food molecules.Only in the dissolved state can these molecules reactwith chemoreceptors in the mouth, giving rise to thesensation of taste (Chapter 9).

The next segments of the tract, the pharynx andesophagus, contribute nothing to digestion but pro-vide the pathway by which ingested materials reachthe stomach. The muscles in the walls of these seg-ments control swallowing.

The stomach is a saclike organ, located betweenthe esophagus and the small intestine. Its functions areto store, dissolve, and partially digest the macromole-cules in food and to regulate the rate at which the stom-ach’s contents empty into the small intestine. Theglands lining the stomach wall secrete a strong acid,hydrochloric acid, and several protein-digesting en-zymes collectively known as pepsin (actually a pre-cursor of pepsin known as pepsinogen is secreted andconverted to pepsin in the lumen of the stomach).

The primary function of hydrochloric acid is to dis-solve the particulate matter in food. The acid environ-ment in the gastric (adjective for “stomach”) lumen al-ters the ionization of polar molecules, especially proteins,disrupting the extracellular network of connectivetissue proteins that form the structural framework ofthe tissues in food. The proteins and polysaccharidesreleased by hydrochloric acid’s dissolving action arepartially digested in the stomach by pepsin and amy-lase, the latter contributed by the salivary glands. Amajor food component that is not dissolved by acid isfat.

Hydrochloric acid also kills most of the bacteriathat enter along with food. This process is not 100 per-cent effective, and some bacteria survive to take up res-idence and multiply in the gastrointestinal tract, par-ticularly the large intestine.

The digestive actions of the stomach reduce foodparticles to a solution known as chyme, which con-tains molecular fragments of proteins and polysaccha-rides, droplets of fat, and salt, water, and various othersmall molecules ingested in the food. Virtually none ofthese molecules, except water, can cross the epitheliumof the gastric wall, and thus little absorption of organicnutrients occurs in the stomach.

Digestion’s final stages and most absorption oc-cur in the next section of the tract, the small intestine,a tube about 1.5 inches in diameter and 9 ft in lengththat leads from the stomach to the large intestine. Heremolecules of intact or partially digested carbohy-drates, fats, and proteins are broken down by hy-drolytic enzymes into monosaccharides, fatty acids,and amino acids. Some of these enzymes are on the

555The Digestion and Absorption of Food CHAPTER SEVENTEEN

Esophagus

Stomach

Mouth

Food andwater

Digestion

ColonSmall intestine

Rectum

Anus

Feces

Hepaticportal vein

Absorption

Heart

Liver

Secretion

Motility

&

FIGURE 17–2Four processes carried out by the gastrointestinal tract: digestion, secretion, absorption, and motility.





556 PART THREE Coordinated Body Functions

OrganExocrinesecretions Functions

Mouth and pharynx

Esophagus

Stomach

Pancreas

Liver

Gallbladder

Small intestine

Large intestine

Salt and water

Mucus

Amylase

Chewing begins; initiation of swallowing reflex

Moisten food

Lubrication

Polysaccharide-digesting enzyme

Move food to stomach by peristaltic waves

LubricationMucus

Store, mix, dissolve, and continue digestion of food; regulate emptying of dissolved food into small intestine

Solubilization of food particles; kill microbes

Protein-digesting enzyme

Lubricate and protect epithelial surface

HCl

Pepsin

Mucus

Secretion of enzymes and bicarbonate; also has nondigestive endocrine functions

Digest carbohydrates, fats, proteins, and nucleic acids

Neutralize HCl entering small intestine from stomach

Enzymes

Bicarbonate

Secretion of bile; many other nondigestive functions

Solubilize water-insoluble fats

Neutralize HCl entering small intestine from stomach

Elimination in feces

Bile salts

Bicarbonate

Organic waste products and trace metals

Store and concentrate bile between meals

Digestion and absorption of most substances; mixing and propulsion of contents

Food digestion

Maintain fluidity of luminal contents

Lubrication

Enzymes

Salt and water

Mucus

Storage and concentration of undigested matter; absorption of salt and water; mixing and propulsion of contents; defecation

LubricationMucus

Salivary glands

FIGURE 17–3Functions of the gastrointestinal organs.





luminal surface of the intestinal lining cells, while oth-ers are secreted by the pancreas and enter the intes-tinal lumen. The products of digestion are absorbedacross the epithelial cells and enter the blood and/orlymph. Vitamins, minerals, and water, which do notrequire enzymatic digestion, are also absorbed in thesmall intestine.

The small intestine is divided into three segments:An initial short segment, the duodenum, is followedby the jejunum and then by the longest segment, theileum. Normally, most of the chyme entering from thestomach is digested and absorbed in the first quarterof the small intestine, in the duodenum and jejunum.

Two major glands—the pancreas and liver—se-crete substances that flow via ducts into the duode-num. The pancreas, an elongated gland located behind

the stomach, has both endocrine (Chapter 18) and ex-ocrine functions, but only the latter are directly in-volved in gastrointestinal function and are describedin this chapter. The exocrine portion of the pancreassecretes (1) digestive enzymes and (2) a fluid rich inbicarbonate ions. The high acidity of the chyme com-ing from the stomach would inactivate the pancreaticenzymes in the small intestine if the acid were not neu-tralized by the bicarbonate ions in the pancreatic fluid.

The liver, a large gland located in the upper rightportion of the abdomen, has a variety of functions,which are described in various chapters. This is a con-venient place to provide, in Table 17–1, a comprehen-sive reference list of these hepatic (the term means“pertaining to the liver”) functions and the chapters inwhich they are described. We will be concerned in this


TABLE 17–1 Summary of Liver Functions

A. Exocrine (digestive) functions (Chapter 17)1. Synthesizes and secretes bile salts, which are necessary for adequate digestion and absorption of fats.2. Secretes into the bile a bicarbonate-rich solution, which helps neutralize acid in the duodenum.

B. Endocrine functions1. In response to growth hormone, secretes insulin-like growth factor I (IGF-I), which promotes growth by stimulating cell

division in various tissues, including bone (Chapter 18).2. Contributes to the activation of vitamin D (Chapter 16).3. Forms triiodothyronine (T3) from thyroxine (T4) (Chapter 10).4. Secretes angiotensinogen, which is acted upon by renin to form angiotensin I (Chapter 16).5. Metabolizes hormones (Chapter 10).6. Secretes cytokines involved in immune defenses (Chapter 20).

C. Clotting functions1. Produces many of the plasma clotting factors, including prothrombin and fibrinogen (Chapter 14).2. Produces bile salts, which are essential for the gastrointestinal absorption of vitamin K, which is, in turn, needed for

production of the clotting factors (Chapter 14).

D. Plasma proteins1. Synthesizes and secretes plasma albumin (Chapter 14), acute phase proteins (Chapter 20), binding proteins for various

hormones (Chapter 10) and trace elements (Chapter 14), lipoproteins (Chapter 18), and other proteins mentioned elsewherein this table.

E. Organic metabolism (Chapter 18)1. Converts plasma glucose into glycogen and triacylglycerols during absorptive period.2. Converts plasma amino acids to fatty acids, which can be incorporated into triacylglycerols during absorptive period.3. Synthesizes triacylglycerols and secretes them as lipoproteins during absorptive period.4. Produces glucose from glycogen (glycogenolysis) and other sources (gluconeogenesis) during postabsorptive period and

releases the glucose into the blood.5. Converts fatty acids into ketones during fasting.6. Produces urea, the major end product of amino acid (protein) catabolism, and releases it into the blood.

F. Cholesterol metabolism (Chapter 18)1. Synthesizes cholesterol and releases it into the blood.2. Secretes plasma cholesterol into the bile.3. Converts plasma cholesterol into bile salts.

G. Excretory and degradative functions1. Secretes bilirubin and other bile pigments into the bile (Chapter 17).2. Excretes, via the bile, many endogenous and foreign organic molecules as well as trace metals (Chapter 20).3. Biotransforms many endogenous and foreign organic molecules (Chapter 20).4. Destroys old erythrocytes (Chapter 14).





chapter only with the liver’s exocrine functions thatare directly related to the secretion of bile.

Bile contains bicarbonate ions, cholesterol, phos-pholipids, bile pigments, a number of organic wastesand—most important—a group of substances collec-tively termed bile salts. The bicarbonate ions, likethose from the pancreas, help neutralize acid from thestomach, while the bile salts, as we shall see, solubi-lize dietary fat. These fats would otherwise be insolu-ble in water, and their solubilization increases the ratesat which they are digested and absorbed.

Bile is secreted by the liver into small ducts thatjoin to form a single duct called the common hepaticduct. Between meals, secreted bile is stored in the gall-bladder, a small sac underneath the liver that branchesfrom the common hepatic duct. The gallbladder con-centrates the organic molecules in bile by absorbingsalts and water. During a meal, the smooth muscles inthe gallbladder wall contract, causing a concentratedbile solution to be injected into the duodenum via thecommon bile duct (Figure 17–4), an extension of thecommon hepatic duct. The gallbladder can be surgi-cally removed without impairing bile secretion by theliver or its flow into the intestinal tract. In fact, manyanimals that secrete bile do not have a gallbladder.

In the small intestine, monosaccharides and aminoacids are absorbed by specific transporter-mediated

processes in the plasma membranes of the intestinalepithelial cells, whereas fatty acids enter these cells bydiffusion. Most mineral ions are actively absorbed bytransporters, and water diffuses passively down os-motic gradients.

The motility of the small intestine, brought aboutby the smooth muscles in its walls, (1) mixes the lu-minal contents with the various secretions, (2) bringsthe contents into contact with the epithelial surfacewhere absorption takes place, and (3) slowly advancesthe luminal material toward the large intestine. Sincemost substances are absorbed in the small intestine,only a small volume of water, salts, and undigestedmaterial is passed on to the large intestine. The largeintestine temporarily stores the undigested material(some of which is metabolized by bacteria) and con-centrates it by absorbing salts and water. Contractionsof the rectum, the final segment of the large intestine,and relaxation of associated sphincter muscles expelthe feces—defecation.

The average adult consumes about 800 g of foodand 1200 ml of water per day, but this is only a frac-tion of the material entering the lumen of the gas-trointestinal tract. An additional 7000 ml of fluidfrom salivary glands, gastric glands, pancreas, liver,and intestinal glands is secreted into the tract eachday (Figure 17–5). Of the 8 L of fluid entering the


Bile ductfrom liver

Bile ductfrom liver

GallbladderCommon hepatic duct

Common bile duct

Sphincterof Oddi

Duodenum

Pancreatic duct

Pancreas

FIGURE 17–4Bile ducts from the liver converge to form the common hepatic duct, from which branches the duct leading to thegallbladder. Beyond this branch, the common hepatic duct becomes the common bile duct. The common bile duct and thepancreatic duct converge and empty their contents into the duodenum at the sphincter of Oddi.





tract, 99 percent is absorbed; only about 100 ml isnormally lost in the feces. This small amount of fluidloss represents only 4 percent of the total fluids lostby the body each day (most fluid loss is via the kid-neys and respiratory system). Almost all the salts inthe secreted fluids are also reabsorbed into the blood.Moreover, the secreted digestive enzymes are them-selves digested, and the resulting amino acids are ab-sorbed into the blood.

This completes our overview of the gastrointesti-nal system. Since its major task is digestion and ab-sorption, we begin our more detailed description withthese processes. Subsequent sections of the chapter willthen describe, organ by organ, regulation of the secre-tions and motility that produce the optimal conditionsfor digestion and absorption. A prerequisite for thisphysiology, however, is a knowledge of the structureof the gastrointestinal tract wall.

Structure of the GastrointestinalTract WallFrom the midesophagus to the anus, the wall of thegastrointestinal tract has the general structure illus-trated in Figure 17–6. Most of the tube’s luminal surface is highly convoluted, a feature that greatly

increases the surface area available for absorption.From the stomach on, this surface is covered by a sin-gle layer of epithelial cells linked together along theedges of their luminal surfaces by tight junctions.

Included in this epithelial layer are exocrine cellsthat secrete mucus into the lumen of the tract and en-docrine cells that release hormones into the blood. In-vaginations of the epithelium into the underlying tis-sue form exocrine glands that secrete acid, enzymes,water, and ions, as well as mucus.

Just below the epithelium is a layer of connectivetissue, the lamina propria, through which pass smallblood vessels, nerve fibers, and lymphatic ducts.(These structures are not shown in Figure 17–6 but arein Figure 17–7.) The lamina propria is separated fromunderlying tissues by a thin layer of smooth muscle,the muscularis mucosa. The combination of these threelayers—the epithelium, lamina propria, and muscu-laris mucosa—is called the mucosa (Figure 17–6).

Beneath the mucosa is a second connective tissuelayer, the submucosa, containing a network of nervecells, termed the submucous plexus, and blood andlymphatic vessels whose branches penetrate into boththe overlying mucosa and the underlying layers ofsmooth muscle called the muscularis externa. Con-tractions of these muscles provide the forces for mov-ing and mixing the gastrointestinal contents. The mus-cularis externa has two layers: (1) a relatively thickinner layer of circular muscle, whose fibers are ori-ented in a circular pattern around the tube such thatcontraction produces a narrowing of the lumen, and(2) a thinner outer layer of longitudinal muscle, whosecontraction shortens the tube. Between these two mus-cle layers is a second network of nerve cells known asthe myenteric plexus.

Finally, surrounding the outer surface of the tubeis a thin layer of connective tissue called the serosa.Thin sheets of connective tissue connect the serosa tothe abdominal wall, supporting the gastrointestinaltract in the abdominal cavity.

Extending from the luminal surface of the smallintestine are fingerlike projections known as villi (Fig-ure 17–7). The surface of each villus is covered with alayer of epithelial cells whose surface membranes formsmall projections called microvilli (also known collec-tively as the brush border) (Figure 17–8). The combi-nation of folded mucosa, villi, and microvilli increasesthe small intestine’s surface area about 600-fold overthat of a flat-surfaced tube having the same length anddiameter. The human small intestine’s total surfacearea is about 300 m2, the area of a tennis court.

Epithelial surfaces in the gastrointestinal tract arecontinuously being replaced by new epithelial cells. Inthe small intestine, new cells arise by cell division fromcells at the base of the villi. These cells differentiate as


1400 mlinto blood

6700 mlinto blood

Feces 100 ml water; 50 g solids

1500 ml intestinal secretions

1500 mlpancreatic secretions

500 ml bile

2000 ml gastric secretions

1500 ml saliva

1200 ml water/day; 800 g solids/day

1500 ml

FIGURE 17–5Average amounts of solids and fluid ingested, secreted,absorbed, and excreted from the gastrointestinal tract daily.





they migrate to the top of the villus, replacing older cellsthat disintegrate and are discharged into the intestinallumen. These disintegrating cells release into the lumentheir intracellular enzymes, which then contribute to thedigestive process. About 17 billion epithelial cells are replaced each day, and the entire epithelium of the smallintestine is replaced approximately every 5 days. It isbecause of this rapid cell turnover that the lining of theintestinal tract is so susceptible to damage by agents,such as radiation and anticancer drugs, that inhibit celldivision.

