chapter 62

U n i t X II
General Principles of Gastrointestinal Function—
Motility, Nervous Control, and Blood Circulation

The alimentary tract pro-

vides the body with a con-
tinual supply of water,
electrolytes, vitamins, and
Parotid gland
nutrients. To achieve this
Mouth
requires (1) movement of Salivary glands
food through the alimen-
tary tract; (2) secretion of digestive juices and digestion Esophagus
of the food; (3) absorption of water, various electrolytes,
vitamins, and digestive products; (4) circulation of blood
through the gastrointestinal organs to carry away the
absorbed substances; and (5) control of all these functions
by local, nervous, and hormonal systems.
Figure 62-1 shows the entire alimentary tract. Each
Liver Stomach
part is adapted to its specific functions: some to simple
Gallbladder Pancreas
passage of food, such as the esophagus; others to tempo-
rary storage of food, such as the stomach; and others to Duodenum
digestion and absorption, such as the small intestine. In Transverse Jejunum
colon
this chapter, we discuss the basic principles of function
Ascending Descending
in the entire alimentary tract; in the following chapters, colon colon
we discuss the specific functions of different segments of Ileum
the tract.
Anus

General Principles of Gastrointestinal Figure 62-1  Alimentary tract.

Motility

Physiologic Anatomy of the Gastrointestinal Gastrointestinal Smooth Muscle Functions

Wall as a Syncytium.  The individual smooth muscle fibers in
Figure 62-2 shows a typical cross section of the intesti- the gastrointestinal tract are 200 to 500 micrometers in
nal wall, including the following layers from outer sur- length and 2 to 10 micrometers in diameter, and they are
face inward: (1) the serosa, (2) a longitudinal smooth arranged in bundles of as many as 1000 parallel fibers. In
muscle layer, (3) a circular smooth muscle layer, (4) the the longitudinal muscle layer, the bundles extend longi-
submucosa, and (5) the mucosa. In addition, sparse bun- tudinally down the intestinal tract; in the circular muscle
dles of smooth muscle fibers, the mucosal muscle, lie in layer, they extend around the gut.
the deeper layers of the mucosa. The motor functions of Within each bundle, the muscle fibers are electrically
the gut are performed by the different layers of smooth connected with one another through large numbers
muscle. of gap junctions that allow low-resistance movement
The general characteristics of smooth muscle and its of ions from one muscle cell to the next. Therefore,
function are discussed in Chapter 8, which should be ­electrical signals that initiate muscle contractions can
reviewed as a background for the following sections of this travel readily from one fiber to the next within each bun-
chapter. The specific characteristics of smooth ­muscle in dle but more rapidly along the length of the bundle than
the gut are the following. sideways.

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Unit XII  Gastrointestinal Physiology

Serosa Spikes

Membrane potential (millivolts)

Circular muscle 0 Depolarization
Longitudinal -10
muscle -20 Slow
waves
Submucosa -30
-40 Stimulation by
Meissner's 1. Norepinephrine
nerve plexus -50 2. Sympathetics
Mucosa -60 Resting Stimulation by
Epithelial -70 1. Stretch
Hyperpolarization
lining 2. Acetylcholine
3. Parasympathetics
Mucosal
muscle 0 6 12 18 24 30 36 42 48 54
Mucosal gland Seconds
Myenteric nerve Figure 62-3  Membrane potentials in intestinal smooth muscle.
plexus Note the slow waves, the spike potentials, total depolarization, and
Submucosal gland hyperpolarization, all of which occur under different physiologic
conditions of the intestine.
Mesentery
Figure 62-2  Typical cross section of the gut.
in the body of the stomach, as much as 12 in the duode-
num, and about 8 or 9 in the terminal ileum. Therefore,
Each bundle of smooth muscle fibers is partly sepa- the rhythm of contraction of the body of the stomach is
rated from the next by loose connective tissue, but the usually about 3 per minute, of the duodenum about 12 per
muscle bundles fuse with one another at many points, minute, and of the ileum 8 to 9 per minute.
so in reality each muscle layer represents a branching The precise cause of the slow waves is not completely
latticework of smooth muscle bundles. Therefore, each understood, although they appear to be caused by com-
muscle layer functions as a syncytium; that is, when an plex interactions among the smooth muscle cells and spe-
action potential is elicited anywhere within the muscle cialized cells, called the interstitial cells of Cajal, that are
mass, it generally travels in all directions in the muscle. believed to act as electrical pacemakers for smooth mus-
The distance that it travels depends on the excitability cle cells. These interstitial cells form a network with each
of the muscle; sometimes it stops after only a few mil- other and are interposed between the smooth muscle lay-
limeters and at other times it travels many centimeters ers, with synaptic-like contacts to smooth muscle cells.
or even the entire length and breadth of the intestinal The interstitial cells of Cajal undergo cyclic changes in
tract. membrane potential due to unique ion channels that peri-
Also, a few connections exist between the longitudinal odically open and produce inward (pacemaker) currents
and circular muscle layers, so excitation of one of these that may generate slow wave activity.
layers often excites the other as well. The slow waves usually do not by themselves cause
muscle contraction in most parts of the gastrointestinal
tract, except perhaps in the stomach. Instead, they mainly
Electrical Activity of Gastrointestinal excite the appearance of intermittent spike potentials,
Smooth Muscle and the spike potentials in turn actually excite the muscle
The smooth muscle of the gastrointestinal tract is excited contraction.
by almost continual slow, intrinsic electrical activity along Spike Potentials.  The spike potentials are true action
the membranes of the muscle fibers. This activity has potentials. They occur automatically when the rest-
two basic types of electrical waves: (1) slow waves and (2) ing membrane potential of the gastrointestinal smooth
spikes, both of which are shown in Figure 62-3. In addi- ­muscle becomes more positive than about −40 millivolts
tion, the voltage of the resting membrane potential of the (the normal resting membrane potential in the smooth
gastrointestinal smooth muscle can be made to change to muscle fibers of the gut is between −50 and −60 milli-
different levels, and this, too, can have important effects volts). Note in Figure 62-3 that each time the peaks of
in controlling motor activity of the gastrointestinal tract. the  slow waves temporarily become more positive than
Slow Waves.  Most gastrointestinal contractions occur −40 millivolts, spike potentials appear on these peaks.
rhythmically, and this rhythm is determined mainly by The higher the slow wave potential rises, the greater the
the frequency of so-called “slow waves” of smooth muscle frequency of the spike potentials, usually ranging between
membrane potential. These waves, shown in Figure 62-3, 1 and 10 spikes per second. The spike potentials last 10 to
are not action potentials. Instead, they are slow, undu- 40 times as long in gastrointestinal muscle as the action
lating changes in the resting membrane potential. Their potentials in large nerve fibers, each gastrointestinal spike
intensity usually varies between 5 and 15 millivolts, and lasting as long as 10 to 20 milliseconds.
their frequency ranges in different parts of the human Another important difference between the action
­gastrointestinal tract from 3 to 12 per minute: about 3 potentials of the gastrointestinal smooth muscle and

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 Chapter 62  General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

those of nerve fibers is the manner in which they are gen- ous, not associated with the basic electrical rhythm of
erated. In nerve fibers, the action potentials are caused the slow waves but often lasting several minutes or even
almost entirely by rapid entry of sodium ions through hours. The tonic contraction often increases or decreases
sodium channels to the interior of the fibers. In gastro- in intensity but continues.

U n i t X II
intestinal smooth muscle fibers, the channels responsi- Tonic contraction is sometimes caused by contin-
ble for the action potentials are somewhat different; they uous repetitive spike potentials—the greater the fre-
allow especially large numbers of calcium ions to enter quency, the greater the degree of contraction. At other
along with smaller numbers of sodium ions and therefore times, tonic contraction is caused by hormones or other
are called calcium-sodium channels. These channels are factors that bring about continuous partial depolariza-
much slower to open and close than are the rapid sodium tion of the smooth muscle membrane without causing
channels of large nerve fibers. The slowness of opening action potentials. A third cause of tonic contraction is
and closing of the calcium-sodium channels accounts for continuous entry of calcium ions into the interior of the
the long duration of the action potentials. Also, the move- cell brought about in ways not associated with changes
ment of large amounts of calcium ions to the interior of in membrane potential. The details of these mechanisms
the muscle fiber during the action potential plays a special are still unclear.
role in causing the intestinal muscle fibers to contract, as
we discuss shortly.
Changes in Voltage of the Resting Membrane Neural Control of Gastrointestinal
Potential.  In addition to the slow waves and spike poten- Function—Enteric Nervous System
tials, the baseline voltage level of the smooth muscle rest-
ing membrane potential can also change. Under normal The gastrointestinal tract has a nervous system all its
conditions, the resting membrane potential averages own called the enteric nervous system. It lies entirely
about −56 millivolts, but multiple factors can change this in the wall of the gut, beginning in the esophagus and
level. When the potential becomes less negative, which is extending all the way to the anus. The number of neu-
called depolarization of the membrane, the muscle fibers rons in this enteric system is about 100 million, almost
become more excitable. When the potential becomes exactly equal to the number in the entire spinal cord.
more negative, which is called hyperpolarization, the This highly developed enteric nervous system is espe-
fibers become less excitable. cially important in controlling gastrointestinal move-
Factors that depolarize the membrane—that is, make ments and secretion.
it more excitable—are (1) stretching of the muscle, (2) The enteric nervous system is composed mainly of
stimulation by acetylcholine released from the endings two plexuses, shown in Figure 62-4: (1) an outer plexus
of parasympathetic nerves, and (3) stimulation by several lying between the longitudinal and circular muscle lay-
specific gastrointestinal hormones. ers, called the myenteric plexus or Auerbach’s plexus,
Important factors that make the membrane potential and (2) an inner plexus, called the submucosal plexus or
more negative—that is, hyperpolarize the membrane and Meissner’s plexus, that lies in the submucosa. The nervous
make the muscle fibers less excitable—are (1) the effect connections within and between these two plexuses are
of norepinephrine or epinephrine on the fiber membrane also shown in Figure 62-4.
and (2) stimulation of the sympathetic nerves that secrete The myenteric plexus controls mainly the gastroin-
mainly norepinephrine at their endings. testinal movements, and the submucosal plexus con-
Calcium Ions and Muscle Contraction.  Smooth mus- trols mainly gastrointestinal secretion and local blood
cle contraction occurs in response to entry of calcium flow.
ions into the muscle fiber. As explained in Chapter 8, cal- Note especially in Figure 62-4 the extrinsic sympa-
cium ions, acting through a calmodulin control mecha- thetic and parasympathetic fibers that connect to both the
nism, activate the myosin filaments in the fiber, causing myenteric and submucosal plexuses. Although the enteric
attractive forces to develop between the myosin filaments nervous system can function independently of these
and the actin filaments, thereby causing the muscle to extrinsic nerves, stimulation by the parasympathetic and
contract. sympathetic systems can greatly enhance or inhibit gas-
The slow waves do not cause calcium ions to enter the trointestinal functions, as we discuss later.
smooth muscle fiber (only sodium ions). Therefore, the Also shown in Figure 62-4 are sensory nerve end-
slow waves by themselves usually cause no muscle con- ings that originate in the gastrointestinal epithelium or
traction. Instead, it is during the spike potentials, gen- gut wall and send afferent fibers to both plexuses of the
erated at the peaks of the slow waves, that significant enteric system, as well as (1) to the prevertebral ganglia
quantities of calcium ions do enter the fibers and cause of the sympathetic nervous system, (2) to the spinal cord,
most of the contraction. and (3) in the vagus nerves all the way to the brain stem.
Tonic Contraction of Some Gastrointestinal Smooth These sensory nerves can elicit local reflexes within the
Muscle.  Some smooth muscle of the gastrointestinal gut wall itself and still other reflexes that are relayed to
tract exhibits tonic contraction, as well as, or instead of, the gut from either the prevertebral ganglia or the basal
rhythmical contractions. Tonic contraction is continu- regions of the brain.

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Unit XII  Gastrointestinal Physiology

Figure 62-4  Neural control of the gut Sympathetic Parasympathetic

wall, showing (1) the myenteric and To prevertebral
submucosal plexuses (black fibers); (2) ganglia, spinal (mainly postganglionic) (preganglionic)
extrinsic control of these plexuses by the cord, and brain
sympathetic and parasympathetic ner- stem
vous systems (red fibers); and (3) sensory
fibers passing from the luminal epithelium
and gut wall to the enteric plexuses, then
to the prevertebral ganglia of the spinal Myenteric
cord and directly to the spinal cord and plexus
brain stem (dashed fibers).

Submucosal
plexus

Sensory
neurons

Epithelium

Differences Between the Myenteric ­submucosal muscle that causes various degrees of infold-
and Submucosal Plexuses ing of the gastrointestinal mucosa.
The myenteric plexus consists mostly of a linear chain of
many interconnecting neurons that extends the entire
Types of Neurotransmitters Secreted
length of the gastrointestinal tract. A section of this chain
by Enteric Neurons
is shown in Figure 62-4. In an attempt to understand better the multiple functions
Because the myenteric plexus extends all the way along of the gastrointestinal enteric nervous system, research
the intestinal wall and because it lies between the longi- workers the world over have identified a dozen or more
tudinal and circular layers of intestinal smooth muscle, different neurotransmitter substances that are released
it is concerned mainly with controlling muscle activity by the nerve endings of different types of enteric neu-
along the length of the gut. When this plexus is stimu- rons. Two of them with which we are already familiar
lated, its principal effects are (1) increased tonic contrac- are (1) acetylcholine and (2) norepinephrine. Others are
tion, or “tone,” of the gut wall; (2) increased intensity of (3) adenosine triphosphate, (4) serotonin, (5) dopamine,
the rhythmical contractions; (3) slightly increased rate of (6) cholecystokinin, (7) substance P, (8) vasoactive intes-
the rhythm of contraction; and (4) increased velocity of tinal polypeptide, (9) somatostatin, (10) leu-enkephalin,
conduction of excitatory waves along the gut wall, causing (11) met-enkephalin, and (12) bombesin. The specific
more rapid movement of the gut peristaltic waves. functions of many of these are not known well enough
The myenteric plexus should not be considered entirely to justify discussion here, other than to point out the
excitatory because some of its neurons are inhibitory; their following.
fiber endings secrete an inhibitory transmitter, possibly Acetylcholine most often excites gastrointestinal activ-
vasoactive intestinal polypeptide or some other inhibi- ity. Norepinephrine almost always inhibits gastrointestinal
tory peptide. The resulting inhibitory signals are espe- activity. This is also true of epinephrine, which reaches the
cially useful for inhibiting some of the intestinal sphincter gastrointestinal tract mainly by way of the blood after it is
muscles that impede movement of food along successive secreted by the adrenal medullae into the circulation. The
segments of the gastrointestinal tract, such as the pyloric other aforementioned transmitter substances are a mix-
sphincter, which controls emptying of the stomach into ture of excitatory and inhibitory agents, some of which we
the duodenum, and the sphincter of the ileocecal valve, discuss in the following chapter.
which controls emptying from the small intestine into the
cecum. Autonomic Control of the Gastrointestinal Tract
The submucosal plexus, in contrast to the myenteric Parasympathetic Stimulation Increases Activity of
plexus, is mainly concerned with controlling function the Enteric Nervous System.  The parasympathetic sup-
within the inner wall of each minute segment of the intes- ply to the gut is divided into cranial and sacral divisions,
tine. For instance, many sensory signals originate from which were discussed in Chapter 60.
the gastrointestinal epithelium and are then integrated Except for a few parasympathetic fibers to the mouth
in the submucosal plexus to help control local intestinal and pharyngeal regions of the alimentary tract, the ­cranial
secretion, local absorption, and local contraction of the parasympathetic nerve fibers are almost entirely in the

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 Chapter 62  General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

vagus nerves. These fibers provide extensive innervation c­ onditions, inhibition of intestinal movements or intes-
to the esophagus, stomach, and pancreas and somewhat tinal secretion.
less to the intestines down through the first half of the In addition, other sensory signals from the gut go all
large intestine. the way to multiple areas of the spinal cord and even the

U n i t X II
The sacral parasympathetics originate in the second, brain stem. For example, 80 percent of the nerve fibers in
third, and fourth sacral segments of the spinal cord and the vagus nerves are afferent rather than efferent. These
pass through the pelvic nerves to the distal half of the large afferent fibers transmit sensory signals from the gastroin-
intestine and all the way to the anus. The sigmoidal, rec- testinal tract into the brain medulla, which in turn initi-
tal, and anal regions are considerably better supplied with ates vagal reflex signals that return to the gastrointestinal
parasympathetic fibers than are the other intestinal areas. tract to control many of its functions.
These fibers function especially to execute the defecation
reflexes, discussed in Chapter 63. Gastrointestinal Reflexes
The postganglionic neurons of the gastrointestinal The anatomical arrangement of the enteric nervous
parasympathetic system are located mainly in the myen- system and its connections with the sympathetic and
teric and submucosal plexuses. Stimulation of these para- parasympathetic systems support three types of gastroin-
sympathetic nerves causes general increase in activity of testinal reflexes that are essential to gastrointestinal con-
the entire enteric nervous system. This in turn enhances trol. They are the following:
activity of most gastrointestinal functions.
Sympathetic Stimulation Usually Inhibits Gastro­ 1. Reflexes that are integrated entirely within the gut wall
intestinal Tract Activity.  The sympathetic fibers to the enteric nervous system. These include reflexes that con-
gastrointestinal tract originate in the spinal cord between trol much gastrointestinal secretion, peristalsis, mixing
segments T5 and L2. Most of the preganglionic fibers that contractions, local inhibitory effects, and so forth.
innervate the gut, after leaving the cord, enter the sympa- 2. Reflexes from the gut to the prevertebral sympathetic
thetic chains that lie lateral to the spinal column, and many ganglia and then back to the gastrointestinal tract.
of these fibers then pass on through the chains to outlying These reflexes transmit signals long distances to other
ganglia such as to the celiac ganglion and various mesen- areas of the gastrointestinal tract, such as signals from
teric ganglia. Most of the postganglionic sympathetic neu- the stomach to cause evacuation of the colon (the gas-
ron bodies are in these ganglia, and postganglionic fibers trocolic reflex), signals from the colon and small intes-
then spread through postganglionic sympathetic nerves tine to inhibit stomach motility and stomach secretion
to all parts of the gut. The sympathetics innervate essen- (the enterogastric reflexes), and reflexes from the colon
tially all of the gastrointestinal tract, rather than being to inhibit emptying of ileal contents into the colon
more extensive nearest the oral cavity and anus, as is true (the colonoileal reflex).
of the parasympathetics. The sympathetic nerve endings 3. Reflexes from the gut to the spinal cord or brain stem and
secrete mainly norepinephrine but also small amounts of then back to the gastrointestinal tract. These include
epinephrine. especially (1) reflexes from the stomach and duode-
In general, stimulation of the sympathetic nervous sys- num to the brain stem and back to the stomach—by
tem inhibits activity of the gastrointestinal tract, causing way of the vagus nerves—to control gastric motor and
many effects opposite to those of the parasympathetic sys- secretory activity; (2) pain reflexes that cause general
tem. It exerts its effects in two ways: (1) to a slight extent inhibition of the entire gastrointestinal tract; and (3)
by direct effect of secreted norepinephrine to inhibit defecation reflexes that travel from the colon and rec-
intestinal tract smooth muscle (except the mucosal mus- tum to the spinal cord and back again to produce the
cle, which it excites) and (2) to a major extent by an inhib- powerful colonic, rectal, and abdominal contractions
itory effect of norepinephrine on the neurons of the entire required for defecation (the defecation reflexes).
enteric nervous system.
Strong stimulation of the sympathetic system can
inhibit motor movements of the gut so greatly that this Hormonal Control of Gastrointestinal Motility
can literally block movement of food through the gastro- The gastrointestinal hormones are released into the portal
intestinal tract. circulation and exert physiological actions on target cells
with specific receptors for the hormone. The effects of
Afferent Sensory Nerve Fibers from the Gut the hormones persist even after all nervous connections
Many afferent sensory nerve fibers innervate the gut. between the site of release and the site of action have been
Some of them have their cell bodies in the enteric ner- severed. Table 62-1 outlines the actions of each gastroin-
vous system itself and some in the dorsal root ganglia testinal hormone, as well as the stimuli for secretion and
of the spinal cord. These sensory nerves can be stimu- sites at which secretion takes place.
lated by (1) irritation of the gut mucosa, (2) excessive In Chapter 64, we discuss the extreme importance of
distention of the gut, or (3) presence of specific chemi- several hormones for controlling gastrointestinal secre-
cal substances in the gut. Signals transmitted through tion. Most of these same hormones also affect motility
the fibers can then cause excitation or, under other in some parts of the gastrointestinal tract. Although the

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Unit XII  Gastrointestinal Physiology

Table 62-1  Gastrointestinal Hormone Actions, Stimuli for Secretion, and Site of Secretion

Hormone Stimuli for Secretion Site of Secretion Actions

Gastrin Protein G cells of the antrum, duodenum, Stimulates

Distention and jejunum   Gastric acid secretion
Nerve   Mucosal growth
(Acid inhibits release)

Cholecystokinin Protein I cells of the duodenum, jejunum, Stimulates

Fat and ileum   Pancreatic enzyme secretion
Acid   Pancreatic bicarbonate secretion
  Gallbladder contraction
  Growth of exocrine pancreas
Inhibits
  Gastric emptying
Secretin Acid S cells of the duodenum, jejunum, Stimulates
Fat and ileum   Pepsin secretion
  Pancreatic bicarbonate secretion
  Biliary bicarbonate secretion
  Growth of exocrine pancreas
Inhibits
  Gastric acid secretion
Gastric inhibitory peptide Protein K cells of the duodenum Stimulates
Fat and jejunum   Insulin release
Carbohydrate Inhibits
  Gastric acid secretion
Motilin Fat M cells of the duodenum Stimulates
Acid and jejunum   Gastric motility
Nerve   Intestinal motility

motility effects are usually less important than the secre- to inhibit feeding centers in the brain as discussed in
tory effects of the hormones, some of the more important Chapter 71.
of them are the following. Secretin was the first gastrointestinal hormone dis-
Gastrin is secreted by the “G” cells of the antrum of the covered and is secreted by the “S” cells in the mucosa of
stomach in response to stimuli associated with ingestion the duodenum in response to acidic gastric juice empty-
of a meal, such as distention of the stomach, the products ing into the duodenum from the pylorus of the stomach.
of proteins, and gastrin releasing peptide, which is released Secretin has a mild effect on motility of the gastrointes-
by the nerves of the gastric mucosa during vagal stimula- tinal tract and acts to promote pancreatic secretion of
tion. The primary actions of gastrin are (1) stimulation of bicarbonate, which in turn helps to neutralize the acid in
gastric acid secretion and (2) stimulation of growth of the the small intestine.
gastric mucosa. Gastric inhibitory peptide (GIP) is secreted by the
Cholecystokinin (CCK) is secreted by “I” cells in mucosa of the upper small intestine, mainly in response
the mucosa of the duodenum and jejunum mainly in to fatty acids and amino acids but to a lesser extent in
response to digestive products of fat, fatty acids, and response to carbohydrate. It has a mild effect in decreas-
monoglycerides in the intestinal contents. This hor- ing motor activity of the stomach and therefore slows
mone strongly contracts the gallbladder, expelling bile emptying of gastric contents into the duodenum when
into the small intestine, where the bile in turn plays the upper small intestine is already overloaded with food
important roles in emulsifying fatty substances, and products. GIP, at blood levels even lower than those
allowing them to be digested and absorbed. CCK also needed to inhibit gastric motility, also stimulates insulin
inhibits stomach contraction moderately. Therefore, at secretion and for this reason is also known as glucose-
the same time that this hormone causes emptying of the dependent insulinotropic peptide.
gallbladder, it also slows the emptying of food from the Motilin is secreted by the stomach and upper duode-
stomach to give adequate time for digestion of the fats num during fasting, and the only known function of this
in the upper intestinal tract. CCK also inhibits appe- hormone is to increase gastrointestinal motility. Motilin
tite to prevent overeating during meals by stimulating is released cyclically and stimulates waves of gastrointes-
sensory afferent nerve fibers in the duodenum; these tinal motility called interdigestive myoelectric complexes
fibers, in turn, send signals by way of the vagus nerve that move through the stomach and small intestine every

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 Chapter 62  General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

90 minutes in a fasted person. Motilin secretion is inhib- c­ ompletely blocked in the entire gut when a person is
ited after ingestion by mechanisms that are not fully treated with atropine to paralyze the cholinergic nerve
understood. endings of the myenteric plexus. Therefore, effectual peri-
stalsis requires an active myenteric plexus.

U n i t X II
Functional Types of Movements Directional Movement of Peristaltic Waves Toward
in the Gastrointestinal Tract the Anus.  Peristalsis, theoretically, can occur in either
direction from a stimulated point, but it normally dies out
Two types of movements occur in the gastrointesti- rapidly in the orad (toward the mouth) direction while
nal tract: (1) propulsive movements, which cause food continuing for a considerable distance toward the anus.
to move forward along the tract at an appropriate rate The exact cause of this directional transmission of peri-
to accommodate digestion and absorption, and (2) mix- stalsis has never been ascertained, although it probably
ing movements, which keep the intestinal contents thor- results mainly from the fact that the myenteric plexus
oughly mixed at all times. itself is “polarized” in the anal direction, which can be
explained as follows.
Propulsive Movements—Peristalsis Peristaltic Reflex and the “Law of the Gut”.  When
The basic propulsive movement of the gastrointesti- a segment of the intestinal tract is excited by distention
nal tract is peristalsis, which is illustrated in Figure 62-5. and thereby initiates peristalsis, the contractile ring caus-
A contractile ring appears around the gut and then moves ing the peristalsis normally begins on the orad side of the
forward; this is analogous to putting one’s fingers around distended segment and moves toward the distended seg-
a thin distended tube, then constricting the fingers and ment, pushing the intestinal contents in the anal direction
sliding them forward along the tube. Any material in front for 5 to 10 centimeters before dying out. At the same time,
of the contractile ring is moved forward. the gut sometimes relaxes several centimeters down-
Peristalsis is an inherent property of many syncytial stream toward the anus, which is called “receptive relax-
smooth muscle tubes; stimulation at any point in the ation,” thus allowing the food to be propelled more easily
gut can cause a contractile ring to appear in the circu- toward the anus than toward the mouth.
lar muscle, and this ring then spreads along the gut tube. This complex pattern does not occur in the absence of
(Peristalsis also occurs in the bile ducts, glandular ducts, the myenteric plexus. Therefore, the complex is called the
ureters, and many other smooth muscle tubes of the myenteric reflex or the peristaltic reflex. The peristaltic
body.) reflex plus the anal direction of movement of the peristal-
The usual stimulus for intestinal peristalsis is disten- sis is called the “law of the gut.”
tion of the gut. That is, if a large amount of food collects at
any point in the gut, the stretching of the gut wall stimu- Mixing Movements
lates the enteric nervous system to contract the gut wall 2 Mixing movements differ in different parts of the ali-
to 3 centimeters behind this point, and a contractile ring mentary tract. In some areas, the peristaltic contrac-
appears that initiates a peristaltic movement. Other stim- tions themselves cause most of the mixing. This is
uli that can initiate peristalsis include chemical or physi- especially true when forward progression of the intes-
cal irritation of the epithelial lining in the gut. Also, strong tinal contents is blocked by a sphincter so that a peri-
parasympathetic nervous signals to the gut will elicit staltic wave can then only churn the intestinal contents,
strong peristalsis. rather than propelling them forward. At other times,
local intermittent constrictive contractions occur every
Function of the Myenteric Plexus in Peristalsis.  few centimeters in the gut wall. These constrictions
Peristalsis occurs only weakly or not at all in any portion usually last only 5 to 30 seconds; then new constrictions
of the gastrointestinal tract that has congenital absence occur at other points in the gut, thus “chopping” and
of the myenteric plexus. Also, it is greatly depressed or “shearing” the contents first here and then there. These
peristaltic and constrictive movements are modified in
different parts of the gastrointestinal tract for proper
Peristaltic contraction
propulsion and mixing, as discussed for each portion of
Leading wave of distention
the tract in Chapter 63.

Zero time Gastrointestinal Blood Flow—“Splanchnic

Circulation”

The blood vessels of the gastrointestinal system are part

5 seconds later of a more extensive system called the splanchnic circu-
Figure 62-5  Peristalsis. lation, shown in Figure 62-6. It includes the blood flow

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Unit XII  Gastrointestinal Physiology

Vena cava ­ illions of minute liver sinusoids and finally leaves the
m
liver by way of hepatic veins that empty into the vena cava
Hepatic artery
Hepatic Hepatic vein of the general circulation. This flow of blood through the
sinuses liver, before it empties into the vena cava, allows the retic-
uloendothelial cells that line the liver sinusoids to remove
Aorta
bacteria and other particulate matter that might enter
the blood from the gastrointestinal tract, thus prevent-
ing direct transport of potentially harmful agents into the
remainder of the body.
The nonfat, water-soluble nutrients absorbed from the
gut (such as carbohydrates and proteins) are transported
Splenic in the portal venous blood to the same liver sinusoids.
vein
Portal
Here, both the reticuloendothelial cells and the principal
vein parenchymal cells of the liver, the hepatic cells, absorb
and store temporarily from one half to three quarters of
the nutrients. Also, much chemical intermediary pro-
cessing of these nutrients occurs in the liver cells. We dis-
Intestinal vein Intestinal artery cuss these nutritional functions of the liver in Chapters
67 through 71. Almost all of the fats absorbed from the
intestinal tract are not carried in the portal blood but
instead are absorbed into the intestinal lymphatics and
Capillary then conducted to the systemic circulating blood by way
Figure 62-6  Splanchnic circulation. of the thoracic duct, bypassing the liver.

through the gut itself plus blood flows through the spleen,
pancreas, and liver. The design of this system is such that Anatomy of the Gastrointestinal Blood Supply
all the blood that courses through the gut, spleen, and Figure 62-7 shows the general plan of the arterial blood
pancreas then flows immediately into the liver by way supply to the gut, including the superior mesenteric and
of the portal vein. In the liver, the blood passes through inferior mesenteric arteries supplying the walls of the

Aorta

Transverse
colon

Branch of
Middle colic inferior
mesenteric
Ascending
colon
Superior
Right colic mesenteric
Descending
colon
Ileocolic
Jejunum

Jejunal

Ileal

Ileum
Figure 62-7  Arterial blood supply to the intestines through the mesenteric web.

760
 Chapter 62  General Principles of Gastrointestinal Function—Motility, Nervous Control, and Blood Circulation

small and large intestines by way of an arching arterial flow in the villi and adjacent regions of the submucosa
system. Not shown in the figure is the celiac artery, which is increased as much as eightfold. Likewise, blood flow
provides a similar blood supply to the stomach. in the muscle layers of the intestinal wall increases with
On entering the wall of the gut, the arteries branch and increased motor activity in the gut. For instance, after a

U n i t X II
send smaller arteries circling in both directions around meal, the motor activity, secretory activity, and absorp-
the gut, with the tips of these arteries meeting on the side tive activity all increase; likewise, the blood flow increases
of the gut wall opposite the mesenteric attachment. From greatly but then decreases back to the resting level over
the circling arteries, still much smaller arteries penetrate another 2 to 4 hours.
into the intestinal wall and spread (1) along the muscle
bundles, (2) into the intestinal villi, and (3) into submu- Possible Causes of the Increased Blood Flow
cosal vessels beneath the epithelium to serve the secre- During Gastrointestinal Activity.  Although the pre-
tory and absorptive functions of the gut. cise causes of the increased blood flow during increased
Figure 62-8 shows the special organization of the gastrointestinal activity are still unclear, some facts are
blood flow through an intestinal villus, including a small known.
arteriole and venule that interconnect with a system of First, several vasodilator substances are released from
multiple looping capillaries. The walls of the arterioles the mucosa of the intestinal tract during the digestive
are highly muscular and are highly active in controlling process. Most of these are peptide hormones, including
villus blood flow. cholecystokinin, vasoactive intestinal peptide, gastrin, and
secretin. These same hormones control specific motor and
Effect of Gut Activity and Metabolic Factors secretory activities of the gut, as discussed in Chapters 63
on Gastrointestinal Blood Flow and 64.
Under normal conditions, the blood flow in each area of Second, some of the gastrointestinal glands also release
the gastrointestinal tract, as well as in each layer of the into the gut wall two kinins, kallidin and bradykinin, at
gut wall, is directly related to the level of local activity. the same time that they secrete other substances into the
For instance, during active absorption of nutrients, blood lumen. These kinins are powerful vasodilators that are
believed to cause much of the increased mucosal vasodi-
lation that occurs along with secretion.
Third, decreased oxygen concentration in the gut wall
can increase intestinal blood flow at least 50 to 100 per-
cent; therefore, the increased mucosal and gut wall meta-
bolic rate during gut activity probably lowers the oxygen
concentration enough to cause much of the vasodilation.
The decrease in oxygen can also lead to as much as a four-
Central lacteal fold increase of adenosine, a well-known vasodilator that
could be responsible for much of the increased flow.
Thus, the increased blood flow during increased
gastrointestinal activity is probably a combination of
Blood capillaries
many of the aforementioned factors plus still others yet
undiscovered.