The center of each intestinal villus is occupied bothby a single blind-ended lymphatic vessel termed alacteal and by a capillary network (see Figure 17–7).As we will see, most of the fat absorbed in the smallintestine enters the lacteals, while other absorbed nu-trients enter the blood capillaries. The venous drainagefrom the small intestine, as well as from the large


FIGURE 17–6Structure of the gastrointestinal wall in longitudinal section. Not shown are the smaller blood vessels and lymphatics, neuralconnections between the two nerve plexuses, and neural terminations on muscles, glands and epithelium.

Ducts from externalexocrine glands(liver, pancreas, salivaryglands)

Abdominal cavity

Mucosa

Submucosa

Muscularisexterna

Serosa

Epithelium

Lamina propria

Muscularismucosa

Submucusnerve plexus

Circular muscle

Myentericnerve plexus

Longitudinalmuscle

Major blood andlymphatic vessels

Endocrinecells

Mucous cells

Exocrineglands

Lumen of gastrointestinal tract

Lumen

Capillaries

Nerve fiber

Venule

Lacteal

Muscularismucosae

Villus Epithelial cells

Microvilli

Arteriole

VeinLymph duct ArteryFIGURE 17–7Structure of villi in small intestine.






Tightjunctions

Intestinallumen

Microvilli

FIGURE 17–8Microvilli on the surface of intestinal epithelial cells.From D. W. Fawcett, J. Histochem. Cytochem. 13: 75–91 (1965). Courtesy of Susumo Ito.





intestine, pancreas, and portions of the stomach, doesnot empty directly into the vena cava but passes first,via the hepatic portal vein, to the liver. There it flowsthrough a second capillary network before leaving theliver to return to the heart. Thus, material absorbedinto the intestinal capillaries, in contrast to the lacteals,can be processed by the liver before entering the gen-eral circulation.

Digestion and AbsorptionCarbohydrateCarbohydrate intake per day ranges from about 250 to800 g in a typical American diet. About two-thirds ofthis carbohydrate is the plant polysaccharide starch,and most of the remainder consists of the disaccha-rides sucrose (table sugar) and lactose (milk sugar)(Table 17–2). Only small amounts of monosaccharidesare normally present in the diet. Cellulose and certainother complex polysaccharides found in vegetablematter—referred to as fiber—cannot be broken downby the enzymes in the small intestine and are passedon to the large intestine, where they are partially me-tabolized by bacteria.

Starch digestion by salivary amylase begins in themouth and continues in the upper part of the stomachbefore the amylase is destroyed by gastric acid. Starchdigestion is completed in the small intestine by pan-creatic amylase. The products produced by both amy-lases are the disaccharide maltose and a mixture ofshort, branched chains of glucose molecules. Theseproducts, along with ingested sucrose and lactose, arebroken down into monosaccharides—glucose, galac-tose, and fructose—by enzymes located on the lumi-nal membranes of the small-intestine epithelial cells.These monosaccharides are then transported across theintestinal epithelium into the blood. Fructose enters theepithelial cells by facilitated diffusion, while glucoseand galactose undergo secondary active transport cou-pled to sodium. These monosaccharides then leave theepithelial cells and enter the blood by way of facili-tated diffusion transporters in the basolateral mem-branes of the epithelial cells. Most ingested carbohy-drate is digested and absorbed within the first 20percent of the small intestine.

ProteinOnly 40 to 50 g of protein per day is required by a nor-mal adult to supply essential amino acids and replacethe amino acid nitrogen converted to urea. A typicalAmerican diet contains about 125 g of protein per day.In addition, a large amount of protein, in the form ofenzymes and mucus, is secreted into the gastrointesti-nal tract or enters it via the disintegration of epithelialcells. Regardless of source, most of the protein in the

lumen is broken down into amino acids and absorbedby the small intestine.

Proteins are broken down to peptide fragments inthe stomach by pepsin, and in the small intestine bytrypsin and chymotrypsin, the major proteases se-creted by the pancreas. These fragments are further di-gested to free amino acids by carboxypeptidase fromthe pancreas and aminopeptidase, located on the lu-minal membranes of the small-intestine epithelial cells.These last two enzymes split off amino acids from thecarboxyl and amino ends of peptide chains, respec-tively. At least 20 different peptidases are located onthe luminal membrane of the epithelial cells, with var-ious specificities for the peptide bonds they attack.

The free amino acids then enter the epithelial cellsby secondary active transport coupled to sodium.There are multiple transporters with different speci-ficities for the 20 types of amino acids. Short chains oftwo or three amino acids are also absorbed by a sec-ondary active transport that is coupled to the hydrogen-ion gradient. (This is in contrast to carbohydrate absorption, in which molecules larger than monosac-charides are not absorbed.) Within the epithelial cell,these di- and tripeptides are hydrolyzed to aminoacids, which then leave the cell and enter the bloodthrough a facilitated diffusion carrier in the basolateralmembranes. As with carbohydrates, protein digestionand absorption are largely completed in the upper por-tion of the small intestine.

Very small amounts of intact proteins are able tocross the intestinal epithelium and gain access to theinterstitial fluid. They do so by a combination of en-docytosis and exocytosis. The absorptive capacity forintact proteins is much greater in infants than in adults,and antibodies (proteins involved in the immunologi-cal defense system of the body) secreted into themother’s milk can be absorbed by the infant, provid-ing some immunity until the infant begins to produceits own antibodies.


TABLE 17–2 Carbohydrates in Food

Class Examples Made of

Polysaccharides Starch GlucoseCellulose GlucoseGlycogen Glucose

Disaccharides Sucrose Glucose-fructoseLactose Glucose-galactoseMaltose Glucose-glucose

Monosaccharides GlucoseFructoseGalactose





FatFat intake ranges from about 25 to 160 g/day in a typ-ical American diet; most is in the form of triacylglyc-erols. Fat digestion occurs almost entirely in the smallintestine. The major digestive enzyme in this processis pancreatic lipase, which catalyzes the splitting ofbonds linking fatty acids to the first and third carbonatoms of glycerol, producing two free fatty acids anda monoglyceride as products:

LipaseTriacylglycerol 8888n Monoglyceride � 2 Fatty acids

The fats in the ingested foods are insoluble in wa-ter and aggregate into large lipid droplets in the up-per portion of the stomach. Since pancreatic lipase isa water-soluble enzyme, its digestive action in thesmall intestine can take place only at the surface of alipid droplet. Therefore, if most of the ingested fat re-mained in large lipid droplets, the rate of lipid diges-tion would be very slow. The rate of digestion is, how-ever, substantially increased by division of the largelipid droplets into a number of much smaller droplets,each about 1 mm in diameter, thereby increasing theirsurface area and accessibility to lipase action. Thisprocess is known as emulsification, and the resultingsuspension of small lipid droplets is an emulsion.

The emulsification of fat requires (1) mechanicaldisruption of the large fat droplets into smallerdroplets, and (2) an emulsifying agent, which acts toprevent the smaller droplets from reaggregating backinto large droplets. The mechanical disruption is pro-vided by contractile activity, occurring in the lowerportion of the stomach and in the small intestine,which acts to grind and mix the luminal contents.Phospholipids in food and phospholipids and bile saltssecreted in the bile provide the emulsifying agents,whose action is as follows.

Phospholipids are amphipathic molecules (Chap-ter 2) consisting of two nonpolar fatty acid chains at-tached to glycerol, with a charged phosphate group lo-cated on glycerol’s third carbon. Bile salts are formedfrom cholesterol in the liver and are also amphipathic(Figure 17–9). The nonpolar portions of the phospho-lipids and bile salts associate with the nonpolar inte-rior of the lipid droplets, leaving the polar portions ex-posed at the water surface. There they repel other lipiddroplets that are similarly coated with these emulsify-ing agents, thereby preventing their reaggregation intolarger fat droplets (Figure 17–10).

The coating of the lipid droplets with these emul-sifying agents, however, impairs the accessibility of thewater-soluble lipase to its lipid substrate. To overcomethis problem, the pancreas secretes a protein known ascolipase, which is amphipathic and lodges on the lipiddroplet surface. Colipase binds the lipase enzyme,holding it on the surface of the lipid droplet.


C – NH – CH2 – COO–

O

CH3

CH3

OH

CH3

OHHO

Bile salt (glycocholic acid)

(a)

(b) Nonpolar side

Hydroxylgroups

Polar side

Peptide bond

Carboxyl group

FIGURE 17–9Structure of bile salts. (a) Chemical formula of glycocholicacid, one of several bile salts secreted by the liver (polargroups in color). (b) Three-dimensional structure of a bilesalt, showing its polar and nonpolar surfaces.

Emulsification

Bile salt Phospholipid

Fat globule

Emulsion droplet

+

FIGURE 17–10Emulsification of fat by bile salts and phospholipids.





Although digestion is speeded up by emulsifica-tion, absorption of the water-insoluble products of thelipase reaction would still be very slow if it were notfor a second action of the bile salts, the formation ofmicelles, which are similar in structure to emulsiondroplets but are much smaller—4 to 7 nm in diame-ter. Micelles consist of bile salts, fatty acids, mono-glycerides, and phospholipids all clustered togetherwith the polar ends of each molecule oriented towardthe micelle’s surface and the nonpolar portions form-ing the micelle’s core (Figure 17–11). Also included in

the core of the micelle are small amounts of fat-soluble vitamins and cholesterol.

How do micelles increase absorption? Althoughfatty acids and monoglycerides have an extremely lowsolubility in water, a few molecules do exist in solu-tion and are free to diffuse across the lipid portion ofthe luminal plasma membranes of the epithelial cellslining the small intestine. Micelles, containing theproducts of fat digestion, are in equilibrium with thesmall concentration of fat digestion products that arefree in solution. Thus, micelles are continuously break-ing down and reforming. When a micelle breaks down,its contents are released into the solution and becomeavailable to diffuse across the intestinal lining. As theconcentrations of free lipids fall, because of their dif-fusion into epithelial cells, more lipids are released intothe free phase as micelles break down (Figure 17–11).Thus, the micelles provide a means of keeping most ofthe insoluble fat digestion products in small solubleaggregates, while at the same time replenishing thesmall amount of products that are free in solution andare able to diffuse into the intestinal epithelium. Notethat it is not the micelle that is absorbed but rather theindividual lipid molecules that are released from themicelle.

Although fatty acids and monoglycerides enter ep-ithelial cells from the intestinal lumen, it is triacyl-glycerol that is released on the other side of the cellinto the interstitial fluid. In other words, during theirpassage through the epithelial cells, fatty acids andmonoglycerides are resynthesized into triacylglyc-erols. This occurs in the agranular (smooth) endoplas-mic reticulum, where the enzymes for triacylglycerolsynthesis are located. This process lowers the concen-tration of cytosolic free fatty acids and monoglyceridesand thus maintains a diffusion gradient for these mol-ecules into the cell. Within this organelle, the resyn-thesized fat aggregates into small droplets coated withamphipathic proteins that perform an emulsifyingfunction similar to that of bile salts.

The exit of these fat droplets from the cell followsthe same pathway as a secreted protein. Vesicles con-taining the droplet pinch off the endoplasmic reticu-lum, are processed through the Golgi apparatus, andeventually fuse with the plasma membrane, releasingthe fat droplet into the interstitial fluid. These one-micron-diameter, extracellular fat droplets are knownas chylomicrons. Chylomicrons contain not only tri-acylglycerols but other lipids (including phospho-lipids, cholesterol, and fat-soluble vitamins) that havebeen absorbed by the same process that led to fattyacid and monoglyceride movement into the epithelialcells of the small intestine.

The chylomicrons released from the epithelial cells pass into lacteals—lymphatic capillaries in the


Fatty acidsMonoglyceride

Triglyceride

Micelle

Bile salt

Emulsion droplet

Lipase

Diffusion

Intestinalepithelialcell

Micellereformation

Micellebreakdown

FIGURE 17–11The products of fat digestion by lipase are held in solution inthe micellar state, combined with bile salts andphospholipids. For simplicity, the phospholipids and colipase(see text) are not shown and the size of the micelle is greatlyexaggerated.





intestinal villi—rather than into the blood capillaries.The chylomicrons cannot enter the blood capillaries be-cause the basement membrane (an extracellular gly-coprotein layer) at the outer surface of the capillaryprovides a barrier to the diffusion of large chylomi-crons. In contrast, the lacteals do not have basementmembranes and have large slit pores between their en-dothelial cells through which the chylomicrons canpass into the lymph. The lymph from the small intes-tine, as from everywhere else in the body, eventuallyempties into systemic veins. In Chapter 18 we describehow the lipids in the circulating blood chylomicronsare made available to the cells of the body.

Figure 17–12 summarizes the pathway taken byfat in moving from the intestinal lumen into the lym-phatic system.

VitaminsThe fat-soluble vitamins—A, D, E, and K—follow thepathway for fat absorption described in the previoussection. They are solubilized in micelles; thus, any in-terference with the secretion of bile or the action of bilesalts in the intestine decreases the absorption of the fat-soluble vitamins.

With one exception, water-soluble vitamins are ab-sorbed by diffusion or mediated transport. The excep-tion, vitamin B12, is a very large, charged molecule. Inorder to be absorbed, vitamin B12 must first bind to aprotein, known as intrinsic factor, secreted by the acid-secreting cells in the stomach. Intrinsic factor withbound vitamin B12 then binds to specific sites on theepithelial cells in the lower portion of the ileum, wherevitamin B12 is absorbed by endocytosis. As describedin Chapter 14, vitamin B12 is required for erythrocyteformation, and deficiencies result in pernicious ane-mia. This form of anemia may occur when the stom-ach either has been removed (as, for example, to treatulcers or gastric cancer) or fails to secrete intrinsic fac-tor. Since the absorption of vitamin B12 occurs in thelower part of the ileum, removal of this segment be-cause of disease can also result in pernicious anemia.

Water and MineralsWater is the most abundant substance in chyme. Ap-proximately 8000 ml of ingested and secreted water en-ters the small intestine each day, but only 1500 ml ispassed on to the large intestine since 80 percent of thefluid is absorbed in the small intestine. Small amountsof water are absorbed in the stomach, but the stomachhas a much smaller surface area available for diffusionand lacks the solute-absorbing mechanisms that createthe osmotic gradients necessary for net water absorp-tion. The epithelial membranes of the small intestineare very permeable to water, and net water diffusionoccurs across the epithelium whenever a water-concentration difference is established by the active ab-sorption of solutes. The mechanisms coupling soluteand water absorption by epithelial cells were describedin Chapter 6.