“Countercurrent” Blood Flow in the Villi.  Note in

Figure 62-8 that the arterial flow into the villus and the
venous flow out of the villus are in directions opposite
to each other, and that the vessels lie in close appo-
sition to each other. Because of this vascular arrange-
ment, much of the blood oxygen diffuses out of the
Vein
arterioles directly into the adjacent venules without
ever being carried in the blood to the tips of the villi. As
much as 80 percent of the oxygen may take this short-
circuit route and therefore not be available for local
metabolic functions of the villi. The reader will recog-
nize that this type of countercurrent mechanism in the
Artery
villi is analogous to the countercurrent mechanism in
the vasa recta of the kidney medulla, discussed in detail
in Chapter 28.
Under normal conditions, this shunting of oxygen
Figure 62-8  Microvasculature of the villus, showing a countercur- from the arterioles to the venules is not harmful to the
rent arrangement of blood flow in the arterioles and venules. villi, but in disease conditions in which blood flow to

761
Unit XII  Gastrointestinal Physiology

the gut becomes greatly curtailed, such as in circulatory Bibliography

shock, the oxygen deficit in the tips of the villi can become
Adelson DW, Million M: Tracking the moveable feast: sonomicrometry and
so great that the villus tip or even the whole villus suffers gastrointestinal motility, News Physiol Sci 19:27, 2004.
ischemic death and can disintegrate. Therefore, for this Daniel EE: Physiology and pathophysiology of the interstitial cell of Cajal:
reason and others, in many gastrointestinal diseases the from bench to bedside. III. Interaction of interstitial cells of Cajal with
villi become seriously blunted, leading to greatly dimin- neuromediators: an interim assessment, Am J Physiol Gastrointest Liver
Physiol 281:G1329, 2001.
ished intestinal absorptive capacity.
Grundy D, Al-Chaer ED, Aziz Q, et al: Fundamentals of neurogastroenterol-
ogy: basic science, Gastroenterology 130:1391, 2006.
Nervous Control of Gastrointestinal Blood Flow Hobson AR, Aziz Q: Central nervous system processing of human visceral
pain in health and disease, News Physiol Sci 18:109, 2003.
Stimulation of the parasympathetic nerves going to the Holst JJ: The physiology of glucagon-like peptide 1, Physiol Rev 87:1409,
stomach and lower colon increases local blood flow at 2009.
the same time that it increases glandular secretion. This Huizinga JD: Physiology and pathophysiology of the interstitial cell of Cajal:
increased flow probably results secondarily from the from bench to bedside. II. Gastric motility: lessons from mutant mice
on slow waves and innervation, Am J Physiol Gastrointest Liver Physiol
increased glandular activity and not as a direct effect of
281:G1129, 2001.
the nervous stimulation. Huizinga JD, Lammers WJ: Gut peristalsis is governed by a multitude of
Sympathetic stimulation, by contrast, has a direct effect cooperating mechanisms, Am J Physiol Gastrointest Liver Physiol 296:G1,
on essentially all the gastrointestinal tract to cause intense 2009.
vasoconstriction of the arterioles with greatly decreased Jeays AD, Lawford PV, Gillott R, et al: A framework for the modeling of
gut blood flow regulation and postprandial hyperaemia, World J
blood flow. After a few minutes of this vasoconstric-
Gastroenterol 13:1393, 2007.
tion, the flow often returns to near normal by means of Johnson LR: Gastrointestinal Physiology, ed 3, St. Louis, 2001, Mosby.
a mechanism called “autoregulatory escape.” That is, the Kim W, Egan JM: The role of incretins in glucose homeostasis and diabetes
local metabolic vasodilator mechanisms that are elicited treatment, Pharmacol Rev 60:470, 2009.
by ischemia override the sympathetic vasoconstriction, Kolkman JJ, Bargeman M, Huisman AB, Geelkerken RH: Diagnosis and
management of splanchnic ischemia, World J Gastroenterol 14:7309,
returning toward normal the necessary nutrient blood
2008.
flow to the gastrointestinal glands and muscle. Lammers WJ, Slack JR: Of slow waves and spike patches, News Physiol Sci
16:138, 2001.
Importance of Nervous Depression of Gastro­ Moran TH, Dailey MJ: Minireview: Gut peptides: targets for antiobesity drug
development? Endocrinology 150:2526, 2009.
intestinal Blood Flow When Other Parts of the Body Nauck MA: Unraveling the science of incretin biology, Am J Med 122(Suppl
Need Extra Blood Flow.  A major value of sympathetic 6):S3, 2009.
vasoconstriction in the gut is that it allows shutoff of gas- Powley TL, Phillips RJ: Musings on the wanderer: what’s new in our under-
trointestinal and other splanchnic blood flow for short standing of vago-vagal reflexes? I. Morphology and topography of vagal
periods of time during heavy exercise, when the skeletal afferents innervating the GI tract, Am J Physiol Gastrointest Liver Physiol
283:G1217, 2002.
muscle and heart need increased flow. Also, in circulatory
Phillips RJ, Powley TL: Innervation of the gastrointestinal tract: patterns of
shock, when all the body’s vital tissues are in danger of aging, Auton Neurosci 136:1, 2007.
cellular death for lack of blood flow—especially the brain Sanders KM, Ordog T, Ward SM: Physiology and pathophysiology of the
and the heart—sympathetic stimulation can decrease interstitial cells of Cajal: from bench to bedside. IV. Genetic and
splanchnic blood flow to very little for many hours. animal models of GI motility disorders caused by loss of intersti-
tial cells of Cajal, Am J Physiol Gastrointest Liver Physiol 282:G747,
Sympathetic stimulation also causes strong vasocon-
2002.
striction of the large-volume intestinal and mesenteric Schubert ML, Peura DA: Control of gastric acid secretion in health and dis-
veins. This decreases the volume of these veins, thereby dis- ease, Gastroenterology 134:1842, 2008.
placing large amounts of blood into other parts of the cir- Vanden Berghe P, Tack J, Boesmans W: Highlighting synaptic commu-
culation. In hemorrhagic shock or other states of low blood nication in the enteric nervous system, Gastroenterology 135:20,
2008.
volume, this mechanism can provide as much as 200 to 400
milliliters of extra blood to sustain the general circulation.

762
 chapter 64

Unit XiI
Secretory Functions of the Alimentary Tract

Throughout the gastro- liver—that provide secretions for digestion or emulsification

intestinal tract, secretory of food. The liver has a highly specialized structure that is
glands subserve two pri- discussed in Chapter 70. The salivary glands and the pan-
mary functions: First, diges- creas are compound acinous glands of the type shown in
Figure 64-2. These glands lie outside the walls of the alimen-
tive enzymes are secreted in
tary tract and, in this, differ from all other alimentary glands.
most areas of the alimentary
They contain millions of acini lined with secreting glandular
tract, from the mouth to the cells; these acini feed into a system of ducts that finally empty
distal end of the ileum. Second, mucous glands, from the into the alimentary tract itself.
mouth to the anus, provide mucus for lubrication and
protection of all parts of the alimentary tract.
Basic Mechanisms of Stimulation
Most digestive secretions are formed only in response
of the Alimentary Tract Glands
to the presence of food in the alimentary tract, and the
quantity secreted in each segment of the tract is usu- Contact of Food with the Epithelium Stimulates
ally the precise amount needed for proper digestion. Secretion—Function of Enteric Nervous Stimuli. 
Furthermore, in some portions of the gastrointestinal The mechanical presence of food in a particular segment
tract, even the types of enzymes and other constituents of of the gastrointestinal tract usually causes the glands of
the secretions are varied in accordance with the types of that region and adjacent regions to secrete moderate to
food present. The purpose of this chapter is to describe large quantities of juices. Part of this local effect, espe-
the different alimentary secretions, their functions, and cially the secretion of mucus by mucous cells, results from
regulation of their production. direct contact stimulation of the surface glandular cells by
the food.
In addition, local epithelial stimulation also activates
General Principles of Alimentary Tract Secretion the enteric nervous system of the gut wall. The types of
stimuli that do this are (1) tactile stimulation, (2) chemical
Anatomical Types of Glands irritation, and (3) distention of the gut wall. The resulting
Several types of glands provide the different types of alimen- nervous reflexes stimulate both the mucous cells on the
tary tract secretions. First, on the surface of the epithelium in gut epithelial surface and the deep glands in the gut wall
most parts of the gastrointestinal tract are billions of single- to increase their secretion.
cell mucous glands called simply mucous cells or sometimes
goblet cells because they look like goblets. They function
Autonomic Stimulation of Secretion
mainly in response to local irritation of the epithelium: They
extrude mucus directly onto the epithelial surface to act as Parasympathetic Stimulation Increases Alimentary
a lubricant that also protects the surfaces from excoriation Tract Glandular Secretion Rate.  Stimulation of the
and digestion. parasympathetic nerves to the alimentary tract almost
Second, many surface areas of the gastrointestinal tract invariably increases the rates of alimentary glandular
are lined by pits that represent invaginations of the epithe- secretion. This is especially true of the glands in the
lium into the submucosa. In the small intestine, these pits, upper portion of the tract (innervated by the glossopha-
called crypts of Lieberkühn, are deep and contain specialized
ryngeal and vagus parasympathetic nerves) such as the
secretory cells. One of these cells is shown in Figure 64-1.
Third, in the stomach and upper duodenum are large
salivary glands, esophageal glands, gastric glands, pan-
numbers of deep tubular glands. A typical tubular gland can creas, and Brunner’s glands in the duodenum. It is also
be seen in Figure 64-4, which shows an acid- and pepsino- true of some glands in the distal portion of the large
gen-secreting gland of the stomach (oxyntic gland). intestine, innervated by pelvic parasympathetic nerves.
Fourth, also associated with the alimentary tract are sev- Secretion in the remainder of the small intestine and in
eral complex glands—the salivary glands, pancreas, and the first two thirds of the large intestine occurs mainly

773
Unit XII  Gastrointestinal Physiology

Nerve Endoplasmic Golgi the gastrointestinal mucosa in response to the presence

Capillary fiber reticulum apparatus of food in the lumen of the gut. The hormones are then
absorbed into the blood and carried to the glands, where
Secretion
they stimulate secretion. This type of stimulation is par-
ticularly valuable to increase the output of gastric juice
and pancreatic juice when food enters the stomach or
duodenum.
Chemically, the gastrointestinal hormones are poly-
peptides or polypeptide derivatives.

Basic Mechanism of Secretion by Glandular Cells

Secretion of Organic Substances.  Although all the
Basement Mitochondria Ribosomes Zymogen basic mechanisms by which glandular cells function are
membrane granules not known, experimental evidence points to the following
Figure 64-1  Typical function of a glandular cell for formation and principles of secretion, as shown in Figure 64-1.
secretion of enzymes and other secretory substances.
1. The nutrient material needed for formation of the
secretion must first diffuse or be actively transported
by the blood in the capillaries into the base of the glan-
Primary secretion:
1. Ptyalin dular cell.
2. Mucus 2. Many mitochondria located inside the glandular cell
3. Extracellular fluid
near its base use oxidative energy to form adenosine
triphosphate (ATP).
3. Energy from the ATP, along with appropriate substrates
provided by the nutrients, is then used to synthesize
Na+ active absorption
Cl− passive absorption
the organic secretory substances; this synthesis occurs
K+ active secretion almost entirely in the endoplasmic reticulum and Golgi
HCO3− secretion complex of the glandular cell. Ribosomes adherent to
the reticulum are specifically responsible for formation
of the proteins that are secreted.
4. The secretory materials are transported through the
tubules of the endoplasmic reticulum, passing in about
Saliva
20 minutes all the way to the vesicles of the Golgi
Figure 64-2  Formation and secretion of saliva by a submandibu- complex.
lar salivary gland.
5. In the Golgi complex, the materials are modified, added
to, concentrated, and discharged into the cytoplasm in
in response to local neural and hormonal stimuli in each
the form of secretory vesicles, which are stored in the
segment of the gut.
apical ends of the secretory cells.
Sympathetic Stimulation Has a Dual Effect on
Alimentary Tract Glandular Secretion Rate.  Stimulation 6. These vesicles remain stored until nervous or hor-
of the sympathetic nerves going to the gastrointestinal monal control signals cause the cells to extrude the
tract causes a slight to moderate increase in secretion vesicular contents through the cells’ surface. This prob-
by some of the local glands. But sympathetic stimulation ably occurs in the following way: The control signal
also results in constriction of the blood vessels that sup- first increases the cell membrane permeability to cal-
ply the glands. Therefore, sympathetic stimulation can cium ions, and calcium enters the cell. The calcium in
have a dual effect: (1) sympathetic stimulation alone usu- turn causes many of the vesicles to fuse with the apical
ally slightly increases secretion and (2) if parasympathetic cell membrane. Then the apical cell membrane breaks
or hormonal stimulation is already causing copious secre- open, thus emptying the vesicles to the exterior; this
tion by the glands, superimposed sympathetic stimulation process is called exocytosis.
usually reduces the secretion, sometimes significantly so,
mainly because of vasoconstrictive reduction of the blood Water and Electrolyte Secretion.  A second neces-
supply. sity for glandular secretion is secretion of sufficient water
Regulation of Glandular Secretion by Hormones.  In and electrolytes to go along with the organic substances.
the stomach and intestine, several different gastrointes- Secretion by the salivary glands, discussed in more detail
tinal hormones help regulate the volume and character later, provides an example of how nervous stimulation
of the secretions. These hormones are liberated from causes water and salts to pass through the glandular

774
 Chapter 64  Secretory Functions of the Alimentary Tract

cells in great profusion, washing the organic substances Table 64-1  Daily Secretion of Intestinal Juices
through the secretory border of the cells at the same time.
Hormones acting on the cell membrane of some glandu- Daily Volume (ml) pH
lar cells are believed also to cause secretory effects similar

U n i t X II
to those caused by nervous stimulation. Saliva 1000 6.0-7.0
Gastric secretion 1500 1.0-3.5
Lubricating and Protective Properties of Mucus, and Pancreatic secretion 1000 8.0-8.3
Importance of Mucus in the Gastrointestinal Tract
Mucus is a thick secretion composed mainly of water, elec- Bile 1000 7.8
trolytes, and a mixture of several glycoproteins, which them- Small intestine secretion 1800 7.5-8.0
selves are composed of large polysaccharides bound with
Brunner’s gland secretion 200 8.0-8.9
much smaller quantities of protein. Mucus is slightly differ-
ent in different parts of the gastrointestinal tract, but every- Large intestinal secretion 200 7.5-8.0
where it has several important characteristics that make Total 6700
it both an excellent lubricant and a protectant for the wall
of the gut. First, mucus has adherent qualities that make it
adhere tightly to the food or other particles and to spread as Secretion of Ions in Saliva.  Saliva contains espe-
a thin film over the surfaces. Second, it has sufficient body cially large quantities of potassium and bicarbonate ions.
that it coats the wall of the gut and prevents actual contact Conversely, the concentrations of both sodium and chlo-
of most food particles with the mucosa. Third, mucus has a ride ions are several times less in saliva than in plasma.
low resistance for slippage, so the particles can slide along One can understand these special concentrations of ions
the epithelium with great ease. Fourth, mucus causes fecal in the saliva from the following description of the mecha-
particles to adhere to one another to form the feces that are
nism for secretion of saliva.
expelled during a bowel movement. Fifth, mucus is strongly
Figure 64-2 shows secretion by the submandibular
resistant to digestion by the gastrointestinal enzymes. And
sixth, the glycoproteins of mucus have amphoteric proper- gland, a typical compound gland that contains acini and
ties, which means that they are capable of buffering small salivary ducts. Salivary secretion is a two-stage opera-
amounts of either acids or alkalies; also, mucus often con- tion: The first stage involves the acini, and the second,
tains moderate quantities of bicarbonate ions, which specifi- the salivary ducts. The acini secrete a primary secretion
cally neutralize acids. that contains ptyalin and/or mucin in a solution of ions in
In summary, mucus has the ability to allow easy slip- concentrations not greatly different from those of typical
page of food along the gastrointestinal tract and to prevent extracellular fluid. As the primary secretion flows through
excoriative or chemical damage to the epithelium. A person the ducts, two major active transport processes take place
becomes acutely aware of the lubricating qualities of mucus that markedly modify the ionic composition of the fluid
when the salivary glands fail to secrete saliva, because then it
in the saliva.
is difficult to swallow solid food even when it is eaten along
First, sodium ions are actively reabsorbed from all the
with large amounts of water.
salivary ducts and potassium ions are actively secreted in
exchange for the sodium. Therefore, the sodium ion concen-
tration of the saliva becomes greatly reduced, whereas the
Secretion of Saliva potassium ion concentration becomes increased. However,
there is excess sodium reabsorption over potassium secre-
Saliva Contains a Serous Secretion and a Mucus tion, and this creates electrical negativity of about −70 milli-
Secretion.  The principal glands of salivation are the volts in the salivary ducts; this in turn causes chloride ions to
parotid, submandibular, and sublingual glands; in addi- be reabsorbed passively. Therefore, the chloride ion concen-
tion, there are many tiny buccal glands. Daily secretion tration in the salivary fluid falls to a very low level, matching
of saliva normally ranges between 800 and 1500 millili- the ductal decrease in sodium ion concentration.
ters, as shown by the average value of 1000 milliliters in Second, bicarbonate ions are secreted by the ductal epi-
Table 64-1. thelium into the lumen of the duct. This is at least partly
Saliva contains two major types of protein secretion: caused by passive exchange of bicarbonate for chloride
(1) a serous secretion that contains ptyalin (an α-amylase), ions, but it may also result partly from an active secre-
which is an enzyme for digesting starches, and (2) mucus tory process.
secretion that contains mucin for lubricating and for sur- The net result of these transport processes is that under
face protective purposes. resting conditions, the concentrations of sodium and chlo-
The parotid glands secrete almost entirely the serous ride ions in the saliva are only about 15 mEq/L each, about
type of secretion, whereas the submandibular and sub- one-seventh to one-tenth their concentrations in plasma.
lingual glands secrete both serous secretion and mucus. Conversely, the concentration of potassium ions is about
The buccal glands secrete only mucus. Saliva has a pH 30 mEq/L, seven times as great as in plasma, and the con-
between 6.0 and 7.0, a favorable range for the digestive centration of bicarbonate ions is 50 to 70 mEq/L, about
action of ptyalin. two to three times that of plasma.

775
Unit XII  Gastrointestinal Physiology

During maximal salivation, the salivary ionic con- glands are controlled mainly by parasympathetic nervous
centrations change considerably because the rate of for- signals all the way from the superior and inferior saliva-
mation of primary secretion by the acini can increase as tory nuclei in the brain stem.
much as 20-fold. This acinar secretion then flows through The salivatory nuclei are located approximately at the
the ducts so rapidly that the ductal reconditioning of the juncture of the medulla and pons and are excited by both
secretion is considerably reduced. Therefore, when copi- taste and tactile stimuli from the tongue and other areas
ous quantities of saliva are being secreted, the sodium of the mouth and pharynx. Many taste stimuli, especially
chloride concentration is about one-half or two-thirds the sour taste (caused by acids), elicit copious secretion of
that of plasma, and the potassium concentration rises to saliva—often 8 to 20 times the basal rate of secretion. Also,
only four times that of plasma. certain tactile stimuli, such as the presence of smooth
objects in the mouth (e.g., a pebble), cause marked sal-
Function of Saliva for Oral Hygiene.  Under basal awake
ivation, whereas rough objects cause less salivation and
conditions, about 0.5 milliliter of saliva, almost entirely of
the mucous type, is secreted each minute; but during sleep, occasionally even inhibit salivation.
little secretion occurs. This secretion plays an exceedingly Salivation can also be stimulated or inhibited by ner-
important role for maintaining healthy oral tissues. The vous signals arriving in the salivatory nuclei from higher
mouth is loaded with pathogenic bacteria that can easily centers of the central nervous system. For instance, when
destroy tissues and cause dental caries. Saliva helps prevent a person smells or eats favorite foods, salivation is greater
the deteriorative processes in several ways. than when disliked food is smelled or eaten. The appetite
First, the flow of saliva itself helps wash away pathogenic area of the brain, which partially regulates these effects, is
bacteria, as well as food particles that provide their metabolic located in proximity to the parasympathetic centers of the
support. anterior hypothalamus, and it functions to a great extent
Second, saliva contains several factors that destroy bac-
in response to signals from the taste and smell areas of the
teria. One of these is thiocyanate ions and another is several
proteolytic enzymes—most important, lysozyme—that (a)
cerebral cortex or amygdala.
attack the bacteria, (b) aid the thiocyanate ions in entering Salivation also occurs in response to reflexes origi-
the bacteria where these ions in turn become bactericidal, nating in the stomach and upper small intestines—par-
and (c) digest food particles, thus helping further to remove ticularly when irritating foods are swallowed or when a
the bacterial metabolic support. person is nauseated because of some gastrointestinal
Third, saliva often contains significant amounts of protein abnormality. The saliva, when swallowed, helps to remove
antibodies that can destroy oral bacteria, including some that the irritating factor in the gastrointestinal tract by diluting
cause dental caries. In the absence of salivation, oral tissues or neutralizing the irritant substances.
often become ulcerated and otherwise infected, and caries of Sympathetic stimulation can also increase salivation a
the teeth can become rampant. slight amount, much less so than does parasympathetic
stimulation. The sympathetic nerves originate from the
Nervous Regulation of Salivary Secretion superior cervical ganglia and travel along the surfaces of
Figure 64-3 shows the parasympathetic nervous pathways the blood vessel walls to the salivary glands.
for regulating salivation, demonstrating that the salivary A secondary factor that also affects salivary secretion
is the blood supply to the glands because secretion always
requires adequate nutrients from the blood. The para-
Tractus Superior and inferior sympathetic nerve signals that induce copious salivation
solitarius salivatory nuclei
also moderately dilate the blood vessels. In addition, sali-
Submandibular gland vation itself directly dilates the blood vessels, thus provid-
Submandibular ing increased salivatory gland nutrition as needed by the
ganglion
secreting cells. Part of this additional vasodilator effect
is caused by kallikrein secreted by the activated salivary
Facial
nerve cells, which in turn acts as an enzyme to split one of the
blood proteins, an alpha2-globulin, to form bradykinin, a
Chorda strong vasodilator.
tympani Sublingual gland

Parotid
gland Esophageal Secretion
Otic ganglion Taste and
tactile stimuli The esophageal secretions are entirely mucous and mainly
Glossopharyngeal provide lubrication for swallowing. The main body of the
nerve esophagus is lined with many simple mucous glands. At the
Tongue gastric end and to a lesser extent in the initial portion of the
esophagus, there are also many compound mucous glands.
Figure 64-3  Parasympathetic nervous regulation of salivary The mucus secreted by the compound glands in the upper
secretion. esophagus prevents mucosal ­excoriation by newly entering
­

776
 Chapter 64  Secretory Functions of the Alimentary Tract

food, whereas the compound glands located near the 3 million times that of the arterial blood. To concentrate
esophagogastric junction protect the esophageal wall from the ­hydrogen ions this tremendous amount requires more
digestion by acidic gastric juices that often reflux from the than 1500 calories of energy per liter of gastric juice. At
stomach back into the lower esophagus. Despite this protec- the same time that hydrogen ions are secreted, bicarbon-

U n i t X II
tion, a peptic ulcer at times can still occur at the gastric end
ate ions diffuse into the blood so that gastric venous blood
of the esophagus.
has a higher pH than arterial blood when the stomach is
secreting acid.
Figure 64-5 shows schematically the functional struc-
Gastric Secretion ture of a parietal cell (also called oxyntic cell), demonstrat-
ing that it contains large branching intracellular canaliculi.
Characteristics of the Gastric Secretions
The hydrochloric acid is formed at the villus-like projec-
In addition to mucus-secreting cells that line the entire tions inside these canaliculi and is then conducted through
surface of the stomach, the stomach mucosa has two the canaliculi to the secretory end of the cell.
important types of tubular glands: oxyntic glands (also The main driving force for hydrochloric acid secretion
called gastric glands) and pyloric glands. The oxyntic by the parietal cells is a hydrogen-potassium pump (H+-K+
(acid-forming) glands secrete hydrochloric acid, pepsino- ATPase). The chemical mechanism of hydrochloric acid
gen, intrinsic factor, and mucus. The pyloric glands secrete formation is shown in Figure 64-6 and consists of the fol-
mainly mucus for protection of the pyloric mucosa from lowing steps:
the stomach acid. They also secrete the hormone gastrin.
The oxyntic glands are located on the inside surfaces 1. Water inside the parietal cell becomes dissociated
of the body and fundus of the stomach, constituting the into H+ and OH− in the cell cytoplasm. The H+ is then
proximal 80 percent of the stomach. The pyloric glands actively secreted into the canaliculus in exchange for
are located in the antral portion of the stomach, the distal K+, an active exchange process that is catalyzed by H+-
20 percent of the stomach. K+ ATPase. Potassium ions transported into the cell
by the Na+-K+ ATPase pump on the basolateral (extra-
Secretions from the Oxyntic (Gastric) Glands cellular) side of the membrane tend to leak into the
lumen but are recycled back into the cell by the H+-K+
A typical stomach oxyntic gland is shown in Figure 64-4. ATPase. The basolateral Na+-K+ ATPase creates low
It is composed of three types of cells: (1) mucous neck ­intracellular Na+, which contributes to Na+ reabsorp-
cells, which secrete mainly mucus; (2) peptic (or chief) tion from the lumen of the canaliculus. Thus, most of
cells, which secrete large quantities of pepsinogen; and the K+ and Na+ in the canaliculus is reabsorbed into the
(3) parietal (or oxyntic) cells, which secrete hydrochlo- cell cytoplasm, and hydrogen ions take their place in the
ric acid and intrinsic factor. Secretion of hydrochloric canaliculus.
acid by the parietal cells involves special mechanisms,
2. The pumping of H+ out of the cell by the H+-K+ ATPase
as follows.
permits OH− to accumulate and form HCO3− from CO2,
Basic Mechanism of Hydrochloric Acid Secretion. 
either formed during metabolism in the cell or ­entering
When stimulated, the parietal cells secrete an acid solu-
tion that contains about 160 mmol/L of hydrochloric acid,
which is nearly isotonic with the body fluids. The pH of
this acid is about 0.8, demonstrating its extreme acid-
ity. At this pH, the hydrogen ion concentration is about Mucous
neck cells

Surface
epithelium

Mucous neck
Oxyntic
cells
(parietal)
cell Secretion
Oxyntic
(or parietal)
cells Canaliculi

Peptic
(or chief)
cells

Figure 64-5  Schematic anatomy of the canaliculi in a parietal

Figure 64-4  Oxyntic gland from the body of the stomach. (oxyntic) cell.

777
Unit XII  Gastrointestinal Physiology

Extracellular fluid Parietal cell Lumen of canaliculus

CO2 CO2 H2O

H+ (155 mEq/L)

HCO 3- HCO 3- CO2 + OH- + H+

P
Cl- Cl-

K+ K+ K+ K+ (15 mEq/L)
P
Na+ Na+ Na+ Na+ (3 mEq/L)

Cl- Cl- Cl- Cl- (173 mEq/L)

(Osmosis)
H2O H2O

Figure 64-6  Postulated mechanism for secretion of hydrochloric acid. (The points labeled “P” indicate active pumps, and the dashed lines
represent free diffusion and osmosis.)

the cell from the blood. This reaction is catalyzed by peptic and mucous cells of the gastric glands. Even so, all
carbonic anhydrase. The HCO3− is then transported the pepsinogens perform the same functions.
across the basolateral membrane into the extracellular When pepsinogen is first secreted, it has no diges-
fluid in exchange for chloride ions, which enter the cell tive activity. However, as soon as it comes in contact with
and are secreted through chloride channels into the hydrochloric acid, it is activated to form active pepsin. In
canaliculus, giving a strong solution of hydrochloric this process, the pepsinogen molecule, having a molecu-
acid in the canaliculus. The hydrochloric acid is then lar weight of about 42,500, is split to form a pepsin mol-
secreted outward through the open end of the canali- ecule, having a molecular weight of about 35,000.
culus into the lumen of the gland. Pepsin functions as an active proteolytic enzyme
3. Water passes into the canaliculus by osmosis because in a highly acid medium (optimum pH 1.8 to 3.5), but
of extra ions secreted into the canaliculus. Thus, the above a pH of about 5 it has almost no proteolytic activ-
final secretion from the canaliculus contains water, ity and becomes completely inactivated in a short time.
hydrochloric acid at a concentration of about 150 to Hydrochloric acid is as necessary as pepsin for protein
160 mEq/L, potassium chloride at a concentration of digestion in the stomach, as discussed in Chapter 65.
15 mEq/L, and a small amount of sodium chloride. Secretion of Intrinsic Factor by Parietal Cells.  The sub-
stance intrinsic factor, essential for absorption of vitamin B12
To produce a concentration of hydrogen ions as great in the ileum, is secreted by the parietal cells along with the
as that found in gastric juice requires minimal back leak secretion of hydrochloric acid. When the acid-producing
into the mucosa of the secreted acid. A major part of parietal cells of the stomach are destroyed, which frequently
the stomach’s ability to prevent back leak of acid can be occurs in chronic gastritis, the person develops not only
attributed to the gastric barrier due to the formation of achlorhydria (lack of stomach acid secretion) but often also
alkaline mucus and to tight junctions between epithelia pernicious anemia because of failure of maturation of the red
cells as described later. If this barrier is damaged by toxic blood cells in the absence of vitamin B12 stimulation of the
substances, such as occurs with excessive use of aspi- bone marrow. This is discussed in detail in Chapter 32.
rin or alcohol, the secreted acid does leak down an elec-
trochemical gradient into the mucosa, causing stomach
mucosal damage. Pyloric Glands—Secretion of Mucus and Gastrin
Basic Factors That Stimulate Gastric Secretion Are The pyloric glands are structurally similar to the oxyntic
Acetylcholine, Gastrin, and Histamine.  Acetylcholine glands but contain few peptic cells and almost no parietal
released by parasympathetic stimulation excites secre- cells. Instead, they contain mostly mucous cells that are iden-
tion of pepsinogen by peptic cells, hydrochloric acid by tical with the mucous neck cells of the oxyntic glands. These
parietal cells, and mucus by mucous cells. In comparison, cells secrete a small amount of pepsinogen, as discussed ear-
both gastrin and histamine strongly stimulate secretion lier, and an especially large amount of thin mucus that helps
of acid by parietal cells but have little effect on the other to lubricate food movement, as well as to protect the stom-
cells. ach wall from digestion by the gastric enzymes. The pyloric
Secretion and Activation of Pepsinogen.  Several glands also secrete the hormone gastrin, which plays a key
slightly different types of pepsinogen are secreted by the role in controlling gastric secretion, as we discuss shortly.

778
 Chapter 64  Secretory Functions of the Alimentary Tract

Surface Mucous Cells on the gastrin cells in the pyloric glands to cause release
of gastrin into the blood to be transported to the ECL
The entire surface of the stomach mucosa between glands
cells of the stomach. The vigorous mixing of the gastric
has a continuous layer of a special type of mucous cells
juices transports the gastrin rapidly to the ECL cells in

U n i t X II
called simply “surface mucous cells.” They secrete large
the body of the stomach, causing release of histamine
quantities of viscid mucus that coats the stomach mucosa
directly into the deep oxyntic glands. The histamine
with a gel layer of mucus often more than 1 millimeter
then acts quickly to stimulate gastric hydrochloric acid
thick, thus providing a major shell of protection for the
secretion.
stomach wall, as well as contributing to lubrication of
food transport.
Another characteristic of this mucus is that it is alka- Regulation of Pepsinogen Secretion
line. Therefore, the normal underlying stomach wall Regulation of pepsinogen secretion by the peptic cells in
is not directly exposed to the highly acidic, proteolytic the oxyntic glands occurs in response to two main types
stomach secretion. Even the slightest contact with food or of signals: (1) stimulation of the peptic cells by acetylcho-
any irritation of the mucosa directly stimulates the surface line released from the vagus nerves or from the gastric
mucous cells to secrete additional quantities of this thick, enteric nervous plexus, and (2) stimulation of peptic cell
alkaline, viscid mucus. secretion in response to acid in the stomach. The acid
probably does not stimulate the peptic cells directly but
Stimulation of Gastric Acid Secretion instead elicits additional enteric nervous reflexes that
support the original nervous signals to the peptic cells.
Parietal Cells of the Oxyntic Glands Are the Only
Therefore, the rate of secretion of pepsinogen, the pre-
Cells That Secrete Hydrochloric Acid.  The parietal
cursor of the enzyme pepsin that causes protein diges-
cells, located deep in the oxyntic glands of the main body
tion, is strongly influenced by the amount of acid in the
of the stomach, are the only cells that secrete hydrochlo-
stomach. In people who have lost the ability to secrete
ric acid. As noted earlier in the chapter, the acidity of
normal amounts of acid, secretion of pepsinogen is also
the fluid secreted by these cells can be great, with pH as
decreased, even though the peptic cells may otherwise
low as 0.8. However, secretion of this acid is under con-
appear to be normal.
tinuous control by both endocrine and nervous signals.
Furthermore, the parietal cells operate in close associa-
tion with another type of cell called enterochromaffin- Phases of Gastric Secretion
Gastric secretion is said to occur in three “phases” (as shown
like cells (ECL cells), the primary function of which is to
in Figure 64-7): a cephalic phase, a gastric phase, and an
secrete histamine.
intestinal phase.
The ECL cells lie in the deep recesses of the oxyntic Cephalic Phase.  The cephalic phase of gastric secre-
glands and therefore release histamine in direct contact tion occurs even before food enters the stomach, espe-
with the parietal cells of the glands. The rate of formation cially while it is being eaten. It results from the sight, smell,
and secretion of hydrochloric acid by the parietal cells is thought, or taste of food, and the greater the appetite, the
directly related to the amount of histamine secreted by the more intense is the stimulation. Neurogenic signals that
ECL cells. In turn, the ECL cells are stimulated to secrete cause the cephalic phase of gastric secretion originate in the
histamine by the hormonal substance gastrin, which is cerebral cortex and in the appetite centers of the amygdala
formed almost entirely in the antral portion of the stom- and hypothalamus. They are transmitted through the dor-
ach mucosa in response to proteins in the foods being sal motor nuclei of the vagi and thence through the vagus
nerves to the stomach. This phase of secretion normally
digested. The ECL cells may also be stimulated by hor-
accounts for about 30 percent of the gastric secretion asso-
monal substances secreted by the enteric nervous system
ciated with eating a meal.
of the stomach wall. Let us discuss first the gastrin mech- Gastric Phase.  Once food enters the stomach, it excites
anism for control of the ECL cells and their subsequent (1) long vagovagal reflexes from the stomach to the brain and
control of parietal cell secretion of hydrochloric acid. back to the stomach, (2) local enteric reflexes, and (3) the
gastrin mechanism, all of which in turn cause secretion of
Stimulation of Acid Secretion by Gastrin.  Gastrin gastric juice during several hours while food remains in the
is itself a hormone secreted by gastrin cells, also called G stomach. The gastric phase of secretion accounts for about
cells. These cells are located in the pyloric glands in the 60 percent of the total gastric secretion associated with eat-
distal end of the stomach. Gastrin is a large polypeptide ing a meal and therefore accounts for most of the total daily
gastric secretion of about 1500 milliliters.
secreted in two forms: a large form called G-34, which
Intestinal Phase.  The presence of food in the upper
contains 34 amino acids, and a smaller form, G-17, which
portion of the small intestine, particularly in the duode-
contains 17 amino acids. Although both of these are num, will continue to cause stomach secretion of small
important, the smaller is more abundant. amounts of gastric juice, probably partly because of small
When meats or other protein-containing foods amounts of gastrin released by the duodenal mucosa. This
reach the antral end of the stomach, some of the pro- accounts for about 10 percent of the acid response to a
teins from these foods have a special stimulatory effect meal.