Sodium ions account for much of the activelytransported solute because they constitute the mostabundant solute in chyme. Sodium absorption is a pri-mary active process, using the Na,K-ATPase pumps ina manner described in Chapter 6 and similar to thatfor renal tubular sodium and water reabsorption(Chapter 16). Chloride and bicarbonate ions are ab-sorbed with the sodium ions and contribute anotherlarge fraction of the absorbed solute.


Lumen ofintestinaltract

Epithelialcell

Lacteal

Diffusion

Free moleculesof fatty acids andmonoglycerides

Micelles

Bile saltsPancreatic lipase

Bile saltsPhospholipids

Emulsiondroplets

Fatty acids andmonoglycerides

Triacylglycerol syntheticenzymes in endoplasmicreticulum

Droplets of triacylglycerolenclosed by membranefrom the endoplasmic reticulum

Chylomicron

Fat droplet

FIGURE 17–12Summary of fat absorption across the walls of the smallintestine.





Other minerals present in smaller concentrations,such as potassium, magnesium, and calcium, are alsoabsorbed, as are trace elements such as iron, zinc, andiodide. Consideration of the transport processes asso-ciated with each of these is beyond the scope of thisbook, and we shall briefly consider as an example theabsorption of only one—iron. Calcium absorption andits regulation were described in Chapter 16.

Iron Only about 10 percent of ingested iron is ab-sorbed into the blood each day. Iron ions are activelytransported into intestinal epithelial cells, where mostof them are incorporated into ferritin, the protein-ironcomplex that functions as an intracellular iron store(Chapter 14). The absorbed iron that does not bind toferritin is released on the blood side where it circulatesthroughout the body bound to the plasma proteintransferrin. Most of the iron bound to ferritin in the ep-ithelial cells is released back into the intestinal lumenwhen the cells at the tips of the villi disintegrate, andit is excreted in the feces.

Iron absorption depends on the body’s iron con-tent. When body stores are ample, the increased con-centration of free iron in the plasma and intestinal ep-ithelial cells leads to an increased transcription of thegene encoding the ferritin protein and thus an in-creased synthesis of ferritin. This results in the in-creased binding of iron in the intestinal epithelial cellsand a reduction in the amount of iron released into theblood. When the body stores drop, for example, whenthere is a loss of hemoglobin during hemorrhage, theproduction and hence the concentration of intestinalferritin decreases; the amount of iron bound to ferritindecreases, thereby increasing the unbound iron re-leased into the blood.

Once iron has entered the blood, the body has verylittle means of excreting it, and it accumulates in tis-sues. Although the control mechanisms for iron ab-sorption just described tend to maintain the iron con-tent of the body fairly constant, a very large ingestionof iron can overwhelm them, leading to an increaseddeposition of iron in tissues and producing toxic ef-fects. This condition is termed hemochromatosis. Somepeople have genetically defective control mechanismsand therefore develop hemochromatosis even wheniron ingestion is normal.

Iron absorption also depends on the type of foodingested because it binds to many negatively chargedions in food, which can retard its absorption. For ex-ample, iron in ingested liver is much more absorbablethan iron in egg yolk since the latter contains phos-phates that bind the iron to form an insoluble and un-absorbable complex.

The absorption of iron is typical of that of mosttrace metals in several respects: (1) Cellular storage

proteins and plasma carrier proteins are involved, and(2) the control of absorption, rather than urinary ex-cretion, is the major mechanism for the homeostaticcontrol of the body’s content of the trace metal.

Regulation of GastrointestinalProcessesUnlike control systems that regulate variables in theinternal environment, the control mechanisms of thegastrointestinal system regulate conditions in the lu-men of the tract. With few exceptions, like those justdiscussed for iron and other trace metals, these controlmechanisms are governed not by the nutritional stateof the body, but rather by the volume and compositionof the luminal contents.

Basic PrinciplesGastrointestinal reflexes are initiated by a relativelysmall number of luminal stimuli: (1) distension of thewall by the volume of the luminal contents; (2) chymeosmolarity (total solute concentration); (3) chyme acid-ity; and (4) chyme concentrations of specific digestionproducts (monosaccharides, fatty acids, peptides, andamino acids). These stimuli act on receptors located inthe wall of the tract (mechanoreceptors, osmorecep-tors, and chemoreceptors) to trigger reflexes that in-fluence the effectors—the muscle layers in the wall ofthe tract and the exocrine glands that secrete sub-stances into its lumen.

Neural Regulation The gastrointestinal tract has itsown local nervous system, known as the enteric ner-vous system, in the form of two nerve networks, themyenteric plexus and the submucous plexus (see Fig-ure 17–6). These neurons either synapse with otherneurons in the plexus or end near smooth muscles,glands, and epithelial cells. Many axons leave themyenteric plexus and synapse with neurons in the sub-mucous plexus, and vice versa, so that neural activityin one plexus influences the activity in the other. More-over, stimulation at one point in the plexus can lead toimpulses that are conducted both up and down thetract. Thus, for example, stimuli in the upper part ofthe small intestine may affect smooth muscle andgland activity in the stomach as well as in the lowerpart of the intestinal tract.

The enteric nervous system contains adrenergicand cholinergic neurons as well as nonadrenergic, non-cholinergic neurons that release neurotransmitters,such as nitric oxide, several neuropeptides, and ATP.

Many of the effectors mentioned earlier—musclecells and exocrine glands—are supplied by neurons thatare part of the enteric nervous system. This permits






neural reflexes that are completely within the tract—that is, independent of the central nervous system(CNS). In addition, nerve fibers from both the sympa-thetic and parasympathetic branches of the autonomicnervous system enter the intestinal tract and synapsewith neurons in both plexuses. Via these pathways, theCNS can influence the motility and secretory activityof the gastrointestinal tract.

Thus, two types of neural reflex arcs exist (Figure17–13): (1) short reflexes from receptors through thenerve plexuses to effector cells; and (2) long reflexesfrom receptors in the tract to the CNS by way of af-ferent nerves and back to the nerve plexuses and ef-fector cells by way of autonomic nerve fibers. Somecontrols are mediated either solely by short reflexes orsolely by long reflexes, whereas other controls involveboth.

Finally, it should be noted that not all neural re-flexes are indicated by signals within the tract. Thesight or smell of food and the emotional state of an in-dividual can have significant effects on the gastroin-testinal tract, effects that are mediated by the CNS viaautonomic neurons.

Hormonal Regulation The hormones that controlthe gastrointestinal system are secreted mainly by en-docrine cells scattered throughout the epithelium ofthe stomach and small intestine; that is, these cells arenot clustered into discrete organs like the thyroid oradrenal glands. One surface of each endocrine cell isexposed to the lumen of the gastrointestinal tract. At

this surface, various chemical substances in the chymestimulate the cell to release its hormones from the op-posite side of the cell into the blood. Although someof these hormones can also be detected in the lumenand may therefore act locally as paracrine agents, mostof the gastrointestinal hormones reach their target cellsvia the circulation.

Several dozen substances are currently being inves-tigated as possible gastrointestinal hormones, but onlyfour—secretin, cholecystokinin (CCK), gastrin, andglucose-dependent insulinotropic peptide (GIP)—have met all the criteria for true hormones. They, as wellas several candidate hormones, also exist in the CNS andin gastrointestinal plexus neurons, where they functionas neurotransmitters or neuromodulators.

Table 17–3, which summarizes the major charac-teristics of the four established GI hormones, not onlyserves as a reference for future discussions but also il-lustrates the following generalizations: (1) Each hor-mone participates in a feedback control system thatregulates some aspect of the GI luminal environment,and (2) each hormone affects more than one type oftarget cell.

These two generalizations can be illustrated byCCK. The presence of fatty acids and amino acids inthe small intestine triggers CCK secretion from cells inthe small intestine into the blood. Circulating CCKthen stimulates secretion by the pancreas of digestiveenzymes. CCK also causes the gallbladder to contract,delivering to the intestine the bile salts required for mi-celle formation. As fat and amino acids are absorbed,


SHORT REFLEXES

LONGREFLEXES Efferent autonomic neurons

Gastrointestinal wall

Gastrointestinal lumen

Afferent neurons

Emotional states

Sight, smell,taste of food

Stimulus Response

Chemoreceptors,osmoreceptors, ormechanoreceptors

Nerve plexus Smooth muscle or gland

Central nervous system

FIGURE 17–13Long and short neural reflex pathways activated by stimuli in the gastrointestinal tract. The long reflexes utilize neurons thatlink the central nervous system to the gastrointestinal tract.





the stimuli (fatty acids and amino acids in the lumen)for CCK release are removed.

In many cases, a single effector cell contains re-ceptors for more than one hormone, as well as recep-tors for neurotransmitters and paracrine agents, withthe result that a variety of inputs can affect the cell’sresponse. One such event is the phenomenon knownas potentiation, which is exemplified by the interac-tion between secretin and CCK. Secretin strongly stim-ulates pancreatic bicarbonate secretion, whereas CCKis a weak stimulus of bicarbonate secretion. Both hor-mones together, however, stimulate pancreatic bicar-bonate secretion more strongly than would be pre-dicted by the sum of their individual stimulatory

effects. This is because CCK potentiates the effect ofsecretin. One of the consequences of potentiation isthat small changes in the plasma concentration of onegastrointestinal hormone can have large effects on theactions of other gastrointestinal hormones.

In addition to their stimulation (or in some casesinhibition) of effector-cell functions, the gastrointesti-nal hormones also have tropic (growth-promoting) ef-fects on various tissues, including the gastric and in-testinal mucosa and the exocrine portions of thepancreas.

Phases of Gastrointestinal Control The neural andhormonal control of the gastrointestinal system is, in


TABLE 17–3 Properties of Gastrointestinal Hormones

Gastrin CCK Secretin GIP

Structure Peptide Peptide Peptide PeptideEndocrine-Cell Antrum of stomach Small intestine Small intestine Small intestinelocation

Stimuli for Amino acids, peptides Amino acids, fatty Acid in small intestine Glucose, fat in smallhormone release in stomach; acids in small intestine

parasympathetic intestinenerves

Stimuli inhibiting Acid in stomach;hormone release somatostatin

Target-Cell Responses

StomachAcid secretion Stimulates Inhibits InhibitsMotility Stimulates Inhibits InhibitsGrowth Stimulates

PancreasBicarbonate Potentiates secretin’s Stimulates

secretion actionsEnzyme Stimulates Potentiates CCK’s

secretion actionsInsulin secretion StimulatesGrowth of exocrine Stimulates Stimulates Stimulates

pancreas

Liver (bile ducts)Bicarbonate Potentiates secretin’s Stimulates

secretion actions

GallbladderContraction Stimulates

Sphincter of Oddi Relaxes

Small intestineMotility Stimulates ileumGrowth Stimulates

Large intestine Stimulates massmovement





large part, divisible into three phases—cephalic, gas-tric, and intestinal—according to stimulus location.

The cephalic phase is initiated when receptors inthe head (cephalic, head) are stimulated by sight, smell,taste, and chewing. It is also initiated by various emo-tional states. The efferent pathways for these reflexesinclude both parasympathetic fibers, mostly in the va-gus nerves, and sympathetic fibers. These fibers acti-vate neurons in the gastrointestinal nerve plexuses,which in turn affect secretory and contractile activity.

Four types of stimuli in the stomach initiate the re-flexes that constitute the gastric phase of regulation:distension, acidity, amino acids, and peptides formedduring the digestion of ingested protein. The responsesto these stimuli are mediated by short and long neu-ral reflexes and by release of the hormone gastrin.

Finally, the intestinal phase is initiated by stimuliin the intestinal tract: distension, acidity, osmolarity,and various digestive products. The intestinal phase ismediated by both short and long neural reflexes andby the gastrointestinal hormones secretin, CCK, andGIP, all of which are secreted by endocrine cells in thesmall intestine.

We reemphasize that each of these phases is namedfor the site at which the various stimuli initiate the re-flex and not for the sites of effector activity. Each phaseis characterized by efferent output to virtually all or-gans in the gastrointestinal tract. Also, these phases donot occur in temporal sequence except at the very be-ginning of a meal. Rather, during ingestion and themuch longer absorptive period, reflexes characteristicof all three phases may occur simultaneously.

Keeping in mind the neural and hormonal mech-anisms available for regulating gastrointestinal activ-ity, we can now examine the specific contractile andsecretory processes that occur in each segment of thegastrointestinal system.

Mouth, Pharynx, and EsophagusChewing Chewing is controlled by the somaticnerves to the skeletal muscles of the mouth and jaw.In addition to the voluntary control of these muscles,rhythmical chewing motions are reflexly activated bythe pressure of food against the gums, hard palate atthe roof of the mouth, and tongue. Activation of thesemechanoreceptors leads to reflexive inhibition of themuscles holding the jaw closed. The resulting relax-ation of the jaw reduces the pressure on the variousmechanoreceptors, leading to a new cycle of contrac-tion and relaxation.

Although chewing prolongs the subjective pleas-ure of taste, it does not appreciably alter the rate atwhich the food will be digested and absorbed. On theother hand, attempting to swallow a large particle offood can lead to choking if the particle lodges over the

trachea, blocking the entry of air into the lungs. A num-ber of preventable deaths occur each year from chok-ing, the symptoms of which are often confused withthose of a heart attack so that no attempt is made toremove the obstruction from the airway. The Heimlichmaneuver, described in Chapter 15, can often dislodgethe obstructing particle from the airways.

Saliva The secretion of saliva is controlled by bothsympathetic and parasympathetic neurons; unliketheir antagonistic activity in most organs, both systemsstimulate salivary secretion, with the parasympathet-ics producing the greater response. There is no hor-monal regulation of salivary secretion. In the absenceof ingested material, a low rate of salivary secretionkeeps the mouth moist. In the presence of food, sali-vary secretion increases markedly. This reflex responseis initiated by chemoreceptors (acidic fruit juices are aparticularly strong stimulus) and pressure receptors inthe walls of the mouth and on the tongue.

Increased secretion of saliva is accomplished by alarge increase in blood flow to the salivary glands,which is mediated by both neural activity andparacrine/autocrine agents released by the active cellsin the salivary gland. The volume of saliva secretedper gram of tissue is the largest secretion of any of thebody’s exocrine glands.

Swallowing Swallowing is a complex reflex initiatedwhen pressure receptors in the walls of the pharynxare stimulated by food or drink forced into the rear ofthe mouth by the tongue. These receptors send affer-ent impulses to the swallowing center in the brain-stem medulla oblongata. This center then elicits swal-lowing via efferent fibers to the muscles in the pharynxand esophagus as well as to the respiratory muscles.