779
Unit XII  Gastrointestinal Physiology

Figure 64-7  Phases of gastric secretion and their

regulation. Vagal center
of medulla
Cephalic phase via vagus

Parasympathetics excite
pepsin and acid production
Food Secretory
fiber Gastric phase:
1. Local nervous
Afferent Vagus secretory reflexes
fibers trunk Local nerve
plexus 2. Vagal reflexes
3. Gastrin-histamine
stimulation

Circulatory system
Gastrin

Intestinal phase:
1. Nervous mechanisms
2. Hormonal mechanisms
Small bowel

Inhibition of Gastric Secretion by Other Post-Stomach Unfortunately, emotional stimuli frequently increase
Intestinal Factors interdigestive gastric secretion (highly peptic and acidic)
Although intestinal chyme slightly stimulates gastric secre- to 50 milliliters or more per hour, in much the same way
tion during the early intestinal phase of stomach secretion, that the cephalic phase of gastric secretion excites secre-
it paradoxically inhibits gastric secretion at other times. This tion at the onset of a meal. This increase of secretion in
inhibition results from at least two influences. response to emotional stimuli is believed to be one of the
causative factors in development of peptic ulcers, as dis-
1. The presence of food in the small intestine initiates a
cussed in Chapter 66.
reverse enterogastric reflex, transmitted through the
myenteric nervous system and extrinsic sympathetic
and vagus nerves, that inhibits stomach secretion. This Chemical Composition of Gastrin and Other
reflex can be initiated by distending the small bowel, by Gastrointestinal Hormones
the presence of acid in the upper intestine, by the pres- Gastrin, cholecystokinin (CCK), and secretin are all large
ence of protein breakdown products, or by irritation of polypeptides with approximate molecular weights,
the mucosa. This is part of the complex mechanism dis-
respectively, of 2000, 4200, and 3400. The terminal five
cussed in Chapter 63 for slowing stomach emptying when
amino acids in the gastrin and CCK molecular chains
the intestines are already filled.
are the same. The functional activity of gastrin resides in
2. The presence of acid, fat, protein breakdown products,
the terminal four amino acids, and the activity for CCK
hyperosmotic or hypo-osmotic fluids, or any irritating
resides in the terminal eight amino acids. All the amino
factor in the upper small intestine causes release of sev-
eral intestinal hormones. One of these is secretin, which acids in the secretin molecule are essential.
is especially important for control of pancreatic secre- A synthetic gastrin, composed of the terminal four
tion. However, secretin opposes stomach secretion. amino acids of natural gastrin plus the amino acid alanine,
Three other hormones—gastric inhibitory peptide (glu- has all the same physiologic properties as the natural gas-
cose-dependent insulinotropic peptide), vasoactive intes- trin. This synthetic product is called pentagastrin.
tinal polypeptide, and somatostatin—also have slight to
moderate effects in inhibiting gastric secretion.
The functional purpose of intestinal factors that inhibit Pancreatic Secretion
gastric secretion is presumably to slow passage of chyme
from the stomach when the small intestine is already filled The pancreas, which lies parallel to and beneath the
or already overactive. In fact, the enterogastric inhibi- stomach (illustrated in Figure 64-10), is a large compound
tory reflexes plus inhibitory hormones usually also reduce gland with most of its internal structure similar to that
stomach motility at the same time that they reduce gastric
of the salivary glands shown in Figure 64-2. The pancre-
secretion, as was discussed in Chapter 63.
atic digestive enzymes are secreted by pancreatic acini,
Gastric Secretion During the Interdigestive Period. The
stomach secretes a few milliliters of gastric juice each hour and large volumes of sodium bicarbonate solution are
during the “interdigestive period,” when little or no digestion secreted by the small ductules and larger ducts leading
is occurring anywhere in the gut. The secretion that does from the acini. The combined product of enzymes and
occur is usually almost entirely of the nonoxyntic type, com- sodium bicarbonate then flows through a long pancre-
posed mainly of mucus but little pepsin and almost no acid. atic duct that normally joins the hepatic duct immediately

780
 Chapter 64  Secretory Functions of the Alimentary Tract

before it empties into the duodenum through the papilla until after they have been secreted into the intestine
of Vater, surrounded by the sphincter of Oddi. because the trypsin and the other enzymes would digest
Pancreatic juice is secreted most abundantly in the pancreas itself. Fortunately, the same cells that secrete
response to the presence of chyme in the upper portions proteolytic enzymes into the acini of the pancreas secrete

U n i t X II
of the small intestine, and the characteristics of the pan- simultaneously another substance called trypsin inhibitor.
creatic juice are determined to some extent by the types This substance is formed in the cytoplasm of the glandu-
of food in the chyme. (The pancreas also secretes insu- lar cells, and it prevents activation of trypsin both inside
lin, but this is not secreted by the same pancreatic tissue the secretory cells and in the acini and ducts of the pan-
that secretes intestinal pancreatic juice. Instead, insulin is creas. And, because it is trypsin that activates the other
secreted directly into the blood—not into the intestine— pancreatic proteolytic enzymes, trypsin inhibitor pre-
by the islets of Langerhans that occur in islet patches vents activation of the others as well.
throughout the pancreas. These are discussed in detail in When the pancreas becomes severely damaged
Chapter 78.) or when a duct becomes blocked, large quantities of
pancreatic secretion sometimes become pooled in the
Pancreatic Digestive Enzymes damaged areas of the pancreas. Under these conditions,
Pancreatic secretion contains multiple enzymes for the effect of trypsin inhibitor is often overwhelmed, in
digesting all of the three major types of food: proteins, which case the pancreatic secretions rapidly become
carbohydrates, and fats. It also contains large quantities of activated and can literally digest the entire pancreas
bicarbonate ions, which play an important role in neutral- within a few hours, giving rise to the condition called
izing the acidity of the chyme emptied from the stomach acute pancreatitis. This is sometimes lethal because
into the duodenum. of accompanying circulatory shock; even if not lethal,
The most important of the pancreatic enzymes for it usually leads to a subsequent lifetime of pancreatic
digesting proteins are trypsin, chymotrypsin, and carboxy- insufficiency.
polypeptidase. By far the most abundant of these is trypsin.
Secretion of Bicarbonate Ions
Trypsin and chymotrypsin split whole and partially
digested proteins into peptides of various sizes but do not Although the enzymes of the pancreatic juice are secreted
cause release of individual amino acids. However, car- entirely by the acini of the pancreatic glands, the other
boxypolypeptidase splits some peptides into individual two important components of pancreatic juice, bicarbon-
amino acids, thus completing digestion of some proteins ate ions and water, are secreted mainly by the epithelial
all the way to the amino acid state. cells of the ductules and ducts that lead from the acini.
The pancreatic enzyme for digesting carbohydrates When the pancreas is stimulated to secrete copious quan-
is pancreatic amylase, which hydrolyzes starches, tities of pancreatic juice, the bicarbonate ion concentra-
glycogen, and most other carbohydrates (except tion can rise to as high as 145 mEq/L, a value about five
cellulose) to form mostly disaccharides and a few times that of bicarbonate ions in the plasma. This pro-
trisaccharides. vides a large quantity of alkali in the pancreatic juice that
The main enzymes for fat digestion are (1) pancre- serves to neutralize the hydrochloric acid emptied into
atic lipase, which is capable of hydrolyzing neutral fat the duodenum from the stomach.
into fatty acids and monoglycerides; (2) cholesterol The basic steps in the cellular mechanism for secret-
esterase, which causes hydrolysis of cholesterol esters; ing sodium bicarbonate solution into the pancreatic
and (3) phospholipase, which splits fatty acids from ductules and ducts are shown in Figure 64-8. They are
phospholipids. the following:
When first synthesized in the pancreatic cells, the 1. Carbon dioxide diffuses to the interior of the cell
proteolytic digestive enzymes are in the inactive forms from the blood and, under the influence of carbonic
trypsinogen, chymotrypsinogen, and procarboxypolypepti- anhydrase, combines with water to form carbonic
dase, which are all inactive enzymatically. They become acid (H2CO3). The carbonic acid in turn dissociates
activated only after they are secreted into the intestinal into bicarbonate ions and hydrogen ions (HCO3− and
tract. Trypsinogen is activated by an enzyme called enter- H+). Then the bicarbonate ions are actively trans-
okinase, which is secreted by the intestinal mucosa when ported in association with sodium ions (Na+) through
chyme comes in contact with the mucosa. Also, trypsino- the luminal border of the cell into the lumen of the
gen can be autocatalytically activated by trypsin that has duct.
already been formed from previously secreted trypsino-
2. The hydrogen ions formed by dissociation of car-
gen. Chymotrypsinogen is activated by trypsin to form
bonic acid inside the cell are exchanged for sodium
chymotrypsin, and procarboxypolypeptidase is activated
ions through the blood border of the cell by a secondary
in a similar manner.
active transport process. This supplies the sodium ions
Secretion of Trypsin Inhibitor Prevents Digestion of (Na+) that are transported through the luminal border
the Pancreas Itself.  It is important that the ­proteolytic into the pancreatic duct lumen to provide electrical
enzymes of the pancreatic juice not become activated neutrality for the secreted bicarbonate ions.

781
Unit XII  Gastrointestinal Physiology

another. Thus, pancreatic secretion normally results from

the combined effects of the multiple basic stimuli, not
Blood Lumen
Ductule cells from one alone.

Phases of Pancreatic Secretion

Na+ Na+ Na+ Pancreatic secretion occurs in three phases, the same
H+ H+ HCO−3 HCO−3 as for gastric secretion: the cephalic phase, the gastric
(Active
transport) (Active phase, and the intestinal phase. Their characteristics are
H2CO3 transport)
as follows.
(Carbonic anhydrase)
Cephalic and Gastric Phases.  During the cephalic
H2O
+ phase of pancreatic secretion, the same nervous sig-
CO2 CO2 nals from the brain that cause secretion in the stomach
H2O H2O
also cause acetylcholine release by the vagal nerve end-
ings in the pancreas. This causes moderate amounts of
enzymes to be secreted into the pancreatic acini, account-
ing for about 20 percent of the total secretion of pancre-
Figure 64-8  Secretion of isosmotic sodium bicarbonate solution atic enzymes after a meal. But little of the secretion flows
by the pancreatic ductules and ducts. immediately through the pancreatic ducts into the intes-
tine because only small amounts of water and electrolytes
are secreted along with the enzymes.
3. The overall movement of sodium and bicarbonate ions During the gastric phase, the nervous stimulation of
from the blood into the duct lumen creates an osmotic enzyme secretion continues, accounting for another 5 to
pressure gradient that causes osmosis of water also 10 percent of pancreatic enzymes secreted after a meal.
into the pancreatic duct, thus forming an almost com- But, again, only small amounts reach the duodenum
pletely isosmotic bicarbonate solution. because of continued lack of significant fluid secretion.
Intestinal Phase.  After chyme leaves the stomach and
Regulation of Pancreatic Secretion enters the small intestine, pancreatic secretion becomes
copious, mainly in response to the hormone secretin.
Basic Stimuli That Cause Pancreatic Secretion
Secretin Stimulates Copious Secretion of Bicarbonate
Three basic stimuli are important in causing pancreatic Ions,Which Neutralizes Acidic Stomach Chyme.  Secretin
secretion: is a polypeptide, containing 27 amino acids (molecular
1. Acetylcholine, which is released from the parasympa- weight about 3400), present in an inactive form, prose-
thetic vagus nerve endings and from other cholinergic cretin, in so-called S cells in the mucosa of the duodenum
nerves in the enteric nervous system and jejunum. When acid chyme with pH less than 4.5 to
5.0 enters the duodenum from the stomach, it causes duo-
2. Cholecystokinin, which is secreted by the duodenal denal mucosal release and activation of secretin, which is
and upper jejunal mucosa when food enters the small then absorbed into the blood. The one truly potent con-
intestine stituent of chyme that causes this secretin release is the
3. Secretin, which is also secreted by the duodenal and hydrochloric acid from the stomach.
jejunal mucosa when highly acidic food enters the Secretin in turn causes the pancreas to secrete large
small intestine quantities of fluid containing a high concentration of bicar-
The first two of these stimuli, acetylcholine and chole- bonate ion (up to 145 mEq/L) but a low concentration of
cystokinin, stimulate the acinar cells of the pancreas, caus- chloride ion. The secretin mechanism is especially impor-
ing production of large quantities of pancreatic digestive tant for two reasons: First, secretin begins to be released
enzymes but relatively small quantities of water and elec- from the mucosa of the small intestine when the pH of the
trolytes to go with the enzymes. Without the water, most duodenal contents falls below 4.5 to 5.0, and its release
of the enzymes remain temporarily stored in the acini increases greatly as the pH falls to 3.0. This immediately
and ducts until more fluid secretion comes along to wash causes copious secretion of pancreatic juice containing
them into the duodenum. Secretin, in contrast to the first abundant amounts of sodium bicarbonate. The net result
two basic stimuli, stimulates secretion of large quantities is then the following reaction in the duodenum:
of water solution of sodium bicarbonate by the pancreatic
ductal epithelium. HCl + NaHCO3 Æ NaCl + H2CO3
Multiplicative Effects of Different Stimuli.  When
all the different stimuli of pancreatic secretion occur at Then the carbonic acid immediately dissociates into
once, the total secretion is far greater than the sum of the carbon dioxide and water. The carbon dioxide is absorbed
secretions caused by each one separately. Therefore, the into the blood and expired through the lungs, thus leaving
various stimuli are said to “multiply,” or “potentiate,” one a neutral solution of sodium chloride in the duodenum.

782
 Chapter 64  Secretory Functions of the Alimentary Tract

In this way, the acid contents emptied into the duodenum Acid from stomach
from the stomach become neutralized, so further peptic releases secretin from
wall of duodenum;
digestive activity by the gastric juices in the duodenum fats and amino acids
is immediately blocked. Because the mucosa of the small cause release of

U n i t X II
cholecystokinin Common
intestine cannot withstand the digestive action of acid bile duct
gastric juice, this is an essential protective mechanism to
prevent development of duodenal ulcers, as is discussed Vagal
in further detail in Chapter 66. stimulation
Bicarbonate ion secretion by the pancreas provides releases
enzymes
an appropriate pH for action of the pancreatic digestive into acini
enzymes, which function optimally in a slightly alkaline or
neutral medium, at a pH of 7.0 to 8.0. Fortunately, the pH Secretin causes
of the sodium bicarbonate secretion averages 8.0. copious secretion
Cholecystokinin—Its Contribution to Control of Secretin and of pancreatic fluid
cholecystokinin and bicarbonate;
Digestive Enzyme Secretion by the Pancreas.  The pres- cholecystokinin
absorbed into
ence of food in the upper small intestine also causes a sec- blood stream causes secretion
ond hormone, CCK, a polypeptide containing 33 amino of enzymes
acids, to be released from yet another group of cells, the I
Figure 64-10  Regulation of pancreatic secretion.
cells, in the mucosa of the duodenum and upper jejunum.
This release of CCK results especially from the presence
of proteoses and peptones (products of partial protein
digestion) and long-chain fatty acids in the chyme coming
from the stomach. Figure 64-10 summarizes the more important fac-
CCK, like secretin, passes by way of the blood to the tors in the regulation of pancreatic secretion. The total
pancreas but instead of causing sodium bicarbonate amount secreted each day is about 1 liter.
secretion causes mainly secretion of still much more pan-
creatic digestive enzymes by the acinar cells. This effect
is similar to that caused by vagal stimulation but even Secretion of Bile by the Liver; Functions
more pronounced, accounting for 70 to 80 percent of the of the Biliary Tree
total secretion of the pancreatic digestive enzymes after
a meal. One of the many functions of the liver is to secrete bile,
The differences between the pancreatic stimulatory normally between 600 and 1000 ml/day. Bile serves two
effects of secretin and CCK are shown in Figure 64-9, important functions.
which demonstrates (1) intense sodium bicarbonate First, bile plays an important role in fat digestion and
secretion in response to acid in the duodenum, stimulated absorption, not because of any enzymes in the bile that
by secretin; (2) a dual effect in response to soap (a fat); and cause fat digestion, but because bile acids in the bile do
(3) intense digestive enzyme secretion (when peptones two things: (1) They help to emulsify the large fat par-
enter the duodenum) stimulated by CCK. ticles of the food into many minute particles, the surface
of which can then be attacked by lipase enzymes secreted
in pancreatic juice, and (2) they aid in absorption of the
digested fat end products through the intestinal mucosal
Water and
NaHCO3
membrane.
Second, bile serves as a means for excretion of sev-
Enzymes
eral important waste products from the blood. These
Rate of pancreatic secretion

include especially bilirubin, an end product of hemoglo-

bin destruction, and excesses of cholesterol.