As the ingested material moves into the pharynx,the soft palate is elevated and lodges against the backwall of the pharynx, preventing food from entering thenasal cavity (Figure 17–14b). Impulses from the swal-lowing center inhibit respiration, raise the larynx, andclose the glottis (the area around the vocal cords andthe space between them), keeping food from movinginto the trachea. As the tongue forces the food fartherback into the pharynx, the food tilts a flap of tissue,the epiglottis, backward to cover the closed glottis(Figure 17–14c).

The next stage of swallowing occurs in the esoph-agus, the foot-long tube that passes through the tho-racic cavity, penetrates the diaphragm, which sepa-rates the thoracic cavity from the abdominal cavity,and joins the stomach a few centimeters below the di-aphragm. Skeletal muscles surround the upper thirdof the esophagus, smooth muscles the lower two-thirds.






As described in Chapter 15, the pressure in the tho-racic cavity is 4 to 10 mmHg less than atmosphericpressure, and this subatmospheric pressure is trans-mitted across the thin wall of the intrathoracic portionof the esophagus to the lumen. In contrast, the luminalpressure in the pharynx at the opening to the esopha-gus is equal to atmospheric pressure, and the pressureat the opposite end of the esophagus in the stomach isslightly greater than atmospheric. Therefore, pressuredifferences exist that would tend to force both air (fromabove) and gastric contents (from below) into theesophagus. This does not occur, however, because bothends of the esophagus are normally closed by the con-traction of sphincter muscles. Skeletal muscles sur-round the esophagus just below the pharynx and formthe upper esophageal sphincter, whereas the smoothmuscles in the last portion of the esophagus form thelower esophageal sphincter (Figure 17–15).

The esophageal phase of swallowing begins withrelaxation of the upper esophageal sphincter. Immedi-ately after the food has passed, the sphincter closes,the glottis opens, and breathing resumes. Once in theesophagus, the food is moved toward the stomach bya progressive wave of muscle contractions that pro-ceeds along the esophagus, compressing the lumenand forcing the food ahead of it. Such waves of con-traction in the muscle layers surrounding a tube areknown as peristaltic waves. One esophageal peristalticwave takes about 9 s to reach the stomach. Swallow-ing can occur even when a person is upside down sinceit is not primarily gravity but the peristaltic wave thatmoves the food to the stomach.


Soft palateHard palate

Tongue

Glottis

TracheaEsophagus

(a) (b) (c)

Epiglottis

Food

Upperesophageal

sphincter

(d)

Pharynx

FIGURE 17–14Movements of food through the pharynx and upper esophagus during swallowing.

Trachea

Upperesophagealsphincter

Loweresophagealsphincter

Diaphragm

Stomach

Esophagus

FIGURE 17–15Location of upper and lower esophageal sphincters.

The lower esophageal sphincter opens and re-mains relaxed throughout the period of swallowing,allowing the arriving food to enter the stomach. Afterthe food has passed, the sphincter closes, resealing thejunction between the esophagus and the stomach.





Swallowing is an example of a reflex in which mul-tiple responses occur in a temporal sequence deter-mined by the pattern of synaptic connections betweenneurons in a brain coordinating center. Since bothskeletal and smooth muscles are involved, the swal-lowing center must direct efferent activity in both so-matic nerves (to skeletal muscle) and autonomicnerves (to smooth muscle). Simultaneously, afferentfibers from receptors in the esophageal wall send in-formation to the swallowing center that can alter theefferent activity. For example, if a large food particledoes not reach the stomach during the initial peristalticwave, the maintained distension of the esophagus bythe particle activates receptors that initiate reflexescausing repeated waves of peristaltic activity (second-ary peristalsis) that are not accompanied by the initialpharyngeal events of swallowing.

The ability of the lower esophageal sphincter tomaintain a barrier between the stomach and the esoph-agus when swallowing is not taking place is aided bythe fact that the last portion of the esophagus lies belowthe diaphragm, and is subject to the same abdominalpressures as is the stomach. In other words, if the pres-sure in the abdominal cavity is raised, for example, dur-ing cycles of respiration or by contraction of the ab-dominal muscles, the pressures on both the gastriccontents and the terminal segment of the esophagus areraised together, preventing the formation of a pressuregradient between the stomach and esophagus that couldforce the stomach’s contents into the esophagus.

During pregnancy the growth of the fetus not onlyincreases the pressure on the abdominal contents butalso pushes the terminal segment of the esophagusthrough the diaphragm into the thoracic cavity. Thesphincter is therefore no longer assisted by changes inabdominal pressure. Accordingly, during the last halfof pregnancy there is a tendency for increased ab-dominal pressure to force some of the gastric contentsup into the esophagus. The hydrochloric acid from thestomach irritates the esophageal walls, producing painknown as heartburn (because the pain appears to belocated over the heart). Heartburn often subsides inthe last weeks of pregnancy as the uterus descendslower into the pelvis prior to delivery, decreasing thepressure on the stomach.

Heartburn also occurs in the absence of pregnancy.Some people have less efficient lower esophagealsphincters, resulting in repeated episodes of refluxedgastric contents into the esophagus (gastro-esophagealreflux), heartburn, and in extreme cases, ulceration,scarring, obstruction, or perforation of the loweresophagus. Heartburn can occur after a large meal,which can raise the pressure in the stomach enough toforce acid into the esophagus. Gastro-esophageal re-flux can also cause coughing and irritation of the lar-ynx in the absence of any esophageal symptoms.

The lower esophageal sphincter not only under-goes brief periods of relaxation during a swallow butalso in the absence of a swallow. During these periodsof relaxation, small amounts of the acid contents fromthe stomach are normally refluxed into the esophagus.The acid in the esophagus triggers a secondary peri-staltic wave and also stimulates increased salivary se-cretion, which helps to neutralize the acid and clear itfrom the esophagus.

StomachThe epithelial layer lining the stomach invaginates intothe mucosa, forming numerous tubular glands. Glandsin the thin-walled upper portions of the stomach, thebody and fundus (Figure 17–16), secrete mucus, hy-drochloric acid, and the enzyme precursor pepsino-gen. The lower portion of the stomach, the antrum, hasa much thicker layer of smooth muscle. The glands inthis region secrete little acid but contain the endocrinecells that secrete the hormone gastrin.

Mucus is secreted by the cells at the opening of theglands (Figure 17–17). Lining the walls of the glandsare parietal cells (also known as oxyntic cells), whichsecrete acid and intrinsic factor, and chief cells, whichsecrete pepsinogen. Thus, each of the three major ex-ocrine secretions of the stomach—mucus, acid, andpepsinogen—is secreted by a different cell type. In addition, enterochromaffin-like (ECL) cells, which release the paracrine agent histamine, and cells that secrete the peptide messenger somatostatin, are scattered throughout the tubular glands.


Esophagus

Body (secretesmucus, pepsinogen,and HCI)

Duodenum

Pyloricsphincter

Antrum(secretesmucus,pepsinogen,and gastrin)

Fundus

Upper esophagealsphincter

FIGURE 17–16The three regions of the stomach: fundus, body, andantrum.





HCl Secretion The stomach secretes about 2 L of hy-drochloric acid per day. The concentration of hydro-gen ions in the stomach’s lumen may reach 150 mM,3 million times greater than the concentration in theblood.

Primary H,K-ATPases in the luminal membrane ofthe parietal cells pump hydrogen ions into the stom-ach’s lumen (Figure 17–18). This primary active trans-porter also pumps potassium into the cell, which thenleaks back into the lumen through potassium channels.Excessive vomiting can lead to potassium depletiondue to this leak. As hydrogen ions are secreted into thelumen, bicarbonate ions are being secreted on the

opposite side of the cell into the blood, in exchange forchloride ions. This addition of bicarbonate lowers theacidity in the venous blood from the stomach.

Increased acid secretion, stimulated by factors de-scribed in the next paragraph, is the result of the trans-fer of H,K-ATPase proteins from the membranes of in-tracellular vesicles to the plasma membrane by fusionof these vesicles with the membrane, thus increasingthe number of pump proteins in the plasma mem-brane. This process is analogous to that described inChapter 16 for the transfer of water channels to theplasma membrane of kidney collecting-duct cells in re-sponse to ADH.

Four chemical messengers regulate the insertion ofH,K-ATPases into the plasma membrane and hence acidsecretion: gastrin (a GI hormone), acetylcholine (ACh, aneurotransmitter), histamine, and somatostatin (twoparacrine agents). Parietal cell membranes contain re-ceptors for all four of these agents (Figure 17–19). So-matostatin inhibits acid secretion, while the other threestimulate secretion. Histamine is particularly importantin stimulating acid secretion in that it markedly poten-tiates the response to the other two stimuli, gastrin andACh. As will be discussed later when considering ul-cers, this potentiating effect of histamine is the reasonthat drugs that block histamine receptors in the stom-ach suppress acid secretion. Not only do these chemi-cal messengers act directly on the parietal cells, they alsoinfluence each other’s secretion.

During a meal, the rate of acid secretion increasesmarkedly as stimuli arising from the cephalic, gastric,and intestinal phases alter the release of the four chem-ical messengers described in the previous paragraph.During the cephalic phase, increased activity of theparasympathetic nerves to the stomach’s enteric ner-vous system results in the release of ACh from theplexus neurons, gastrin from the gastrin-releasingcells, and histamine from ECL cells (Figure 17–20).

Once food has reached the stomach, the gastricphase stimuli—distension by the volume of ingestedmaterial and the presence of peptides and amino acidsreleased by digestion of luminal proteins—produce afurther increase in acid secretion. These stimuli usesome of the same neural pathways used during thecephalic phase, in that nerve endings in the mucosa ofthe stomach respond to these luminal stimuli and sendaction potentials to the enteric nervous system, whichin turn, can relay signals to the gastrin-releasing cells,histamine-releasing cells, and parietal cells. In addi-tion, peptides and amino acids can act directly on thegastrin-releasing endocrine cells to promote gastrin secretion.

The concentration of acid in the gastric lumen isitself an important determinant of the rate of acid


Muscularismucosa

Parietalcells

Chiefcell

Mucousneckcells

Gastricpit

Gastriclumen

Glandregion

FIGURE 17–17Gastric glands in the body of the stomach.





secretion for the following reason. Hydrogen ions(acid) stimulate the release of somatostatin from en-docrine cells in the gastric wall. Somatostatin thenacts on the parietal cells to inhibit acid secretion; italso inhibits the release of gastrin and histamine.The net result is a negative-feedback control of acidsecretion; as the acidity of the gastric lumen in-creases, it turns off the stimuli that are promotingacid secretion.

Increasing the protein content of a meal increasesacid secretion. This occurs for two reasons. First, themore protein ingested, the more peptides are gener-ated in the stomach’s lumen, and these peptides, as wehave seen, stimulate acid secretion. The second reasonis more complicated and reflects the effects of proteinson luminal acidity. Before food enters the stomach, theH� concentration in the lumen is high because there arefew buffers present to bind any secreted hydrogenions; therefore, the rate of acid secretion is low becausehigh acidity inhibits acid secretion. The protein in foodis an excellent buffer however, and so as protein en-ters the stomach the H� concentration drops as the hy-drogen ions bind to the proteins. This decrease in acid-ity removes the inhibition of acid secretion. The moreprotein in a meal, the greater the buffering of acid, andthe more acid secreted.

We now come to the intestinal phase controllingacid secretion, the phase in which stimuli in the early


Carbonic anhydrase

Epithelial cellCapillary Stomach

lumen

H2OH2CO3

H+ H+ H+

K+ K+

K+

Cl–

CO2 + H2O

OH–

Cl–

Cl– Cl–HCO–

3 HCO–3

Begin

ADP

ATP

FIGURE 17–18Secretion of hydrochloric acid by parietal cells. The hydrogen ions secreted into the lumen by primary active transport arederived from the breakdown of water molecules, leaving hydroxyl ions (OH�) behind. These hydroxyl ions are neutralized bycombination with other hydrogen ions generated by the reaction between carbon dioxide and water, a reaction catalyzed bythe enzyme carbonic anhydrase, which is present in high concentrations in parietal cells. The bicarbonate ions formed by thisreaction move out of the parietal cell on the blood side, in exchange for chloride ions.

Gastrin Histamine ACh Somatostatin

Second messengers

H,K–ATPase

H+

Acid secretion

Parietal cell

+++

FIGURE 17–19The four inputs to parietal cells that regulate acid secretionby controlling the transfer of the H,K-ATPase pumps incytoplasmic vesicle membranes to the plasma membrane.





portion of the small intestine influence acid secretion bythe stomach. First, high acidity in the duodenum trig-gers reflexes that inhibit gastric acid secretion. This in-hibition is beneficial for the following reason. The di-gestive activity of enzymes and bile salts in the smallintestine is strongly inhibited by acidic solutions, andthis reflex ensures that acid secretion by the stomachwill be reduced whenever chyme entering the smallintestine from the stomach contains so much acid thatit cannot be rapidly neutralized by the bicarbonate-richfluids simultaneously secreted into the intestine by theliver and pancreas.

Acid, distension, hypertonic solutions, and solu-tions containing amino acids, and fatty acids in thesmall intestine reflexly inhibit gastric acid secretion.Thus, the extent to which acid secretion is inhibitedduring the intestinal phase varies, depending upon thevolume and composition of the intestinal contents, butthe net result is the same—balancing the secretory ac-

tivity of the stomach with the digestive and absorptivecapacities of the small intestine.

The inhibition of gastric acid secretion during theintestinal phase is mediated by short and long neuralreflexes and by hormones that inhibit acid secretion byinfluencing the four signals directly controlling acid se-cretion: ACh, gastrin, histamine, and somatostatin. Thehormones released by the intestinal tract that reflexlyinhibit gastric activity are collectively called entero-gastrones and include secretin, CCK, and additionalunidentified hormones.

Table 17–4 summarizes the control of acid secretion.

Pepsin Secretion Pepsin is secreted by chief cells inthe form of an inactive precursor called pepsinogen.The acidity in the stomach’s lumen alters the shape ofpepsinogen, exposing its active site so that this site canact on other pepsinogen molecules to break off a smallchain of amino acids from their ends. This cleavage


Luminal distensionamino acids & peptides

Gastric phase stimuli:

Histaminesecretion

Enteric neural activity

Cephalic phase stimuli

Acid secretion

Parietal cell

Brain

Gastrin secretion

HCl

+

+

+

++ +

FIGURE 17–20Cephalic and gastric phases controlling acid secretion by the stomach.





TABLE 17–4 Control of HCL Secretion during a Meal

Stimuli Pathways Result

Cephalic phase Parasympathetic nerves to enteric hHClSight nervous system secretionSmellTasteChewing

Gastric contents (gastric phase) Long and short neural reflexes, hHClDistension and direct stimulation of secretionhPeptides gastrin secretiongH� concentration

Intestinal contents (intestinal phase) Long and short neural reflexes; secretin, CCK, gHClDistension and other unspecified duodenal hormones secretionhH� concentrationhOsmolarityhNutrient concentrations

converts pepsinogen to pepsin, the fully active form(Figure 17–21). Thus the activation of pepsin is an au-tocatalytic, positive-feedback process.

The synthesis and secretion of pepsinogen, fol-lowed by its intraluminal activation to pepsin, pro-vides an example of a process that occurs with manyother secreted proteolytic enzymes in the gastroin-testinal tract. Because these enzymes are synthesizedin inactive forms, collectively referred to as zymogens,any substrates that these enzymes might be able to act

upon inside the cell producing them are protected fromdigestion, thus preventing damage to the cells.

Pepsin is active only in the presence of a high H�

concentration. It becomes inactive, therefore, when itenters the small intestine, where the hydrogen ions areneutralized by the bicarbonate ions secreted into thesmall intestine.

The primary pathway for stimulating pepsinogensecretion is input to the chief cells from the entericnervous system. During the cephalic, gastric, and in-testinal phases, most of the factors that stimulate or in-hibit acid secretion exert the same effect on pepsino-gen secretion. Thus, pepsinogen secretion parallelsacid secretion.

Pepsin is not essential for protein digestion sincein its absence, as occurs in some pathological condi-tions, protein can be completely digested by enzymesin the small intestine.

Gastric Motility An empty stomach has a volume ofonly about 50 ml, and the diameter of its lumen is onlyslightly larger than that of the small intestine. When ameal is swallowed, however, the smooth muscles inthe fundus and body relax before the arrival of food,allowing the stomach’s volume to increase to as muchas 1.5 L with little increase in pressure. This is calledreceptive relaxation and is mediated by the parasym-pathetic nerves to the stomach’s enteric nerve plexuses,with coordination by the swallowing center in thebrain. Nitric oxide and serotonin released by entericneurons mediate this relaxation.

As in the esophagus, the stomach produces peri-staltic waves in response to the arriving food. Each wavebegins in the body of the stomach and produces only aripple as it proceeds toward the antrum, a contraction


Pepsinogen

Stomach lumen

Stomach wall

HClPepsin

Protein

PeptidesIntrinsicfactor

Parietal cell

Chief cell

+

FIGURE 17–21Conversion of pepsinogen to pepsin in the lumen of thestomach.





too weak to produce much mixing of the luminal con-tents with acid and pepsin. As the wave approachesthe larger mass of wall muscle surrounding theantrum, however, it produces a more powerful con-

traction, which both mixes the luminal contents andcloses the pyloric sphincter, a ring of smooth muscleand connective tissue between the antrum and theduodenum (Figure 17–22). The pyloric sphincter mus-cles contract upon arrival of a peristaltic wave. As aconsequence of sphincter closing, only a small amountof chyme is expelled into the duodenum with eachwave, and most of the antral contents are forced back-ward toward the body of the stomach, thereby con-tributing to the mixing activity in the antrum.

What is responsible for producing gastric peri-staltic waves? Their rhythm (three per minute) is gen-erated by pacemaker cells in the longitudinal smoothmuscle layer. These smooth-muscle cells undergospontaneous depolarization-repolarization cycles(slow waves) known as the basic electrical rhythm ofthe stomach. These slow waves are conducted throughgap junctions along the stomach’s longitudinal musclelayer and also induce similar slow waves in the over-lying circular muscle layer. In the absence of neural orhormonal input, however, these depolarizations aretoo small to cause significant contractions. Excitatoryneurotransmitters and hormones act upon the smoothmuscle to further depolarize the membrane, therebybringing it closer to threshold. Action potentials maybe generated at the peak of the slow wave cycle ifthreshold is reached (Figure 17–23) and thus cause


Esophagus

Loweresophageal

sphincterDuodenum

Pyloricsphincter

Stomach

Peristalticwave

FIGURE 17–22Peristaltic waves passing over the stomach force a smallamount of luminal material into the duodenum. Blackarrows indicate movement of luminal material; purple arrowsindicate movement of the peristaltic wave in the stomachwall.

Action potentials

Slow waves

Membrane depolarization

Time

Thresholdpotential

–60

Sm

oo

th m

usc

le t

ensi

on

Mem

bra

ne

po

ten

tial

(m

V)

0

Time

FIGURE 17–23Slow wave oscillations in the membrane potential of gastricsmooth-muscle fibers trigger bursts of action potentialswhen threshold potential is reached at the wave peak.Membrane depolarization brings the slow wave closer tothreshold, increasing the action-potential frequency and thusthe force of smooth-muscle contraction.





larger contractions. The number of spikes fired witheach wave determines the strength of the muscle con-traction.

Thus, whereas the frequency of contraction is de-termined by the intrinsic basic electrical rhythm andremains essentially constant, the force of contractionand therefore the amount of gastric emptying per con-traction are determined reflexly by neural and hor-monal input to the antral smooth muscle.

The initiation of these reflexes depends upon thecontents of both the stomach and small intestine. Allthe factors previously discussed that regulate acid se-cretion (Table 17–4) can also alter gastric motility. Forexample, gastrin, in sufficiently high concentrations,increases the force of antral smooth-muscle contrac-tions. Distension of the stomach also increases the forceof antral contractions through long and short reflexestriggered by mechanoreceptors in the stomach wall.Therefore, the larger a meal, the faster the stomach’sinitial emptying rate. As the volume of the stomach de-creases, the force of gastric contractions and the rate ofemptying also decrease.

In contrast, distension of the duodenum or the pres-ence of fat, high acidity, or hypertonic solutions in itslumen all inhibit gastric emptying (Figure 17–24) justas they inhibit acid and pepsin secretion. Fat is themost potent of these chemical stimuli.

Autonomic nerve fibers to the stomach can be ac-tivated by the CNS independently of the reflexes orig-inating in the stomach and duodenum and can influ-ence gastric motility. Decreased parasympathetic orincreased sympathetic activity inhibits motility. Viathese pathways, pain and emotions such as sadness,depression, and fear tend to decrease motility, whereasaggression and anger tend to increase it. These rela-tionships are not always predictable, however, and dif-ferent people show different gastrointestinal responsesto apparently similar emotional states.

As we have seen, a hypertonic solution in the duo-denum is one of the stimuli inhibiting gastric empty-ing. This reflex prevents the fluid in the duodenumfrom becoming too hypertonic since it slows the rateof entry of chyme and thereby the delivery of largemolecules that can rapidly be broken down into many


Small intestine

CNS

Stomach

Stimulatesecretion of enterogastrones

Gastric emptying

Plasmaenterogastrones

Sympatheticdischarge

Parasympatheticdischarge

Short neuralreflexes viaenteric neurons

Acid Fat Hypertonic solutions Distension

Stimulateneural receptors

Long neural reflexes

Begin

FIGURE 17–24Intestinal-phase pathways inhibiting gastric emptying.





small molecules by enzymes in the small intestine. Apatient who has had his stomach removed because ofdisease (for example, cancer) must eat a number ofsmall meals. A large meal, in the absence of the con-trolled emptying by the stomach, would rapidly enterthe intestine, producing a hypertonic solution. This hy-pertonic solution can cause enough water to flow (byosmosis) into the intestine from the blood to lower theblood volume and produce circulatory complications.The large distension of the intestine by the enteringfluid can also trigger vomiting in these patients. Allthese symptoms produced by the rapid entry of largequantities of ingested material into the small intestineare known as the dumping syndrome.

Once the contents of the stomach have emptiedover a period of several hours, the peristaltic wavescease and the empty stomach is mostly quiescent. Dur-ing this time, however, there are brief intervals of peri-staltic activity that will be described along with theevents controlling intestinal motility.

Pancreatic SecretionsThe exocrine portion of the pancreas secretes bicarbon-ate ions and a number of digestive enzymes into ductsthat converge into the pancreatic duct, the latter joiningthe common bile duct from the liver just before this ductenters the duodenum (see Figure 17–4). The enzymesare secreted by gland cells at the pancreatic end of the

duct system, whereas bicarbonate ions are secreted bythe epithelial cells lining the ducts (Figure 17–25).

The mechanism of bicarbonate secretion is analo-gous to that of hydrochloric acid secretion by the stom-ach, except that the directions of hydrogen-ion and bicarbonate-ion movement are reversed. Hydrogenions, derived from a carbonic anhydrase-catalyzed re-action between carbon dioxide and water, are activelytransported out of the duct cells by an H-ATPase pumpand released into the blood, while the bicarbonate ionsare secreted into the duct lumen (see Figure 17–18).

The enzymes secreted by the pancreas digest fat,polysaccharides, proteins, and nucleic acids to fattyacids, sugars, amino acids, and nucleotides, respec-tively. A partial list of these enzymes and their activi-ties is given in Table 17–5. The proteolytic enzymes aresecreted in inactive forms (zymogens), as described forpepsinogen in the stomach, and then activated in theduodenum by other enzymes. A key step in this acti-vation is mediated by enterokinase, which is embed-ded in the luminal plasma membranes of the intestinalepithelial cells. It is a proteolytic enzyme that splits offa peptide from pancreatic trypsinogen, forming the ac-tive enzyme trypsin. Trypsin is also a proteolytic en-zyme, and once activated, it activates the other pan-creatic zymogens by splitting off peptide fragments(Figure 17–26). This function is in addition to trypsin’srole in digesting ingested protein.

The nonproteolytic enzymes secreted by the pan-creas (for example, amylase) are released in fully ac-tive form. Along with lipase, the pancreas secretes co-lipase, whose function was described earlier.

Pancreatic secretion increases during a meal,mainly as a result of stimulation by the hormones se-cretin and CCK (see Table 17–3). Secretin is the primarystimulant for bicarbonate secretion, whereas CCKmainly stimulates enzyme secretion. (As noted earlier,these two hormones potentiate each other’s actions.)

Since the function of pancreatic bicarbonate is to


Common bileduct from gallbladderDuodenum

Pancreatic duct

Exocrine cells(secrete enzymes)

Endocrine cellsof pancreas

Duct cells(secretebicarbonate)

Pancreas

FIGURE 17–25Structure of the pancreas.

Epithelial cell

Pancreas

Membrane boundenterokinase

Inactive enzymes

Trypsinogen Trypsin

Active enzymesIntestinal lumen

FIGURE 17–26Activation of pancreatic enzyme precursors in the smallintestine.





neutralize acid entering the duodenum from thestomach, it is appropriate that the major stimulus forsecretin release is increased acidity in the duodenum(Figure 17–27). In analogous fashion, since CCK stim-ulates the secretion of digestive enzymes, includingthose for fat and protein digestion, it is appropriatethat the stimuli for its release are fatty acids andamino acids in the duodenum (Figure 17–28).

Luminal acid and fatty acids also act on afferentnerve endings in the intestinal wall, initiating re-flexes that act on the pancreas to increase both en-zyme and bicarbonate secretion. Thus, the organicnutrients in the small intestine initiate, via hormonaland neural reflexes, the secretions involved in theirown digestion.

Although most of the pancreatic exocrine secre-tions are controlled by stimuli arising from the intes-tinal phase of digestion, cephalic and gastric stimuli,by way of the parasympathetic nerves to the pancreas,also play a role. Thus, the taste of food or the disten-sion of the stomach by food, will lead to increased pan-creatic secretion.

Bile SecretionAs stated earlier, bile is secreted by liver cells into anumber of small ducts, the bile canaliculi (Figure 17–29), which converge to form the common hepaticduct (see Figure 17–4). Bile contains six major ingre-dients: (1) bile salts; (2) lecithin (a phospholipid); (3) bicarbonate ions and other salts; (4) cholesterol; (5) bile pigments and small amounts of other metabolicend products, and (6) trace metals. Bile salts andlecithin are synthesized in the liver and, as we haveseen, help solubilize fat in the small intestine. Bicar-bonate ions neutralize acid in the duodenum, and thelast three ingredients represent substances extractedfrom the blood by the liver and excreted via the bile.

From the standpoint of gastrointestinal function,the most important components of bile are the bile


TABLE 17–5 Pancreatic Enzymes

Enzyme Substrate Action

Trypsin, chymotrypsin, Proteins Breaks peptide bonds in proteinselastase to form peptide fragments

Carboxypeptidase Proteins Splits off terminal amino acid fromcarboxyl end of protein

Lipase Fats Splits off two fatty acids fromtriacylglycerols, forming free fattyacids and monoglycerides

Amylase Polysaccharides Splits polysaccharides into glucoseand maltose

Ribonuclease, Nucleic acids Splits nucleic acids into freedeoxyribonuclease mononucleotides

Small intestine

Pancreas

Small intestine

Acid from stomach

Secretin secretion

Plasma secretin

Bicarbonate secretion

Flow of bicarbonateinto small intestine

Neutralization of intestinal acid

FIGURE 17–27Hormonal regulation of pancreatic bicarbonate secretion.

salts. During the digestion of a fatty meal, most of thebile salts entering the intestinal tract via the bile areabsorbed by specific sodium-coupled transporters in





the ileum (the last segment of the small intestine). Theabsorbed bile salts are returned via the portal vein tothe liver, where they are once again secreted into thebile. This recycling pathway from the intestine to theliver and back to the intestine is known as the entero-hepatic circulation (Figure 17–30). A small amount (5percent) of the bile salts escape this recycling and is lostin the feces, but the liver synthesizes new bile salts fromcholesterol to replace them. During the digestion of ameal the entire bile salt content of the body may be re-cycled several times via the enterohepatic circulation.

In addition to synthesizing bile salts from choles-terol, the liver also secretes cholesterol extracted fromthe blood into the bile. Bile secretion, followed by ex-cretion of cholesterol in the feces, is one of the mech-anisms by which cholesterol homeostasis in the bloodis maintained (Chapter 18). Cholesterol is insoluble inwater, and its solubility in bile is achieved by its in-corporation into micelles (whereas in the blood, cho-lesterol is incorporated into lipoproteins). Gallstones,consisting of precipitated cholesterol, will be discussedat the end of this chapter.


Small intestine

Pancreas

Small intestine

Digestion of fats and protein

Flow of enzymesinto small intestine

Enzyme secretion

Plasma CCK

CCK secretion

Intestinal fatty acidsand amino acids

FIGURE 17–28Hormonal regulation of pancreatic enzyme secretion.