Physiologic Anatomy of Biliary Secretion

Bile is secreted in two stages by the liver: (1) The initial
portion is secreted by the principal functional cells of the
liver, the hepatocytes; this initial secretion contains large
amounts of bile acids, cholesterol, and other organic con-
stituents. It is secreted into minute bile canaliculi that
originate between the hepatic cells.
HCI Soap Peptone (2) Next, the bile flows in the canaliculi toward the
Figure 64-9  Sodium bicarbonate (NaHCO3), water, and enzyme interlobular septa, where the canaliculi empty into ter-
secretion by the pancreas, caused by the presence of acid (HCl), minal bile ducts and then into progressively larger ducts,
fat (soap), or peptone solutions in the duodenum. finally reaching the hepatic duct and common bile duct.

783
Unit XII  Gastrointestinal Physiology

Figure 64-11  Liver secretion and gallbladder Vagal stimulation

emptying. Secretin via Bile acids via blood causes weak
blood stream stimulate parenchymal contraction of
stimulates secretion gallbladder
liver ductal Stomach
secretion

Liver

Acid

Bile stored and

concentrated up
to 15 times in
gallbladder Pancreas

Sphincter of
Oddi Duodenum
Cholecystokinin via blood stream causes:
1. Gallbladder contraction
2. Relaxation of sphincter of Oddi

From these the bile either empties directly into the duo- normally concentrated in this way about 5-fold, but it can
denum or is diverted for minutes up to several hours be concentrated up to a maximum of 20-fold.
through the cystic duct into the gallbladder, shown in
Figure 64-11. Composition of Bile.  Table 64-2 gives the composi-
In its course through the bile ducts, a second portion tion of bile when it is first secreted by the liver and then
of liver secretion is added to the initial bile. This addi- after it has been concentrated in the gallbladder. This
tional secretion is a watery solution of sodium and bicar- table shows that by far the most abundant substances
bonate ions secreted by secretory epithelial cells that line secreted in the bile are bile salts, which account for about
the ductules and ducts. This second secretion sometimes one half of the total solutes also in the bile. Also secreted
increases the total quantity of bile by as much as an addi- or excreted in large concentrations are bilirubin, choles-
tional 100 percent. The second secretion is stimulated terol, lecithin, and the usual electrolytes of plasma.
especially by secretin, which causes release of additional
quantities of bicarbonate ions to supplement the bicar-
bonate ions in pancreatic secretion (for neutralizing acid Table 64-2  Composition of Bile
that empties into the duodenum from the stomach).
Liver Bile Gallbladder Bile
Storing and Concentrating Bile in the Gallbladder. 
Bile is secreted continually by the liver cells, but most of Water 97.5 g/dl 92 g/dl
it is normally stored in the gallbladder until needed in the Bile salts 1.1 g/dl 6 g/dl
duodenum. The maximum volume that the gallbladder can
Bilirubin 0.04 g/dl 0.3 g/dl
hold is only 30 to 60 milliliters. Nevertheless, as much as 12
hours of bile secretion (usually about 450 milliliters) can be Cholesterol 0.1 g/dl 0.3 to 0.9 g/dl
stored in the gallbladder because water, sodium, chloride, Fatty acids 0.12 g/dl 0.3 to 1.2 g/dl
and most other small electrolytes are continually absorbed Lecithin 0.04 g/dl 0.3 g/dl
through the gallbladder mucosa, concentrating the remain-
Na +
145 mEq/L 130 mEq/L
ing bile constituents that contain the bile salts, cholesterol,
lecithin, and bilirubin. K+
5 mEq/L 12 mEq/L
Most of this gallbladder absorption is caused by active Ca++ 5 mEq/L 23 mEq/L
transport of sodium through the gallbladder epithelium, Cl −
100 mEq/L 25 mEq/L
and this is followed by secondary absorption of chloride
HCO −
28 mEq/L 10 mEq/L
ions, water, and most other diffusible constituents. Bile is 3

784
 Chapter 64  Secretory Functions of the Alimentary Tract

In the concentrating process in the gallbladder, water Second, and even more important than the emulsify-
and large portions of the electrolytes (except calcium ing function, bile salts help in the absorption of (1) fatty
ions) are reabsorbed by the gallbladder mucosa; essen- acids, (2) monoglycerides, (3) cholesterol, and (4) other
tially all other constituents, especially the bile salts and lipids from the intestinal tract. They do this by forming

U n i t X II
the lipid substances cholesterol and lecithin, are not reab- small physical complexes with these lipids; the complexes
sorbed and, therefore, become highly concentrated in the are called micelles, and they are semisoluble in the chyme
gallbladder bile. because of the electrical charges of the bile salts. The
intestinal lipids are “ferried” in this form to the intesti-
Emptying of the Gallbladder—Stimulatory Role of nal mucosa, where they are then absorbed into the blood,
Cholecystokinin.  When food begins to be digested in as will be described in detail in Chapter 65. Without the
the upper gastrointestinal tract, the gallbladder begins to presence of bile salts in the intestinal tract, up to 40 per-
empty, especially when fatty foods reach the duodenum cent of the ingested fats are lost into the feces and the
about 30 minutes after a meal. The mechanism of gall- person often develops a metabolic deficit because of this
bladder emptying is rhythmical contractions of the wall of nutrient loss.
the gallbladder, but effective emptying also requires simul- Enterohepatic Circulation of Bile Salts.  About 94 percent of
taneous relaxation of the sphincter of Oddi, which guards the bile salts are reabsorbed into the blood from the small
the exit of the common bile duct into the duodenum. intestine, about one half of this by diffusion through the
By far the most potent stimulus for causing the gall- mucosa in the early portions of the small intestine and the
bladder contractions is the hormone CCK. This is the remainder by an active transport process through the intes-
same CCK discussed earlier that causes increased secre- tinal mucosa in the distal ileum. They then enter the por-
tion of digestive enzymes by the acinar cells of the pan- tal blood and pass back to the liver. On reaching the liver,
creas. The stimulus for CCK entry into the blood from on first passage through the venous sinusoids these salts are
the duodenal mucosa is mainly the presence of fatty foods absorbed almost entirely back into the hepatic cells and then
resecreted into the bile.
in the duodenum.
In this way, about 94 percent of all the bile salts are recir-
The gallbladder is also stimulated less strongly by ace- culated into the bile, so on the average these salts make the
tylcholine-secreting nerve fibers from both the vagi and entire circuit some 17 times before being carried out in the
the intestinal enteric nervous system. They are the same feces. The small quantities of bile salts lost into the feces are
nerves that promote motility and secretion in other parts replaced by new amounts formed continually by the liver
of the upper gastrointestinal tract. cells. This recirculation of the bile salts is called the enterohe-
In summary, the gallbladder empties its store of con- patic circulation of bile salts.
centrated bile into the duodenum mainly in response to The quantity of bile secreted by the liver each day is
the CCK stimulus that itself is initiated mainly by fatty highly dependent on the availability of bile salts—the
foods. When fat is not in the food, the gallbladder emp- greater the quantity of bile salts in the enterohepatic circu-
ties poorly, but when significant quantities of fat are pres- lation (usually a total of only about 2.5 grams), the greater
the rate of bile secretion. Indeed, ingestion of supplemen-
ent, the gallbladder normally empties completely in about
tal bile salts can increase bile secretion by several hundred
1 hour. Figure 64-11 summarizes the secretion of bile, its milliliters per day.
storage in the gallbladder, and its ultimate release from If a bile fistula empties the bile salts to the exterior for sev-
the bladder to the duodenum. eral days to several weeks so that they cannot be reabsorbed
from the ileum, the liver increases its production of bile salts
Function of Bile Salts in Fat Digestion 6- to 10-fold, which increases the rate of bile secretion most
and Absorption of the way back to normal. This demonstrates that the daily
rate of liver bile salt secretion is actively controlled by the
The liver cells synthesize about 6 grams of bile salts daily. availability (or lack of availability) of bile salts in the entero-
The precursor of the bile salts is cholesterol, which is either hepatic circulation.
present in the diet or synthesized in the liver cells during Role of Secretin in Controlling Bile Secretion.  In addi-
the course of fat metabolism. The cholesterol is first con- tion to the strong stimulating effect of bile acids to cause bile
verted to cholic acid or chenodeoxycholic acid in about secretion, the hormone secretin that also stimulates pancre-
equal quantities. These acids in turn combine principally atic secretion increases bile secretion, sometimes more than
with glycine and to a lesser extent with taurine to form doubling its secretion for several hours after a meal. This
glyco- and tauro-conjugated bile acids. The salts of these increase in secretion is almost entirely secretion of a sodium
acids, mainly sodium salts, are then secreted in the bile. bicarbonate–rich watery solution by the epithelial cells of the
bile ductules and ducts, and not increased secretion by the
The bile salts have two important actions in the intes-
liver parenchymal cells themselves. The bicarbonate in turn
tinal tract: passes into the small intestine and joins the bicarbonate from
First, they have a detergent action on the fat particles the pancreas in neutralizing the hydrochloric acid from the
in the food. This decreases the surface tension of the par- stomach. Thus, the secretin feedback mechanism for neu-
ticles and allows agitation in the intestinal tract to break tralizing duodenal acid operates not only through its effects
the fat globules into minute sizes. This is called the emul- on pancreatic secretion but also to a lesser extent through its
sifying or detergent function of bile salts. effect on secretion by the liver ductules and ducts.

785
Unit XII  Gastrointestinal Physiology

Causes of gallstones: of the stomach and the papilla of Vater, where pancreatic
1. Too much absorption of water secretion and bile empty into the duodenum. These glands
from bile
2. Too much absorption of bile
secrete large amounts of alkaline mucus in response to
acids from bile (1) tactile or irritating stimuli on the duodenal mucosa;
3. Too much cholesterol in bile
Stones (2) vagal stimulation, which causes increased Brunner’s
4. Inflammation of epithelium Liver glands secretion concurrently with increase in stomach
secretion; and (3) gastrointestinal hormones, especially
Hepatic duct secretin.
Gallbladder The function of the mucus secreted by Brunner’s glands
Stones Course followed by bile: is to protect the duodenal wall from digestion by the
Cystic duct 1. During rest highly acidic gastric juice emptying from the stomach. In
2. During digestion
addition, the mucus contains a large excess of bicarbonate
Common bile duct ions, which add to the bicarbonate ions from pancreatic
Sphincter of Oddi secretion and liver bile in neutralizing the hydrochloric
acid entering the duodenum from the stomach.
Papilla of Vater Pancreatic duct Brunner’s glands are inhibited by sympathetic stimula-
tion; therefore, such stimulation in very excitable persons
is likely to leave the duodenal bulb unprotected and is per-
Duodenum
haps one of the factors that cause this area of the gastro-
Figure 64-12  Formation of gallstones. intestinal tract to be the site of peptic ulcers in about 50
percent of ulcer patients.
Liver Secretion of Cholesterol and Gallstone Formation
Bile salts are formed in the hepatic cells from cholesterol in
Secretion of Intestinal Digestive Juices by the
the blood plasma. In the process of secreting the bile salts, Crypts of Lieberkühn
about 1 to 2 grams of cholesterol are removed from the blood Located over the entire surface of the small intestine are
plasma and secreted into the bile each day. small pits called crypts of Lieberkühn, one of which is
Cholesterol is almost completely insoluble in pure water, illustrated in Figure 64-13. These crypts lie between the
but the bile salts and lecithin in bile combine physically with intestinal villi. The surfaces of both the crypts and the villi
the cholesterol to form ultramicroscopic micelles in the form
are covered by an epithelium composed of two types of
of a colloidal solution, as explained in more detail in Chapter
65. When the bile becomes concentrated in the gallbladder,
cells: (1) a moderate number of goblet cells, which secrete
the bile salts and lecithin become concentrated along with mucus that lubricates and protects the intestinal surfaces,
the cholesterol, which keeps the cholesterol in solution. and (2) a large number of enterocytes, which, in the crypts,
Under abnormal conditions, the cholesterol may precipi- secrete large quantities of water and electrolytes and, over
tate in the gallbladder, resulting in the formation of choles- the surfaces of adjacent villi, reabsorb the water and elec-
terol gallstones, as shown in Figure 64-12. The amount of trolytes along with end products of digestion.
cholesterol in the bile is determined partly by the quantity The intestinal secretions are formed by the enterocytes
of fat that the person eats, because liver cells synthesize cho- of the crypts at a rate of about 1800 ml/day. These secre-
lesterol as one of the products of fat metabolism in the body. tions are almost pure extracellular fluid and have a slightly
For this reason, people on a high-fat diet over a period of alkaline pH in the range of 7.5 to 8.0. The secretions are
years are prone to the development of gallstones.
Inflammation of the gallbladder epithelium, often result-
ing from low-grade chronic infection, may also change the
absorptive characteristics of the gallbladder mucosa, some-
times allowing excessive absorption of water and bile salts but
leaving behind the cholesterol in the gallbladder in progres-
sively greater concentrations. Then the cholesterol begins to
Mucous goblet
precipitate, first forming many small crystals of cholesterol
cell
on the surface of the inflamed mucosa, but then progressing
to large gallstones.
Epithelial cell

Secretions of the Small Intestine

Paneth cell
Secretion of Mucus by Brunner’s Glands
in the Duodenum
An extensive array of compound mucous glands, called
Figure 64-13  A crypt of Lieberkühn, found in all parts of the small
Brunner’s glands, is located in the wall of the first few cen- intestine between the villi, which secretes almost pure extracel-
timeters of the duodenum, mainly between the ­pylorus lular fluid.

786
 Chapter 64  Secretory Functions of the Alimentary Tract

also rapidly reabsorbed by the villi. This flow of fluid principally by direct, tactile stimulation of the epithelial
from the crypts into the villi supplies a watery vehicle for cells lining the large intestine and by local nervous reflexes
absorption of substances from chyme when it comes in to the mucous cells in the crypts of Lieberkühn.
contact with the villi. Thus, the primary function of the Stimulation of the pelvic nerves from the spinal cord,

U n i t X II
small intestine is to absorb nutrients and their digestive which carry parasympathetic innervation to the distal
products into the blood. one half to two thirds of the large intestine, also can cause
marked increase in mucus secretion. This occurs along
Mechanism of Secretion of the Watery Fluid.  The
with increase in peristaltic motility of the colon, which
exact mechanism that controls the marked secretion of
was discussed in Chapter 63.
watery fluid by the crypts of Lieberkühn is still unclear,
During extreme parasympathetic stimulation, often
but it is believed to involve at least two active secretory
caused by emotional disturbances, so much mucus can
processes: (1) active secretion of chloride ions into the
occasionally be secreted into the large intestine that the
crypts and (2) active secretion of bicarbonate ions. The
person has a bowel movement of ropy mucus as often as
secretion of both ions causes electrical drag of positively
every 30 minutes; this mucus often contains little or no
charged sodium ions through the membrane and into the
fecal material.
secreted fluid as well. Finally, all these ions together cause
Mucus in the large intestine protects the intestinal wall
osmotic movement of water.
against excoriation, but in addition, it provides an adherent
Digestive Enzymes in the Small Intestinal medium for holding fecal matter together. Furthermore, it
Secretion.  When secretions of the small intestine are protects the intestinal wall from the great amount of bac-
collected without cellular debris, they have almost no terial activity that takes place inside the feces, and, finally,
enzymes. The enterocytes of the mucosa, especially those the mucus plus the alkalinity of the secretion (pH of 8.0
that cover the villi, contain digestive enzymes that digest caused by large amounts of sodium bicarbonate) provides
specific food substances while they are being absorbed a barrier to keep acids formed in the feces from attacking
through the epithelium. These enzymes are the follow- the intestinal wall.
ing: (1) several peptidases for splitting small peptides
into amino acids; (2) four enzymes—sucrase, maltase, Diarrhea Caused by Excess Secretion of
isomaltase, and lactase—for splitting disaccharides into Water and  Electrolytes in Response to Irritation. 
monosaccharides; and (3) small amounts of intestinal Whenever a segment of the large intestine becomes
lipase for splitting neutral fats into glycerol and fatty intensely irritated, as occurs when bacterial infection
acids. becomes rampant during enteritis, the mucosa secretes
The epithelial cells deep in the crypts of Lieberkühn extra large quantities of water and electrolytes in addition
continually undergo mitosis, and new cells migrate along to the normal viscid alkaline mucus. This acts to dilute
the basement membrane upward out of the crypts toward the irritating factors and to cause rapid movement of the
the tips of the villi, thus continually replacing the villus feces toward the anus. The result is diarrhea, with loss of
epithelium and also forming new digestive enzymes. As large quantities of water and electrolytes. But the diarrhea
the villus cells age, they are finally shed into the intestinal also washes away irritant factors, which promotes earlier
secretions. The life cycle of an intestinal epithelial cell is recovery from the disease than might otherwise occur.
about 5 days. This rapid growth of new cells also allows
rapid repair of excoriations that occur in the mucosa.
Bibliography
Regulation of Small Intestine Secretion—Local
Allen A, Flemström G: Gastroduodenal mucus bicarbonate barrier:
Stimuli ­protection against acid and pepsin, Am J Physiol Cell Physiol 288:C1,
By far the most important means for regulating small 2005.
Barrett KE: New ways of thinking about (and teaching about) intestinal
intestine secretion are local enteric nervous reflexes,
epithelial function, Adv Physiol Educ 32:25, 2008.
especially reflexes initiated by tactile or irritative stimuli Barrett KE, Keely SJ: Chloride secretion by the intestinal epithelium:
from the chyme in the intestines. ­molecular basis and regulatory aspects, Annu Rev Physiol 62:535,
2000.
Chen D, Aihara T, Zhao CM, Håkanson R, Okabe S: Differentiation of the
Secretion of Mucus by the Large Intestine gastric mucosa. I. Role of histamine in control of function and integrity
of oxyntic mucosa: understanding gastric physiology through disrup-
tion of targeted genes, Am J Physiol Gastrointest Liver Physiol 291:G539,
Mucus Secretion.  The mucosa of the large intes- 2006.
tine, like that of the small intestine, has many crypts of Dockray GJ: Cholecystokinin and gut-brain signalling, Regul Pept 155:6,
Lieberkühn; however, unlike the small intestine, there are 2009.
no villi. The epithelial cells secrete almost no digestive Dockray GJ, Varro A, Dimaline R, Wang T: The gastrins: their production and
biological activities, Annu Rev Physiol 63:119, 2001.
enzymes. Instead, they contain mucous cells that secrete
Flemstrom G, Isenberg JI: Gastroduodenal mucosal alkaline secretion and
only mucus. This mucus contains moderate amounts of mucosal protection, News Physiol Sci 16:23, 2001.
bicarbonate ions secreted by a few non-mucus-secreting Flemström G, Sjöblom M: Epithelial cells and their neighbors. II. New per-
epithelial cells. The rate of secretion of mucus is regulated spectives on efferent signaling between brain, neuroendocrine cells,

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Unit XII  Gastrointestinal Physiology

and gut epithelial cells, Am J Physiol Gastrointest Liver Physiol 289:G377, Portincasa P, Di Ciaula A, Wang HH, et al: Coordinate regulation of ­gallbladder
2005. motor function in the gut-liver axis, Hepatology 47:2112, 2008.
Heitzmann D, Warth R: Physiology and pathophysiology of potassium Portincasa P, Moschetta A, Palasciano G: Cholesterol gallstone disease,
channels in gastrointestinal epithelia, Physiol Rev 88:1119, 2008. Lancet 368:230, 2006.
Hocker M: Molecular mechanisms of gastrin-dependent gene regulation, Russell DW: Fifty years of advances in bile acid synthesis and metabolism,
Ann N Y Acad Sci 1014:97, 2004. J Lipid Res 50(Suppl):S120, 2009.
Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P: Bile acids as regula- Trauner M, Boyer JL: Bile salt transporters: molecular characterization, func-
tory molecules, J Lipid Res 50:1509, 2009. tion, and regulation, Physiol Rev 83:633, 2003.
Jain RN, Samuelson LC: Differentiation of the gastric mucosa. II. Role of gas- Wallace JL: Prostaglandins, NSAIDs, and gastric mucosal protection:
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Gastrointest Liver Physiol 291:G762, 2006. Williams JA, Chen X, Sabbatini ME: Small G proteins as key regulators of
Laine L, Takeuchi K, Tarnawski A: Gastric mucosal defense and cytoprotec- pancreatic digestive enzyme secretion, Am J Physiol Endocrinol Metab
tion: bench to bedside, Gastroenterology 135:41, 2008. 296:E405, 2009.
Lefebvre P, Cariou B, Lien F, et al: Role of bile acids and bile acid recep- Zanner R, Gratzl M, Prinz C: Circle of life of secretory vesicles in gastric
tors in metabolic regulation, Physiol Rev 89:147, 2009. enterochromaffin-like cells, Ann N Y Acad Sci 971:389, 2002.

788
 chapter 65

Unit XiI
Digestion and Absorption
in the Gastrointestinal Tract

The major foods on which digestive

the body lives (with the R¢¢-R¢ + H2O æ ææÆ R¢¢OH + R¢H
enzyme
exception of small quan-
tities of substances such Hydrolysis of Fats.  Almost the entire fat portion of
as vitamins and minerals) the diet consists of triglycerides (neutral fats), which are
can be classified as carbo- combinations of three fatty acid molecules condensed
hydrates, fats, and proteins. with a single glycerol molecule. During condensation,
They generally cannot be absorbed in their natural three molecules of water are removed.
forms through the gastrointestinal mucosa and, for this Digestion of the triglycerides consists of the reverse
reason, are useless as nutrients without preliminary process: the fat-digesting enzymes return three molecules
digestion. Therefore, this chapter discusses the pro- of water to the triglyceride molecule and thereby split the
cesses by which carbohydrates, fats, and proteins are fatty acid molecules away from the glycerol. Here again,
digested into small enough compounds for absorption the digestive process is one of hydrolysis.
and the mechanisms by which the digestive end prod-
ucts, as well as water, electrolytes, and other substances, Hydrolysis of Proteins.  Proteins are formed from
are absorbed. multiple amino acids that are bound together by pep-
tide linkages. At each linkage, a hydroxyl ion has been
removed from one amino acid and a hydrogen ion has
Digestion of the Various Foods been removed from the succeeding one; thus, the suc-
by Hydrolysis cessive amino acids in the protein chain are also bound
together by condensation, and digestion occurs by the
Hydrolysis of Carbohydrates.  Almost all the car- reverse effect: hydrolysis. That is, the proteolytic enzymes
bohydrates of the diet are either large polysaccharides or return hydrogen and hydroxyl ions from water molecules
disaccharides, which are combinations of monosaccha- to the protein molecules to split them into their constitu-
rides bound to one another by condensation. This means ent amino acids.
that a hydrogen ion (H+) has been removed from one of Therefore, the chemistry of digestion is simple because,
the monosaccharides, and a hydroxyl ion (−OH) has been in the case of all three major types of food, the same basic
removed from the next one. The two monosaccharides process of hydrolysis is involved. The only difference lies in
then combine with each other at these sites of removal, the types of enzymes required to promote the ­hydrolysis
and the hydrogen and hydroxyl ions combine to form reactions for each type of food.
water (H2O). All the digestive enzymes are proteins. Their secretion
When carbohydrates are digested, the above process is by the different gastrointestinal glands was discussed in
reversed and the carbohydrates are converted into mono- Chapter 64.
saccharides. Specific enzymes in the digestive juices of the
gastrointestinal tract return the hydrogen and hydroxyl Digestion of Carbohydrates
ions from water to the polysaccharides and thereby sepa- Carbohydrate Foods of the Diet.  Only three major
rate the monosaccharides from each other. This process, sources of carbohydrates exist in the normal human
called hydrolysis, is the following (in which R″-R′ is a diet. They are sucrose, which is the disaccharide known
disaccharide): popularly as cane sugar; lactose, which is a disaccharide

789
Unit XII  Gastrointestinal Physiology

found in milk; and starches, which are large polysaccha- Hydrolysis of Disaccharides and Small Glucose
rides present in almost all nonanimal foods, particularly Polymers into Monosaccharides by Intestinal Epithelial
in potatoes and different types of grains. Other carbohy- Enzymes.  The enterocytes lining the villi of the small
drates ingested to a slight extent are amylose, glycogen, intestine contain four enzymes (lactase, sucrase, maltase,
alcohol, lactic acid, pyruvic acid, pectins, dextrins, and and α-dextrinase), which are capable of splitting the disac-
minor quantities of carbohydrate derivatives in meats. charides lactose, sucrose, and maltose, plus other small
The diet also contains a large amount of cellulose, glucose polymers, into their constituent monosaccharides.
which is a carbohydrate. However, no enzymes capable These enzymes are located in the enterocytes covering the
of hydrolyzing cellulose are secreted in the human diges- intestinal microvilli brush border, so the disaccharides are
tive tract. Consequently, cellulose cannot be considered a digested as they come in contact with these enterocytes.
food for humans. Lactose splits into a molecule of galactose and a
­molecule of glucose. Sucrose splits into a molecule of
Digestion of Carbohydrates in the Mouth and fructose and a molecule of glucose. Maltose and other
Stomach.  When food is chewed, it is mixed with small glucose polymers all split into multiple molecules of
saliva, which contains the digestive enzyme ptyalin (an glucose. Thus, the final products of carbohydrate diges-
α-amylase) secreted mainly by the parotid glands. This tion are all monosaccharides. They are all water soluble
enzyme hydrolyzes starch into the disaccharide maltose and are absorbed immediately into the portal blood.
and other small polymers of glucose that contain three to In the ordinary diet, which contains far more starches
nine glucose molecules, as shown in Figure 65-1. However, than all other carbohydrates combined, glucose represents
the food remains in the mouth only a short time, so prob- more than 80 percent of the final products of carbohy-
ably not more than 5 percent of all the starches will have drate digestion, and galactose and fructose each represent
become hydrolyzed by the time the food is swallowed. seldom more than 10 percent.
However, starch digestion sometimes continues in The major steps in carbohydrate digestion are summa-
the body and fundus of the stomach for as long as 1 hour rized in Figure 65-1.
before the food becomes mixed with the stomach secre-
tions. Then activity of the salivary amylase is blocked Digestion of Proteins
by acid of the gastric secretions because the amylase is
Proteins of the Diet.  The dietary proteins are
essentially nonactive as an enzyme once the pH of the
chemically long chains of amino acids bound together
medium falls below about 4.0. Nevertheless, on the aver-
by peptide linkages. A typical linkage is the following:
age, before food and its accompanying saliva do become
completely mixed with the gastric secretions, as much as NH2 H
30 to 40 percent of the starches will have been hydrolyzed
mainly to form maltose.
R CH C OH + H N CH COOH

Digestion of Carbohydrates in the Small Intestine

O R
Digestion by Pancreatic Amylase.  Pancreatic secre-
NH2 H
tion, like saliva, contains a large quantity of α-amylase
that is almost identical in its function with the α-amylase
of saliva but is several times as powerful. Therefore, R CH C N CH COOH + H2O
within 15 to 30 minutes after the chyme empties from
the stomach into the duodenum and mixes with pancre- O R
atic juice, virtually all the carbohydrates will have become
digested. The characteristics of each protein are determined by
In general, the carbohydrates are almost totally con- the types of amino acids in the protein molecule and by
verted into maltose and/or other small glucose poly- the sequential arrangements of these amino acids. The
mers before passing beyond the duodenum or upper physical and chemical characteristics of different proteins
jejunum. important in human tissues are discussed in Chapter 69.

Figure 65-1  Digestion of carbohydrates. Starches

Ptyalin (saliva)–20-40%
Pancreatic amylase–50-80%

Maltose and 3 to 9 glucose polymers Lactose Sucrose

Lactase Sucrase
Maltase and a-dextrinase (intestine) (intestine)
(intestine)
Glucose Galactose Fructose

790
 Chapter 65  Digestion and Absorption in the Gastrointestinal Tract

Digestion of Proteins in the Stomach.  Pepsin, the Only a small percentage of the proteins are digested all
important peptic enzyme of the stomach, is most active the way to their constituent amino acids by the pancreatic
at a pH of 2.0 to 3.0 and is inactive at a pH above about juices. Most remain as dipeptides and tripeptides.
5.0. Consequently, for this enzyme to cause digestion of

U n i t X II
protein, the stomach juices must be acidic. As explained Digestion of Peptides by Peptidases in the
in Chapter 64, the gastric glands secrete a large quantity Enterocytes That Line the Small Intestinal Villi.  The
of hydrochloric acid. This hydrochloric acid is secreted by last digestive stage of the proteins in the intestinal lumen is
the parietal (oxyntic) cells in the glands at a pH of about achieved by the enterocytes that line the villi of the small
0.8, but by the time it is mixed with the stomach contents intestine, mainly in the duodenum and jejunum. These cells
and with secretions from the nonoxyntic glandular cells have a brush border that consists of hundreds of microvilli
of the stomach, the pH then averages around 2.0 to 3.0, a projecting from the surface of each cell. In the membrane
highly favorable range of acidity for pepsin activity. of each of these microvilli are multiple peptidases that pro-
One of the important features of pepsin digestion is trude through the membranes to the exterior, where they
its ability to digest the protein collagen, an albuminoid come in contact with the intestinal fluids.
type of protein that is affected little by other digestive Two types of peptidase enzymes are especially impor-
enzymes. Collagen is a major constituent of the intercel- tant, aminopolypeptidase and several dipeptidases. They
lular connective tissue of meats; therefore, for the diges- succeed in splitting the remaining larger polypeptides into
tive enzymes of the digestive tract to penetrate meats and tripeptides and dipeptides and a few into amino acids.
digest the other meat proteins, it is necessary that the Both the amino acids plus the dipeptides and tripeptides
­collagen fibers be digested. Consequently, in persons who are easily transported through the microvillar membrane
lack pepsin in the stomach juices, the ingested meats are to the interior of the enterocyte.
less well penetrated by the other digestive enzymes and, Finally, inside the cytosol of the enterocyte are multiple
therefore, may be poorly digested. other peptidases that are specific for the remaining types
As shown in Figure 65-2, pepsin only initiates the pro- of linkages between amino acids. Within minutes, virtu-
cess of protein digestion, usually providing only 10 to 20 ally all the last dipeptides and tripeptides are digested to
percent of the total protein digestion to convert the pro- the final stage to form single amino acids; these then pass
tein to proteoses, peptones, and a few polypeptides. This on through to the other side of the enterocyte and thence
splitting of proteins occurs as a result of hydrolysis at the into the blood.
peptide linkages between amino acids. More than 99 percent of the final protein digestive
products that are absorbed are individual amino acids,
Most Protein Digestion Results from Actions of with only rare absorption of peptides and very, very rare
Pancreatic Proteolytic Enzymes.  Most protein diges- absorption of whole protein molecules. Even these few
tion occurs in the upper small intestine, in the duode- absorbed molecules of whole protein can sometimes
num and jejunum, under the influence of proteolytic cause serious allergic or immunologic disturbances, as
enzymes from pancreatic secretion. Immediately on discussed in Chapter 34.
entering the small intestine from the stomach, the partial
breakdown products of the protein foods are attacked Digestion of Fats
by major proteolytic pancreatic enzymes: trypsin, Fats of the Diet.  By far the most abundant fats of
­chymotrypsin, ­carboxypolypeptidase, and proelastase, the diet are the neutral fats, also known as triglycerides,
as shown in Figure 65-2. each molecule of which is composed of a glycerol nucleus
Both trypsin and chymotrypsin split protein mole- and three fatty acid side chains, as shown in Figure 65-3.
cules into small polypeptides; carboxypolypeptidase then
cleaves individual amino acids from the carboxyl ends of
the polypeptides. Proelastase, in turn, is converted into O
elastase, which then digests elastin fibers that partially CH3 (CH2)16 C O CH2
hold meats together.
O
Lipase
CH3 (CH2)16 C O CH + 2H2O

Pepsin Proteoses O
Proteins Peptones
Polypeptides CH3 (CH2)16 C O CH2
(Tristearin)
Trypsin, chymotrypsin, carboxypolypeptidase,
O HO CH2 O
proelastase
Polypeptides CH3 (CH2)16 C O CH + 2CH3 (CH2)16 C OH
Peptidases
+ Amino acids
Amino acids HO CH2
(2-Monoglyceride) (Stearic acid)
Figure 65-2  Digestion of proteins. Figure 65-3  Hydrolysis of neutral fat catalyzed by lipase.