Branch ofhepatic artery Blood Central vein

Bilecanaliculus

Liver cellsBile ductBranch ofportal vein

FIGURE 17–29A small section of the liver showing location of bile canaliculiand ducts with respect to blood and liver cells. Adapted from Kappas and Alvares.

Bile salts

Synthesis5%

Liver

Commonbile duct

Duodenum Ileum

Bile salts Bile salts

Bile salts

5% lostin feces

Small intestine

Hepatic portal vein

Bile salts

Gall bladder

FIGURE 17–30Enterohepatic circulation of bile salts.

Bile pigments are substances formed from theheme portion of hemoglobin when old or damagederythrocytes are digested in the spleen and liver. Thepredominant bile pigment is bilirubin, which is ex-tracted from the blood by liver cells and actively se-creted into the bile. It is bilirubin that gives bile its yel-low color. After entering the intestinal tract, bilirubinis modified by bacterial enzymes to form the brown





pigments that give feces their characteristic color. Dur-ing their passage through the intestinal tract, some ofthe bile pigments are absorbed into the blood and areeventually excreted in the urine, giving urine its yel-low color.

Like pancreatic secretions, the components of bileare secreted by two different cell types. The bile salts,cholesterol, lecithin, and bile pigments are secreted by hepatocytes (liver cells), whereas most of the bicarbonate-rich salt solution is secreted by the ep-ithelial cells lining the bile ducts. Secretion of the saltsolution by the bile ducts, just like that secreted by thepancreas, is stimulated by secretin in response to thepresence of acid in the duodenum.

Unlike the pancreas, whose secretions are con-trolled by intestinal hormones, bile salt secretion iscontrolled by the concentration of bile salts in theblood—the greater the plasma concentration of bilesalts, the greater their secretion into the bile canaliculi.Absorption of bile salts from the intestine during thedigestion of a meal leads to their increased plasma con-centration and thus to an increased rate of bile salt se-cretion by the liver. Although bile secretion is greatestduring and just after a meal, some bile is always be-ing secreted by the liver. Surrounding the common bileduct at the point where it enters the duodenum is aring of smooth muscle known as the sphincter ofOddi. When this sphincter is closed, the dilute bile se-creted by the liver is shunted into the gallbladderwhere the organic components of bile become concen-trated as NaCl and water are absorbed into the blood.

Shortly after the beginning of a fatty meal, thesphincter of Oddi relaxes and the gallbladder con-tracts, discharging concentrated bile into the duode-num. The signal for gallbladder contraction andsphincter relaxation is the intestinal hormone CCK—appropriately so, since as we have seen, a major stim-ulus for this hormone’s release is the presence of fat inthe duodenum. (It is from this ability to cause con-traction of the gallbladder that cholecystokinin re-ceived its name: chole, bile; cysto, bladder; kinin, tomove). Figure 17–31 summarizes the factors control-ling the entry of bile into the small intestine.

Small IntestineSecretion Approximately 1500 ml of fluid is secretedby the walls of the small intestine from the blood intothe lumen each day. One of the reasons for watermovement into the lumen (secretion) is that the intes-tinal epithelium at the base of the villi secretes a num-ber of mineral ions, notably sodium, chloride, and bi-carbonate ions into the lumen, and water follows byosmosis. These secretions, along with mucus, lubricatethe surface of the intestinal tract and help protect theepithelial cells from excessive damage by the digestive

enzymes in the lumen. Some damage to these cells stilloccurs, however, and the intestinal epithelium has oneof the highest cell renewal rates of any tissue in thebody.

Chloride is the primary ion determining the mag-nitude of fluid secretion. It exits the luminal membranethrough the same chloride channel that is mutated incystic fibrosis (Chapter 6). Various hormonal andparacrine signals—as well as certain bacterial toxins—can increase the opening frequency of these channelsand thus increase fluid secretion.

As stated earlier, water movement into the lumenalso occurs when the chyme entering the small intes-tine from the stomach is hypertonic because of a highconcentration of solutes in the meal and because di-gestion breaks down large molecules into many moresmall molecules. This hypertonicity causes the osmoticmovement of water from the isotonic plasma into theintestinal lumen.

Absorption Normally, virtually all of the fluid se-creted by the small intestine is absorbed back into theblood. In addition, a much larger volume of fluid,which includes salivary, gastric, hepatic, and pancre-atic secretions, as well as ingested water, is simultane-ously absorbed from the intestinal lumen into theblood. Thus, overall there is a large net absorption ofwater from the small intestine. Absorption is achieved


Sphincter of Oddi

Relaxation

Gallbladder

Contraction

Plasma CCK

Fatty acids

CCK secretion

Duodenum

Bile flowinto duodenum

Bile flow intocommon bile duct

FIGURE 17–31Regulation of bile entry into the small intestine.





by the transport of ions, primarily sodium, from theintestinal lumen into the blood, with water followingby osmosis.

The secretory and absorptive capacities of the in-testinal epithelial cells become altered as newly de-rived cells at the base of the villi migrate to the tip.Cells at the base of the villi secrete fluid, while the oldercells near the tip absorb fluid.

Motility In contrast to the peristaltic waves thatsweep over the stomach, the most common motion inthe small intestine during digestion of a meal is a sta-tionary contraction and relaxation of intestinal seg-ments, with little apparent net movement toward thelarge intestine (Figure 17–32). Each contracting seg-ment is only a few centimeters long, and the con-traction lasts a few seconds. The chyme in the lumenof a contracting segment is forced both up and downthe intestine. This rhythmical contraction and relax-ation of the intestine, known as segmentation, pro-duces a continuous division and subdivision of theintestinal contents, thoroughly mixing the chyme inthe lumen and bringing it into contact with the intestinal wall.

These segmenting movements are initiated byelectrical activity generated by pacemaker cells in orassociated with the circular smooth-muscle layer. Likethe slow waves in the stomach, this intestinal basicelectrical rhythm produces oscillations in the smooth-muscle membrane potential that, if threshold isreached, trigger action potentials that increase musclecontraction. The frequency of segmentation is set bythe frequency of the intestinal basic electrical rhythm,but unlike the stomach, which normally has a singlerhythm (three per minute), the intestinal rhythm variesalong the length of the intestine, each successive re-gion having a slightly lower frequency than the oneabove. For example, segmentation in the duodenumoccurs at a frequency of about 12 contractions/min,whereas in the last portion of the ileum the rate is only9 contractions/min. Segmentation produces, therefore,a slow migration of the intestinal contents toward thelarge intestine because more chyme is forced down-ward, on the average, than upward.

The intensity of segmentation can be altered byhormones, the enteric nervous system, and autonomicnerves; parasympathetic activity increases the force ofcontraction, and sympathetic stimulation decreases it.Thus, cephalic phase stimuli, including emotionalstates, can alter intestinal motility. As is true for thestomach, these inputs produce changes in the force ofsmooth-muscle contraction but do not significantlychange the frequencies of the basic electrical rhythms.

After most of a meal has been absorbed, the seg-menting contractions cease and are replaced by a pat-tern of peristaltic activity known as the migrating motil-ity complex. Beginning in the lower portion of thestomach, repeated waves of peristaltic activity travelabout 2 ft along the small intestine and then die out.This short segment of peristaltic activity slowly migratesdown the small intestine, taking about 2 h to reach thelarge intestine. By the time the migrating motility com-plex reaches the end of the ileum, new waves are be-ginning in the stomach, and the process is repeated.

The migrating motility complex moves any undi-gested material still remaining in the small intestineinto the large intestine and also prevents bacteria fromremaining in the small intestine long enough to growand multiply excessively. In diseases in which there isan aberrant migrating motility complex, bacterialovergrowth in the small intestine can become a majorproblem. Upon the arrival of a meal in the stomach,the migrating motility complex rapidly ceases in theintestine and is replaced by segmentation.

A rise in the plasma concentration of a candidateintestinal hormone, motilin, is thought to initiate themigrating motility complex. The mechanisms ofmotilin action and the control of its release have notbeen determined.


Tim

e

FIGURE 17–32Segmentation movements of the small intestine in whichsegments of the intestine contract and relax in a rhythmicalpattern but do not undergo peristalsis. This is the patternencountered during a meal, which mixes the luminalcontents.





The contractile activity in various regions of thesmall intestine can be altered by reflexes initiated atdifferent points along the gastrointestinal tract. For ex-ample, segmentation intensity in the ileum increasesduring periods of gastric emptying, and this is knownas the gastroileal reflex. Large distensions of the in-testine, injury to the intestinal wall, and various bac-terial infections in the intestine lead to a complete ces-sation of motility, the intestino-intestinal reflex.

As much as 500 ml of air may be swallowed dur-ing a meal. Most of this air travels no farther than theesophagus, from which it is eventually expelled bybelching. Some of the air reaches the stomach, how-ever, and is passed on to the intestines, where its per-colation through the chyme as the intestinal contentsare mixed produces gurgling sounds that are oftenquite loud.

Large IntestineThe large intestine is a tube 2.5 in. in diameter andabout 4 ft long. Its first portion, the cecum, forms ablind-ended pouch from which extends the appendix,a small fingerlike projection having no known essen-tial function (Figure 17–33). The colon consists of threerelatively straight segments—the ascending, trans-verse, and descending portions. The terminal portionof the descending colon is S-shaped, forming the sig-moid colon, which empties into a relatively straightsegment of the large intestine, the rectum, which endsat the anus.

Although the large intestine has a greater diame-ter than the small intestine, its epithelial surface areais far less, since the large intestine is about half as longas the small intestine, its surface is not convoluted, and

its mucosa lacks villi. The secretions of the large in-testine are scanty, lack digestive enzymes, and consistmostly of mucus and fluid containing bicarbonate andpotassium ions. The primary function of the large in-testine is to store and concentrate fecal material beforedefecation.

Chyme enters the cecum through the ileocecalsphincter. This sphincter is normally closed, but aftera meal, when the gastroileal reflex increases ileal con-tractions, it relaxes each time the terminal portion ofthe ileum contracts, allowing chyme to enter the largeintestine. Distension of the large intestine, on the otherhand, produces a reflex contraction of the sphincter,preventing fecal material from moving back into thesmall intestine.

About 1500 ml of chyme enters the large intestinefrom the small intestine each day. This material is de-rived largely from the secretions of the lower small in-testine since most of the ingested food has been ab-sorbed before reaching the large intestine. Fluidabsorption by the large intestine normally accounts foronly a small fraction of the fluid entering the gas-trointestinal tract each day.

The primary absorptive process in the large intes-tine is the active transport of sodium from lumen toblood, with the accompanying osmotic absorption ofwater. If fecal material remains in the large intestinefor a long time, almost all the water is absorbed, leav-ing behind hard fecal pellets. There is normally a netmovement of potassium from blood into the large-intestine lumen, and severe depletion of total-bodypotassium can result when large volumes of fluid areexcreted in the feces. There is also a net movement ofbicarbonate ions into the lumen, and loss of this bi-carbonate (a base) in patients with prolonged diarrheacan cause the blood to become acidic.

The large intestine also absorbs some of the prod-ucts formed by the bacteria inhabiting this region.Undigested polysaccharides (fiber) are metabolized toshort-chain fatty acids by bacteria in the large intestineand absorbed by passive diffusion. The bicarbonate se-creted by the large intestine helps to neutralize the in-creased acidity resulting from the formation of thesefatty acids. These bacteria also produce small amountsof vitamins, especially vitamin K, that can be absorbedinto the blood. Although this source of vitamins gen-erally provides only a small part of the normal dailyrequirement, it may make a significant contributionwhen dietary vitamin intake is low. An individual whodepends on absorption of vitamins formed by bacte-ria in the large intestine may become vitamin deficientif treated with antibiotics that inhibit other species ofbacteria as well as the disease-causing bacteria.

Other bacterial products include gas (flatus),which is a mixture of nitrogen and carbon dioxide,


Ascendingcolon

Cecum

Appendix

IleumTransversecolon

Descendingcolon

Sigmoidcolon

Rectum

FIGURE 17–33The large intestine begins with the cecum.





with small amounts of the inflammable gases hydro-gen, methane, and hydrogen sulfide. Bacterial fer-mentation of undigested polysaccharides producesthese gases in the colon (except for nitrogen, which isderived from swallowed air), at the rate of about 400to 700 ml/day. Certain foods (beans, for example) con-tain large amounts of carbohydrates that cannot be di-gested by intestinal enzymes but are readily metabo-lized by bacteria in the large intestine, producing largeamounts of gas.

Motility and Defecation Contractions of the circu-lar smooth muscle in the large intestine produce a seg-mentation motion with a rhythm considerably slower(one every 30 min) than that in the small intestine. Be-cause of the slow propulsion of the large intestine con-tents, material entering the large intestine from thesmall intestine remains for about 18 to 24 h. This pro-vides time for bacteria to grow and multiply. Three tofour times a day, generally following a meal, a waveof intense contraction, known as a mass movement,spreads rapidly over the transverse segment of thelarge intestine toward the rectum. This usually coin-cides with the gastroileal reflex. Unlike a peristalticwave, in which the smooth muscle at each point re-laxes after the wave of contraction has passed, thesmooth muscle of the large intestine remains con-tracted for some time after a mass movement.

The anus, the exit from the rectum, is normallyclosed by the internal anal sphincter, which is com-posed of smooth muscle, and the external anal sphinc-ter, which is composed of skeletal muscle under vol-untary control. The sudden distension of the walls ofthe rectum produced by the mass movement of fecalmaterial into it initiates the neurally mediated defeca-tion reflex.

The conscious urge to defecate, mediated bymechanoreceptors, accompanies distension of the rec-tum. The reflex response consists of a contraction ofthe rectum, relaxation of the internal anal sphincter,but contraction of the external anal sphincter (initially),and increased peristaltic activity in the sigmoid colon.Eventually, a pressure is reached in the rectum thattriggers reflex relaxation of the external anal sphincter,allowing the feces to be expelled.

Brain centers can, however, via descending path-ways to somatic nerves to the external anal sphincter,override the reflex signals that eventually would relaxthe sphincter, thereby keeping the external sphincterclosed and allowing a person to delay defecation. Inthis case, the prolonged distension of the rectum initi-ates a reverse peristalsis, driving the rectal contentsback into the sigmoid colon. The urge to defecate thensubsides until the next mass movement again propelsmore feces into the rectum, increasing its volume and

again initiating the defecation reflex. Voluntary controlof the external anal sphincter is learned during child-hood. Spinal-cord damage can lead to a loss of volun-tary control over defecation.

Defecation is normally assisted by a deep inspira-tion, followed by closure of the glottis and contractionof the abdominal and thoracic muscles, producing anincrease in abdominal pressure that is transmitted tothe contents of the large intestine and rectum. This ma-neuver (termed the Valsalva maneuver) also causes arise in intrathoracic pressure, which leads to a tran-sient rise in blood pressure followed by a fall in pres-sure as the venous return to the heart is decreased. Thecardiovascular changes resulting from excessive strainduring defecation may precipitate a stroke or heart at-tack, especially in constipated elderly individuals withcardiovascular disease.

Pathophysiology of theGastrointestinal TractSince the end result of gastrointestinal function is theabsorption of nutrients, salts, and water, most mal-functions of this organ system affect either the nutri-tional state of the body or its salt and water content.The following provide a few examples of disorderedgastrointestinal function.

UlcersConsidering the high concentration of acid and pepsinsecreted by the stomach, it is natural to wonder whythe stomach does not digest itself. Several of the fac-tors that protect the walls of the stomach from beingdigested are: (1) The surface of the mucosa is lined withcells that secrete a slightly alkaline mucus, which formsa thin layer over the luminal surface. Both the proteincontent of mucus and its alkalinity neutralize hydro-gen ions in the immediate area of the epithelium. Thus,mucus forms a chemical barrier between the highlyacid contents of the lumen and the cell surface. (2) Thetight junctions between the epithelial cells lining thestomach restrict the diffusion of hydrogen ions into theunderlying tissues. (3) Damaged epithelial cells are re-placed every few days by new cells arising by the di-vision of cells within the gastric pits.

Yet these protective mechanisms can prove inade-quate, and erosion (ulcers) of the gastric surface occur.Ulcers can occur not only in the stomach but also inthe lower part of the esophagus and in the duodenum.Indeed, duodenal ulcers are about 10 times more fre-quent than gastric ulcers, affecting about 10 percent ofthe U.S. population. Damage to blood vessels in thetissues underlying the ulcer may cause bleeding intothe gastrointestinal lumen. On occasion, the ulcer may






penetrate the entire wall, resulting in leakage of the lu-minal contents into the abdominal cavity.

Ulcer formation involves breaking the mucosalbarrier and exposing the underlying tissue to the cor-rosive action of acid and pepsin, but it is not alwaysclear what produces the initial damage to the barrier.Although acid is essential for ulcer formation, it is notnecessarily the primary factor, and many patients withulcers have normal or even subnormal rates of acid se-cretion.

Many factors, including genetic susceptibility,drugs, alcohol, bile salts, and an excessive secretion ofacid and pepsin, may contribute to ulcer formation.The major factor, however, is the presence of a bac-terium, Helicobacter pylori, that is present in the stom-achs of a majority of patients with ulcers or gastritis(inflammation of the stomach walls). Suppression ofthese bacteria with antibiotics usually leads to healingof the damaged mucosa.

Once an ulcer has formed, inhibition of acid se-cretion can remove the constant irritation and allowthe ulcer to heal. Two classes of drugs are potent in-hibitors of acid secretion. One class of inhibitors acts byblocking a specific class of histamine receptors foundon parietal cells, which stimulate acid secretion. Thesecond class of drugs directly inhibits the H,K-ATPasepump in parietal cells. Although both classes of drugsare effective in healing ulcers, if the Helicobacter pyloribacteria are not removed, the ulcers tend to recur.

Despite popular notions that ulcers are due toemotional stress and despite the existence of a poten-tial pathway (the parasympathetic nerves) for mediat-ing stress-induced increases in acid secretion, the roleof stress in producing ulcers remains unclear. Once theulcer has been formed, however, emotional stress canaggravate it by increasing acid secretion.

VomitingVomiting is the forceful expulsion of the contents ofthe stomach and upper intestinal tract through themouth. Like swallowing, vomiting is a complex reflexcoordinated by a region in the brainstem medulla ob-longata, in this case known as the vomiting center.Neural input to this center from receptors in many dif-ferent regions of the body can initiate the vomiting re-flex. For example, excessive distension of the stomachor small intestine, various substances acting uponchemoreceptors in the intestinal wall or in the brain,increased pressure within the skull, rotating move-ments of the head (motion sickness), intense pain, andtactile stimuli applied to the back of the throat can allinitiate vomiting.

What is the adaptive value of this reflex? Obvi-ously, the removal of ingested toxic substances be-fore they can be absorbed is of benefit. Moreover, the

nausea that usually accompanies vomiting may havethe adaptive value of conditioning the individual toavoid the future ingestion of foods containing suchtoxic substances. Why other types of stimuli, such asthose producing motion sickness, have becomelinked to the vomiting center is not clear.

Vomiting is usually preceded by increased saliva-tion, sweating, increased heart rate, pallor, and feel-ings of nausea. The events leading to vomiting beginwith a deep inspiration, closure of the glottis, and el-evation of the soft palate. The abdominal muscles thencontract, raising the abdominal pressure, which istransmitted to the stomach’s contents. The loweresophageal sphincter relaxes, and the high abdominalpressure forces the contents of the stomach into theesophagus. This initial sequence of events can occurrepeatedly without expulsion via the mouth and isknown as retching. Vomiting occurs when the abdom-inal contractions become so strong that the increasedintrathoracic pressure forces the contents of the esoph-agus through the upper esophageal sphincter.

Vomiting is also accompanied by strong contractionsin the upper portion of the small intestine, contractionsthat tend to force some of the intestinal contents backinto the stomach from which they can be expelled. Thus,some bile may be present in the vomitus.

Excessive vomiting can lead to large losses fromthe stomach of the water and salts that normally wouldbe absorbed in the small intestine. This can result insevere dehydration, upset the body’s salt balance, andproduce circulatory problems due to a decrease inplasma volume. The loss of acid from vomiting resultsin a metabolic alkalosis (Chapter 16).

GallstonesAs described earlier, bile contains not only bile salts butalso cholesterol and phospholipids, which are water- insoluble and are maintained in soluble form in thebile as micelles. When the concentration of cholesterolin the bile becomes high in relation to the concentra-tions of phospholipid and bile salts, cholesterol crys-tallizes out of solution, forming gallstones. This canoccur if the liver secretes excessive amounts of choles-terol or if the cholesterol becomes overly concentratedin the gallbladder as a result of salt and water ab-sorption. Although cholesterol gallstones are the mostfrequently encountered gallstones in the Westernworld, the precipitation of bile pigments can also oc-casionally be responsible for gallstone formation.

Why some individuals develop gallstones and oth-ers do not is still unclear. Women, for example, haveabout twice the incidence of gallstone formation asmen, and Native Americans have a very high incidencecompared with other ethnic groups in the UnitedStates.






If a gallstone is small, it may pass through the com-mon bile duct into the intestine with no complications.A larger stone may become lodged in the opening ofthe gallbladder, causing painful contractile spasms ofthe smooth muscle. A more serious complication ariseswhen a gallstone lodges in the common bile duct,thereby preventing bile from entering the intestine.The absence of bile in the intestine decreases the rateof fat digestion and absorption, so that approximatelyhalf of ingested fat is not digested and passes on to thelarge intestine and eventually appears in the feces. Fur-thermore, bacteria in the large intestine convert someof this fat into fatty acid derivatives that alter salt andwater movements, leading to a net flow of fluid intothe large intestine. The result is diarrhea and fluid loss.

Since the duct from the pancreas joins the commonbile duct just before it enters the duodenum, a gall-stone that becomes lodged as this point prevents bothbile and pancreatic secretions from entering the intes-tine. This results in failure both to neutralize acid andto digest adequately most organic nutrients, not justfat. The end result is severe nutritional deficiencies.

The buildup of pressure in a blocked common bileduct inhibits further secretion of bile. As a result, biliru-bin, which is normally secreted into the bile from theblood, accumulates in the blood and diffuses into tis-sues, where it produces the yellowish coloration of theskin and eyes known as jaundice.

It should be emphasized, however, that bile ductobstruction is not the only cause of jaundice. Bilirubinaccumulation in the blood can occur if hepatocytes aredamaged by liver disease and therefore fail to secretebilirubin into the bile. It can also occur if the level ofbilirubin in the blood exceeds the capacity of the nor-mal liver to secrete it, as in diseases that result in anincreased breakdown of red blood cells—hemolyticjaundice. At birth, the liver’s capacity to secrete biliru-bin is not fully developed. During the first few daysof life this may result in jaundice, which normallyclears spontaneously. Excessive accumulation of biliru-bin during the neonatal period, as occurs, for example,with hemolytic disease of the newborn (Chapter 20),carries a risk of bilirubin-induced neurological dam-age at a time when a critical phase in the developmentof the nervous system is occurring.

Although surgery may be necessary to remove aninflamed gallbladder or stones from an obstructedduct, newer techniques use drugs to dissolve gall-stones or noninvasive ultrasound to shatter gall-stones.

Lactose IntoleranceLactose is the major carbohydrate in milk. It cannotbe absorbed directly but must first be digested intoits components—glucose and galactose—which are

readily absorbed by active transport. Lactose is di-gested by the enzyme lactase, which is embedded inthe luminal plasma membranes of intestinal epithe-lial cells. Lactase is present at birth, but in approxi-mately 25 percent of white Americans and in mostAsians, its concentration begins to decline when thechild is between 18 and 36 months old. This declinein lactase is genetically determined. In these individ-uals, as the lactase declines ingested lactose cannotbe completely digested—a condition known as lac-tose intolerance—and some lactose remains in thesmall intestine.

Since the absorption of water requires prior ab-sorption of solute to provide an osmotic gradient, theunabsorbed lactose in persons with lactose intoleranceprevents some of the water from being absorbed. Thislactose-containing fluid is passed on to the large in-testine, where bacteria digest the lactose. They thenmetabolize the released monosaccharides, producinglarge quantities of gas (which distends the colon, pro-ducing pain) and short-chain fatty acids, which causefluid movement into the lumen of the large intestine,producing diarrhea. The response to milk ingestion byadults whose lactase levels have diminished variesfrom mild discomfort to severely dehydrating diar-rhea, according to the volume of milk and milk prod-ucts ingested and the amount of lactase present in theintestine. These symptoms can be avoided if the per-son either drinks milk in which the lactose has beenpredigested or takes pills containing lactase along withthe milk.

Constipation and DiarrheaMany people have a mistaken belief that, unless theyhave a bowel movement every day, the absorption of“toxic” substances from fecal material in the large in-testine will somehow poison them. Attempts to iden-tify such toxic agents in the blood following prolongedperiods of fecal retention have been unsuccessful, andthere appears to be no physiological necessity for hav-ing bowel movements at frequent intervals. Whatevermaintains a person in a comfortable state is physio-logically adequate, whether this means a bowel move-ment after every meal, once a day, or only once a week.

On the other hand, there often are symptoms—headache, loss of appetite, nausea, and abdominal dis-tension—that may arise when defecation has not oc-curred for several days or even weeks, depending onthe individual. These symptoms of constipation arecaused not by toxins but by distension of the rectum.The longer that fecal material remains in the large in-testine, the more water is absorbed and the harder anddrier the feces become, making defecation more diffi-cult and sometimes painful. Thus, constipation tendsto promote constipation.






Decreased motility of the large intestine is the pri-mary factor causing constipation. This often occurs inthe elderly, or it may result from damage to the colon’senteric nervous system or from emotional stress.

One of the factors increasing motility in the largeintestine, and thus opposing the development of con-stipation, is distension. As noted earlier, dietary fiber(cellulose and other complex polysaccharides) is notdigested by the enzymes in the small intestine and ispassed on to the large intestine, where its bulk pro-duces distension and thereby increases motility. Bran,most fruits, and vegetables are examples of foods thathave a relatively high fiber content.

Laxatives, agents that increase the frequency orease of defecation, act through a variety of mecha-nisms. Thus, fiber provides a natural laxative. Somelaxatives, such as mineral oil, simply lubricate the fe-ces, making defecation easier and less painful. Otherscontain magnesium and aluminum salts, which arepoorly absorbed and therefore lead to water retentionin the intestinal tract. Still others, such as castor oil,stimulate the motility of the colon and inhibit ion trans-port across the wall, thus affecting water absorption.

Excessive use of laxatives in an attempt to main-tain a preconceived notion of regularity leads to a de-creased responsiveness of the large intestine to normaldefecation-promoting signals. In such cases, a long pe-riod without defecation may occur following cessationof laxative intake, appearing to confirm the necessityof taking laxatives to promote regularity.

Diarrhea is characterized by large, frequent, wa-tery stools. Diarrhea can result from decreased fluidabsorption, increased fluid secretion, or both. The in-creased motility that accompanies diarrhea probablydoes not cause most cases of diarrhea (by decreasingthe time available for fluid absorption) but rather isa result of the distension produced by increased lu-minal fluid.

A number of bacterial, protozoan, and viral dis-eases of the intestinal tract cause secretory diarrhea.Cholera, which is endemic in many parts of the world,is caused by a bacterium that releases a toxin that stim-ulates the production of cyclic AMP in the secretorycells at the base of the intestinal villi. This leads to anincreased frequency of opening of the chloride chan-nels in the luminal membrane and hence increased se-cretion of chloride ions. There is an accompanying os-motic flow of water into the intestinal lumen, resultingin massive diarrhea that can be life-threatening due todehydration and decreased blood volume that leads tocirculatory shock. The salt and water lost by this se-vere form of diarrhea can be balanced by ingesting asimple solution containing salt and glucose. The activeabsorption of these solutes is accompanied by absorp-tion of water, which replaces the fluid lost by diarrhea.

Traveler’s diarrhea, produced by several species ofbacteria, produces a secretory diarrhea by the samemechanism as the cholera bacterium, but is less severe.

In addition to decreased blood volume due to thesalt and water loss, other consequences of severe di-arrhea are potassium depletion and metabolic acidosis(Chapter 16) resulting from the excessive fecal loss ofpotassium and bicarbonate ions, respectively.

I. The gastrointestinal system transfers digestedorganic nutrients, minerals, and water from theexternal environment to the internal environment.The four processes used to accomplish this functionare (a) digestion, (b) secretion, (c) absorption, and (d)motility.a. The system is designed to maximize the

absorption of most nutrients, not to regulate the amount absorbed.

b. The system does not play a major role in theremoval of waste products from the internalenvironment.

Overview: Functions of theGastrointestinal Organs

I. The names and functions of the gastrointestinalorgans are summarized in Figure 17–3.

II. Each day the gastrointestinal tract secretes about 6times more fluid into the lumen than is ingested.Only 1 percent of this fluid is excreted in the feces.

Structure of the Gastrointestinal Tract Wall

I. The structure of the wall of the gastrointestinal tractis summarized in Figure 17–6.a. The area available for absorption in the small

intestine is greatly increased by the folding of theintestinal wall and by the presence of villi andmicrovilli on the surface of the epithelial cells.

b. The epithelial cells lining the intestinal tract arecontinuously replaced by new cells arising fromcell division at the base of the villi.

c. The venous blood from the small intestine,containing absorbed nutrients other than fat,passes to the liver via the hepatic portal veinbefore returning to the heart. Fat is absorbed intothe lymphatic vessels (lacteals) in each villus.

Digestion and AbsorptionI. Starch is digested by amylases secreted by the

salivary glands and pancreas, and the resultingproducts, as well as ingested disaccharides, aredigested to monosaccharides by enzymes in theluminal membranes of epithelial cells in the smallintestine.a. Most monosaccharides are then absorbed by

secondary active transport.

S U M M A R Y






b. Some polysaccharides, such as cellulose, cannotbe digested and pass to the large intestine, wherethey are metabolized by bacteria.

II. Proteins are broken down into small peptides andamino acids, which are absorbed by secondary activetransport in the small intestine.a. The breakdown of proteins to peptides is

catalyzed by pepsin in the stomach and by thepancreatic enzymes trypsin and chymotrypsin inthe small intestine.

b. Peptides are broken down into amino acids bypancreatic carboxypeptidase and intestinalaminopeptidase.

c. Small peptides consisting of two to three aminoacids can be actively absorbed into epithelial cellsand then broken down to amino acids, which arereleased into the blood.

III. The digestion and absorption of fat by the smallintestine requires mechanisms that solubilize the fatand its digestion products.a. Large fat globules leaving the stomach are

emulsified in the small intestine by bile salts andphospholipids secreted by the liver.

b. Lipase from the pancreas digests fat at the surfaceof the emulsion droplets, forming fatty acids andmonoglycerides.

c. These water-insoluble products of lipase action,when combined with bile salts, form micelles,which are in equilibrium with the free molecules.

d. Free fatty acids and monoglycerides diffuse acrossthe luminal membranes of epithelial cells, withinwhich they are enzymatically recombined to formtriacylglycerol, which is released as chylomicronsfrom the blood side of the cell by exocytosis.

e. The released chylomicrons enter lacteals in theintestinal villi and pass, by way of the lymphaticsystem, to the venous blood returning to theheart.

IV. Fat-soluble vitamins are absorbed by the samepathway used for fat absorption. Most water-solublevitamins are absorbed in the small intestine bydiffusion or mediated transport. Vitamin B12 isabsorbed in the ileum by endocytosis aftercombining with intrinsic factor secreted into thelumen by parietal cells in the stomach.

V. Water is absorbed from the small intestine byosmosis following the active absorption of solutes,primarily sodium chloride.

Regulation of Gastrointestinal ProcessesI. Most gastrointestinal reflexes are initiated by luminal

stimuli: (a) distension, (b) osmolarity, (c) acidity, and(d) digestion products.a. Neural reflexes are mediated by short reflexes in

the enteric nervous system and by long reflexesinvolving afferent and efferent neurons to andfrom the CNS.

b. Endocrine cells scattered throughout theepithelium of the stomach secrete gastrin, andcells in the small intestine secrete secretin, CCK,and GIP. The properties of these hormones aresummarized in Table 17–3.

c. The three phases of gastrointestinal regulation—cephalic, gastric, and intestinal—are named forthe location of the stimulus that initiates theresponse.

II. Chewing breaks up food into particles suitable forswallowing, but it is not essential for the eventualdigestion and absorption of food.

III. Salivary secretion is stimulated by food in the mouthacting reflexly via chemoreceptors and pressurereceptors. Both sympathetic and parasympatheticstimulation increase salivary secretion.

IV. Food moved into the pharynx by the tongue initiatesswallowing, which is coordinated by the swallowingcenter in the brainstem medulla oblongata.a. Food is prevented from entering the trachea by

inhibition of respiration and by closure of theglottis.

b. The upper esophageal sphincter relaxes as food ismoved into the esophagus, and then the sphinctercloses.

c. Food is moved through the esophagus toward thestomach by peristaltic waves. The loweresophageal sphincter remains open throughoutswallowing.

d. If food does not reach the stomach with the firstperistaltic wave, distension of the esophagusinitiates secondary peristalsis.

V. The factors controlling acid secretion by parietal cellsin the stomach are summarized in Table 17–4.

VI. Pepsinogen, secreted by the gastric chief cells inresponse to most of the same reflexes that controlacid secretion, is converted to the active proteolyticenzyme pepsin in the stomach’s lumen by acid andby activated pepsin.

VII. Peristaltic waves sweeping over the stomach becomestronger in the antrum, where most mixing occurs.With each wave, only a small portion of thestomach’s contents are expelled into the smallintestine through the pyloric sphincter.a. Cycles of membrane depolarization, the basic

electrical rhythm generated by gastric smoothmuscle, determine gastric peristaltic wavefrequency. Contraction strength can be altered byneural and hormonal changes in membranepotential, which is imposed on the basic electricalrhythm.

b. Distension of the stomach increases the force ofcontractions and the rate of emptying. Distensionof the small intestine, and fat, acid, or hypertonicsolutions in the intestinal lumen inhibit gastriccontractions.

VIII. The exocrine portion of the pancreas secretesdigestive enzymes and bicarbonate ions, all of whichreach the duodenum through the pancreatic duct.






a. The bicarbonate ions neutralize acid entering thesmall intestine from the stomach.

b. Most of the proteolytic enzymes, includingtrypsin, are secreted by the pancreas in inactiveforms. Trypsin is activated by enterokinaselocated on the membranes of the small-intestinecells and in turn activates other inactivepancreatic enzymes.

c. The hormone secretin, released from the smallintestine in response to increased luminal acidity,stimulates pancreatic bicarbonate secretion. CCKis released from the small intestine in response tothe products of fat and protein digestion, andstimulates pancreatic enzyme secretion.

d. Parasympathetic stimulation increases pancreaticsecretion.

IX. The liver secretes bile, the major ingredients ofwhich are bile salts, cholesterol, lecithin, bicarbonateions, bile pigments, and trace metals.a. Bile salts undergo continuous enterohepatic

recirculation during a meal. The liver synthesizesnew bile salts to replace those lost in the feces.

b. The greater the bile salt concentration in thehepatic portal blood, the greater the rate of bilesecretion.

c. Bilirubin, the major bile pigment, is a breakdownproduct of hemoglobin and is absorbed from theblood by the liver and secreted into the bile.

d. Secretin stimulates bicarbonate secretion by thecells lining the bile ducts in the liver.

e. Bile is concentrated in the gallbladder by theabsorption of NaCl and water.

f. Following a meal, the release of CCK from thesmall intestine causes the gallbladder to contractand the sphincter of Oddi to relax, therebyinjecting concentrated bile into the intestine.

X. In the small intestine, the digestion ofpolysaccharides and proteins increases theosmolarity of the luminal contents, producing waterflow into the lumen.

XI. Sodium, chloride, bicarbonate, and water aresecreted by the small intestine. However, most ofthese secreted substances, as well as those enteringthe small intestine from other sources, are absorbedback into the blood.

XII. Intestinal motility is coordinated by the entericnervous system and modified by long and shortreflexes and hormones.a. During and shortly after a meal, the intestinal

contents are mixed by segmenting movements ofthe intestinal wall.

b. After most of the food has been digested andabsorbed, segmentation is replaced by themigrating motility complex, which moves theundigested material into the large intestine by amigrating segment of peristaltic waves.

XIII. The primary function of the large intestine is to storeand concentrate fecal matter before defecation.

a. Water is absorbed from the large intestinesecondary to the active absorption of sodium,leading to the concentration of fecal matter.

b. Flatus is produced by bacterial fermentation ofundigested polysaccharides.

c. Three to four times a day, mass movements in thecolon move its contents into the rectum.

d. Distension of the rectum initiates defecation,which is assisted by a forced expiration against aclosed glottis.

e. Defecation can be voluntarily controlled throughsomatic nerves to the skeletal muscles of theexternal anal sphincter.

Pathophysiology of the Gastrointestinal Tract

I. The factors that normally prevent breakdown of themucosal barrier and formation of ulcers are (1)secretion of an alkaline mucus, (2) tight junctionsbetween epithelial cells, and (3) rapid replacement ofepithelial cells.a. The bacterium Helicobacter pylori is a major cause

of damage to the mucosal barrier leading toulcers.

b. Drugs that block histamine receptors or inhibitthe H,K-ATPase pump inhibit acid secretion andpromote ulcer healing.

II. Vomiting is coordinated by the vomiting center inthe brainstem medulla oblongata. Contractions ofabdominal muscles force the contents of the stomachinto the esophagus (retching), and if the contractionsare strong enough, they force the contents of theesophagus through the upper esophageal sphincterinto the mouth (vomiting).

III. Precipitation of cholesterol or, less often, bilepigments in the gallbladder forms gallstones, whichcan block the exit of the gallbladder or common bileduct. In the latter case, the failure of bile salts toreach the intestine causes decreased digestion andabsorption of fat, and the accumulation of bilepigments in the blood and tissues causes jaundice.

IV. Lactase, which is present at birth, undergoes agenetically determined decrease during childhood inmany individuals. In the absence of lactase, lactosecannot be digested, and its presence in the smallintestine can result in diarrhea and increased flatusproduction when milk is ingested.

V. Constipation is primarily the result of decreasedcolonic motility. The symptoms of constipation areproduced by overdistension of the rectum, not by theabsorption of toxic bacterial products.

VI. Diarrhea can be caused by decreased fluidabsorption, increased fluid secretion, or both.






K E Y T E R M S

1. List the four processes that accomplish the functionsof the gastrointestinal system.

2. List the primary functions performed by each of theorgans in the gastrointestinal system.

3. Approximately how much fluid is secreted into thegastrointestinal tract each day compared with theamount of food and drink ingested? How much ofthis appears in the feces?

4. What structures are responsible for the large surfacearea of the small intestine?

5. Where does the venous blood go after leaving thesmall intestine?

6. Identify the enzymes involved in carbohydratedigestion and the mechanism of carbohydrateabsorption in the small intestine.

7. List three ways in which proteins or their digestionproducts can be absorbed from the small intestine.

8. Describe the process of fat emulsification.9. What is the role of micelles in fat absorption?

10. Describe the movement of fat digestion productsfrom the intestinal lumen to a lacteal.

11. How does the absorption of fat-soluble vitaminsdiffer from that of water-soluble vitamins?

12. Specify two conditions that may lead to failure toabsorb vitamin B12.

13. How are salts and water absorbed in the smallintestine?

14. Describe the role of ferritin in the absorption of iron.15. List the four types of stimuli that initiate most

gastrointestinal reflexes.16. Describe the location of the enteric nervous system

and its role in both short and long reflexes.17. Name the four established gastrointestinal hormones

and state their major functions.18. Describe the neural reflexes leading to increased

salivary secretion.19. Describe the sequence of events that occur during

swallowing.20. List the cephalic, gastric, and intestinal phase stimuli

that stimulate or inhibit acid secretion by thestomach.

21. Describe the function of gastrin and the factorscontrolling its secretion.

22. By what mechanism is pepsinogen converted topepsin in the stomach?

23. Describe the factors that control gastric emptying.24. Describe the mechanisms controlling pancreatic

secretion of bicarbonate and enzymes.25. How are pancreatic proteolytic enzymes activated in

the small intestine?26. List the major constituents of bile.27. Describe the recycling of bile salts by the

enterohepatic circulation.28. What determines the rate of bile secretion by the

liver?29. Describe the effects of secretin and CCK on the bile

ducts and gallbladder.

R E V I E W Q U E S T I O N S


gastrointestinal (GI) system

gastrointestinal tractdigestionsecretionabsorptionmotilityfecesmouthsalivasalivary glandamylasepharynxesophagusstomachhydrochloric acidpepsinchymesmall intestineduodenumjejunumileumpancreasliverhepaticbilebile saltgallbladdercommon bile ductlarge intestinerectumdefecationmucosasubmucous plexusmuscularis externacircular musclelongitudinal musclemyenteric plexusserosavillimicrovillilactealhepatic portal veinfibertrypsinchymotrypsincarboxypeptidaseaminopeptidaselipaseemulsificationmicellecolipasechylomicronintrinsic factorenteric nervous systemshort reflex

long reflexsecretincholecystokinin (CCK)gastringlucose-dependent

insulinotropic peptide (GIP)potentiationcephalic phasegastric phaseintestinal phaseswallowing centerglottisepiglottisupper esophageal sphincterlower esophageal sphincterperistaltic wavessecondary peristalsisbody (of stomach)funduspepsinogenantrumparietal cellchief cellenterochromaffin-like (ECL)

cellsomatostatinenterogastronezymogenreceptive relaxationpyloric sphincterbasic electrical rhythmenterokinasetrypsinogenbile canaliculienterohepatic circulationbile pigmentbilirubinhepatocytesphincter of Oddisegmentationmigrating motility complexmotilingastroileal reflexintestino-intestinal reflexcecumappendixcolonileocecal sphincterflatusmass movementanusinternal anal sphincterexternal anal sphincterdefecation reflexvomiting centerlactase





30. What causes water to move from the blood to thelumen of the duodenum following gastric emptying?

31. Describe the type of intestinal motility found duringand shortly after a meal and the type found severalhours after a meal.

32. Describe the production of flatus by the largeintestine.

33. Describe the factors that initiate and controldefecation.

34. Why is the stomach’s wall normally not digested bythe acid and digestive enzymes in the lumen?

35. Describe the process of vomiting.36. What are the consequences of blocking the common

bile duct with a gallstone?37. What are the consequences of the failure to digest

lactose in the small intestine?38. Contrast the factors that cause constipation with

those that produce diarrhea.

C L I N I C A L T E R M S

(Answers are given in Appendix A.)

1. If the salivary glands were unable to secrete amylase,what effect would this have on starch digestion?

2. Whole milk or a fatty snack consumed before theingestion of alcohol decreases the rate ofintoxication. By what mechanism may fat be actingto produce this effect?

3. A patient brought to a hospital after a period ofprolonged vomiting has an elevated heart rate,decreased blood pressure, and below-normal bloodacidity. Explain these symptoms in terms of theconsequences of excessive vomiting.

4. Can fat be digested and absorbed in the absence ofbile salts? Explain.

5. How might damage to the lower portion of thespinal cord affect defecation?

6. One of the older but no longer used procedures inthe treatment of ulcers is vagotomy, surgical cuttingof the vagus (parasympathetic) nerves to thestomach. By what mechanism might this procedurehelp ulcers to heal and decrease the incidence of newulcers?

T H O U G H T Q U E S T I O N S


pernicious anemiahemochromatosisheartburngastro-esophageal refluxdumping syndromeulcersHelicobacter pylorigastritisretching

gallstonesjaundicehemolytic jaundicelactose intoleranceconstipationlaxativesdiarrheacholeratraveler’s diarrhea

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