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Unit XII  Gastrointestinal Physiology

Neutral fat is a major constituent in food of animal origin The lipase enzymes are water-soluble compounds
but much, much less so in food of plant origin. and can attack the fat globules only on their surfaces.
In the usual diet are also small quantities of phospho- Consequently, this detergent function of bile salts and
lipids, cholesterol, and cholesterol esters. The phospholip- lecithin is very important for digestion of fats.
ids and cholesterol esters contain fatty acid and therefore
can be considered fats. Cholesterol, however, is a sterol Triglycerides Are Digested by Pancreatic Lipase.  By
compound that contains no fatty acid, but it does exhibit far the most important enzyme for digestion of the triglyc-
some of the physical and chemical characteristics of fats; erides is pancreatic lipase, present in enormous quantities
plus, it is derived from fats and is metabolized similarly to in pancreatic juice, enough to digest within 1 minute all
fats. Therefore, cholesterol is considered, from a dietary triglycerides that it can reach. In addition, the enterocytes
point of view, a fat. of the small intestine contain additional lipase, known as
enteric lipase, but this is usually not needed.
Digestion of Fats in the Intestine.  A small amount
of triglycerides is digested in the stomach by lingual lipase End Products of Fat Digestion Are Free Fatty
that is secreted by lingual glands in the mouth and swal- Acids.  Most of the triglycerides of the diet are split by pan-
lowed with the saliva. This amount of digestion is less than creatic lipase into free fatty acids and 2-monoglycerides, as
10 percent and generally unimportant. Instead, essentially shown in Figure 65-4.
all fat digestion occurs in the small intestine as follows.
(Bile + Agitation)
Fat Emulsified fat
The First Step in Fat Digestion Is Emulsification by
Bile Acids and Lecithin.  The first step in fat digestion is Pancreatic lipase
physically to break the fat globules into small sizes so that Emulsified fat Fatty acids and
2-monoglycerides
the water-soluble digestive enzymes can act on the glob-
ule surfaces. This process is called emulsification of the Figure 65-4  Digestion of fats.
fat, and it begins by agitation in the stomach to mix the fat
with the products of stomach digestion. Bile Salts Form Micelles That Accelerate Fat
Then, most of the emulsification occurs in the duo- Digestion.  The hydrolysis of triglycerides is a highly
denum under the influence of bile, the secretion from reversible process; therefore, accumulation of monoglyc-
the liver that does not contain any digestive enzymes. erides and free fatty acids in the vicinity of digesting fats
However, bile does contain a large quantity of bile salts, quickly blocks further digestion. But the bile salts play
as well as the phospholipid lecithin. Both of these, but the additional important role of removing the monoglyc-
especially the lecithin, are extremely important for emul- erides and free fatty acids from the vicinity of the digest-
sification of the fat. The polar parts (the points where ing fat globules almost as rapidly as these end products of
ionization occurs in water) of the bile salts and lecithin digestion are formed. This occurs in the following way.
molecules are highly soluble in water, whereas most of the Bile salts, when in high enough concentration in water,
remaining portions of their molecules are highly soluble have the propensity to form micelles, which are small spher-
in fat. Therefore, the fat-soluble portions of these liver ical, cylindrical globules 3 to 6 nanometers in ­diameter
secretions dissolve in the surface layer of the fat glob- composed of 20 to 40 molecules of bile salt. These develop
ules, with the polar portions projecting. The polar pro- because each bile salt molecule is composed of a sterol
jections, in turn, are soluble in the surrounding watery nucleus that is highly fat-soluble and a polar group that is
fluids, which greatly decreases the interfacial tension of highly water-soluble. The sterol nucleus encompasses the
the fat and makes it soluble as well. fat digestate, forming a small fat globule in the middle of
When the interfacial tension of a globule of nonmisci- a resulting micelle, with polar groups of bile salts project-
ble fluid is low, this nonmiscible fluid, on agitation, can be ing outward to cover the surface of the micelle. Because
broken up into many tiny particles far more easily than it these polar groups are negatively charged, they allow the
can when the interfacial tension is great. Consequently, a entire micelle globule to dissolve in the water of the diges-
major function of the bile salts and lecithin, especially the tive fluids and to remain in stable solution until the fat is
lecithin, in the bile is to make the fat globules readily frag- absorbed into the blood.
mentable by agitation with the water in the small bowel. The bile salt micelles also act as a transport medium to
This action is the same as that of many detergents that are carry the monoglycerides and free fatty acids, both of which
widely used in household cleaners for removing grease. would otherwise be relatively insoluble, to the brush borders
Each time the diameters of the fat globules are signifi- of the intestinal epithelial cells. There the monoglycerides and
cantly decreased as a result of agitation in the small intestine, free fatty acids are absorbed into the blood, as discussed later,
the total surface area of the fat increases manyfold. Because but the bile salts themselves are released back into the chyme
the average diameter of the fat particles in the intestine after to be used again and again for this “ferrying” process.
emulsification has occurred is less than 1 micrometer, this
represents an increase of as much as 1000-fold in total sur- Digestion of Cholesterol Esters and Phos­
face areas of the fats caused by the emulsification process. pholipids.  Most cholesterol in the diet is in the form of

792
 Chapter 65  Digestion and Absorption in the Gastrointestinal Tract

c­ holesterol esters, which are combinations of free cholesterol

and one molecule of fatty acid. Phospholipids also contain
fatty acid within their molecules. Both the cholesterol esters
and the phospholipids are hydrolyzed by two other lipases in Villi

U n i t X II
the pancreatic secretion that free the fatty acids—the enzyme Food
cholesterol ester hydrolase to hydrolyze the cholesterol ester, movement
and phospholipase A2 to hydrolyze the phospholipid.
The bile salt micelles play the same role in “ferrying”
free cholesterol and phospholipid molecule digestates
that they play in “ferrying” monoglycerides and free fatty
acids. Indeed, essentially no cholesterol is absorbed with-
out this function of the micelles. Valvulae
conniventes

Basic Principles of Gastrointestinal

Absorption

It is suggested that the reader review the basic principles Figure 65-5  Longitudinal section of the small intestine, showing
of transport of substances through cell membranes dis- the valvulae conniventes covered by villi.
cussed in Chapter 4. The following paragraphs present
specialized applications of these transport processes dur- Folds of Kerckring, Villi, and Microvilli Increase
ing gastrointestinal absorption. the Mucosal Absorptive Area by Nearly 1000-
Fold.  Figure 65-5 demonstrates the absorptive sur-
Anatomical Basis of Absorption face of the small intestinal mucosa, showing many folds
The total quantity of fluid that must be absorbed each day called valvulae conniventes (or folds of Kerckring), which
by the intestines is equal to the ingested fluid (about 1.5 increase the surface area of the absorptive mucosa about
liters) plus that secreted in the various gastrointestinal threefold. These folds extend circularly most of the way
secretions (about 7 liters). This comes to a total of 8 to around the intestine and are especially well developed in
9 liters. All but about 1.5 liters of this is absorbed in the the duodenum and jejunum, where they often protrude
small intestine, leaving only 1.5 liters to pass through the up to 8 millimeters into the lumen.
ileocecal valve into the colon each day. Also located on the epithelial surface of the small intes-
The stomach is a poor absorptive area of the gastro- tine all the way down to the ileocecal valve are ­millions
intestinal tract because it lacks the typical villus type of of small villi. These project about 1 millimeter from the
absorptive membrane, and also because the junctions surface of the mucosa, as shown on the surfaces of the
between the epithelial cells are tight junctions. Only a few valvulae conniventes in Figure 65-5 and in individual
highly lipid-soluble substances, such as alcohol and some detail in Figure 65-6. The villi lie so close to one another
drugs like aspirin, can be absorbed in small quantities. in the upper small intestine that they touch in most areas,

Figure 65-6  Functional organi-

zation of the villus. A, Longitudinal
section. B, Cross section showing
a basement membrane beneath
the epithelial cells and a brush
Central Brush Basement border at the other ends of these
lacteal border membrane cells.

Blood
capillaries

Venules

Arteriole Central
lacteal

Vein
Capillaries
Artery

A B

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Unit XII  Gastrointestinal Physiology

this: as much as several kilograms of carbohydrates per

day, 500 grams of fat per day, 500 to 700 grams of pro-
teins per day, and 20 or more liters of water per day. The
large intestine can absorb still additional water and ions,
although very few nutrients.

Absorption of Water by Osmosis

Isosmotic Absorption.  Water is transported through
the intestinal membrane entirely by diffusion. Furthermore,
this diffusion obeys the usual laws of osmosis. Therefore,
when the chyme is dilute enough, water is absorbed
through the intestinal mucosa into the blood of the villi
Figure 65-7  Brush border of a gastrointestinal epithelial cell,
showing also absorbed pinocytic vesicles, mitochondria, and endo- almost entirely by osmosis.
plasmic reticulum lying immediately beneath the brush border. Conversely, water can also be transported in the oppo-
(Courtesy Dr. William Lockwood.) site direction—from plasma into the chyme. This occurs
especially when hyperosmotic solutions are discharged
from the stomach into the duodenum. Within minutes,
but their distribution is less profuse in the distal small
sufficient water usually will be transferred by osmosis to
intestine. The presence of villi on the mucosal surface
make the chyme isosmotic with the plasma.
enhances the total absorptive area another 10-fold.
Finally, each intestinal epithelial cell on each villus is
characterized by a brush border, consisting of as many as Absorption of Ions
1000 microvilli 1 micrometer in length and 0.1 micrometer Sodium Is Actively Transported Through the
in diameter protruding into the intestinal chyme; these Intestinal Membrane.  Twenty to 30 grams of sodium
microvilli are shown in the electron micrograph in Figure are secreted in the intestinal secretions each day. In addi-
65-7. This increases the surface area exposed to the intes- tion, the average person eats 5 to 8 grams of sodium each
tinal materials at least another 20-fold. day. Therefore, to prevent net loss of sodium into the
Thus, the combination of the folds of Kerckring, the feces, the intestines must absorb 25 to 35 grams of sodium
villi, and the microvilli increases the total absorptive area each day, which is equal to about one seventh of all the
of the mucosa perhaps 1000-fold, making a tremendous sodium present in the body.
total area of 250 or more square meters for the entire Whenever significant amounts of intestinal secretions
small intestine—about the surface area of a tennis court. are lost to the exterior, as in extreme diarrhea, the sodium
Figure 65-6A shows in longitudinal section the general reserves of the body can sometimes be depleted to lethal
organization of the villus, emphasizing (1) the advanta- levels within hours. Normally, however, less than 0.5
geous arrangement of the vascular system for absorption percent of the intestinal sodium is lost in the feces each
of fluid and dissolved material into the portal blood and day because it is rapidly absorbed through the intestinal
(2) the arrangement of the “central lacteal” lymph ves- mucosa. Sodium also plays an important role in helping
sel for absorption into the lymph. Figure 65-6B shows a to absorb sugars and amino acids, as subsequent discus-
cross section of the villus, and Figure 65-7 shows many sions reveal.
small pinocytic vesicles, which are pinched-off portions The basic mechanism of sodium absorption from the
of infolded enterocyte membrane forming vesicles of intestine is shown in Figure 65-8. The principles of this
absorbed fluids that have been entrapped. Small amounts mechanism, discussed in Chapter 4, are also essentially
of substances are absorbed by this physical process of the same as for absorption of sodium from the gallbladder
pinocytosis. and renal tubules as discussed in Chapter 27.
Extending from the epithelial cell body into each The motive power for sodium absorption is provided
microvillus of the brush border are multiple actin fila- by active transport of sodium from inside the epithe-
ments that contract rhythmically to cause continual move- lial cells through the basal and lateral walls of these cells
ment of the microvilli, keeping them constantly exposed into paracellular spaces. This active transport obeys the
to new quantities of intestinal fluid. usual laws of active transport: It requires energy, and
the energy process is catalyzed by appropriate adeno­
sine triphosphatase (ATP) enzymes in the cell membrane
Absorption in the Small Intestine (see Chapter 4). Part of the sodium is absorbed along with
chloride ions; in fact, the negatively charged chloride ions
Absorption from the small intestine each day consists are mainly passively “dragged” by the positive electrical
of several hundred grams of carbohydrates, 100 or more charges of the sodium ions.
grams of fat, 50 to 100 grams of amino acids, 50 to 100 Active transport of sodium through the basolateral
grams of ions, and 7 to 8 liters of water. The absorptive membranes of the cell reduces the sodium concentra-
capacity of the normal small intestine is far greater than tion inside the cell to a low value (≈50 mEq/L), as shown

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 Chapter 65  Digestion and Absorption in the Gastrointestinal Tract

Interstitial Intestine of the adrenal glands. Within 1 to 3 hours this aldoster-

fluid lumen one causes increased activation of the enzyme and trans-
Cell
H2O H2O port mechanisms for all aspects of sodium absorption
by the intestinal epithelium. And the increased sodium

U n i t X II
K+ absorption in turn causes secondary increases in absorp-
tion of chloride ions, water, and some other substances.
This effect of aldosterone is especially important in the
Na+
colon because it allows virtually no loss of sodium chlo-
Na+
ride in the feces and also little water loss. Thus, the func-
Amino Acids
Na+
tion of aldosterone in the intestinal tract is the same as
Na+
K+ that achieved by aldosterone in the renal tubules, which
Glucose
also serves to conserve sodium chloride and water in the
Na+
H+ body when a person becomes dehydrated.
Cl-
HCO3-
Cl- Absorption of Chloride Ions in the Small
Na+
Intestine.  In the upper part of the small intestine, ­chloride
ion absorption is rapid and occurs mainly by diffusion
(i.e., absorption of sodium ions through the epithelium
H2O K+ H2O creates electro­negativity in the chyme and electropositiv-
ity in the paracellular spaces between the epithelial cells).
Then chloride ions move along this electrical gradient
Figure 65-8  Absorption of sodium, chloride, glucose, and amino to “follow” the sodium ions. Chloride is also absorbed
acids through the intestinal epithelium. Note also osmotic absorp- across the brush border membrane of parts of the ileum
tion of water (i.e., water “follows” sodium through the epithelial and large intestine by a brush border membrane chloride-
membrane). bicarbonate exchanger; chloride exits the cell on the baso-
lateral membrane through chloride channels.
in Figure 65-8. Because the sodium concentration in the
chyme is normally about 142 mEq/L (i.e., about equal to Absorption of Bicarbonate Ions in the Duodenum
that in plasma), sodium moves down this steep electro- and Jejunum.  Often large quantities of bicarbonate
chemical gradient from the chyme through the brush ions must be reabsorbed from the upper small intestine
border of the epithelial cell into the epithelial cell cyto- because large amounts of bicarbonate ions have been
plasm. Sodium is also co-transported through the brush secreted into the duodenum in both pancreatic secretion
border membrane by several specific carrier proteins, and bile. The bicarbonate ion is absorbed in an indirect
including (1) sodium-glucose co-transporter, (2) sodium- way as follows: When sodium ions are absorbed, moder-
amino acid co-transporters, and (3) sodium-hydrogen ate amounts of hydrogen ions are secreted into the lumen
exchanger. These transporters function similarly as in of the gut in exchange for some of the sodium. These
the renal tubules, described in Chapter 27, and provide hydrogen ions in turn combine with the bicarbonate ions
still more sodium ions to be transported by the epithelial to form carbonic acid (H2CO3), which then dissociates to
cells into the paracellular spaces. At the same time they form water and carbon dioxide. The water remains as part
also provide secondary active absorption of glucose and of the chyme in the intestines, but the carbon dioxide is
amino acids, powered by the active Na+-K+ ATPase pump readily absorbed into the blood and subsequently expired
on the basolateral membrane. through the lungs. Thus, this is so-called “active absorp-
tion of bicarbonate ions.” It is the same mechanism that
Osmosis of the Water.  The next step in the trans- occurs in the tubules of the kidneys.
port process is osmosis of water by transcellular and para­
cellular pathways. This occurs because a large osmotic Secretion of Bicarbonate Ions in the Ileum and Large
gradient has been created by the elevated concentration Intestine—Simultaneous Absorption of Chloride Ions
of ions in the paracellular space. Much of this osmosis
occurs through the tight junctions between the apical The epithelial cells on the surfaces of the villi in the ileum, as
borders of the epithelial cells (paracellular pathway), but well as on all surfaces of the large intestine, have a special capa-
much also occurs through the cells themselves (transcel- bility of secreting bicarbonate ions in exchange for absorption
lular pathway). And osmotic movement of water creates of chloride ions (see Figure 65-8). This is important because it
flow of fluid into and through the paracellular spaces and, provides alkaline bicarbonate ions that neutralize acid prod-
finally, into the circulating blood of the villus. ucts formed by bacteria in the large intestine.
Extreme Secretion of Chloride Ions, Sodium Ions, and
Aldosterone Greatly Enhances Sodium Absorp­ Water from the Large Intestine Epithelium in Some Types
tion.  When a person becomes dehydrated, large amounts of Diarrhea.  Deep in the spaces between the intestinal
of aldosterone almost always are secreted by the cortices ­epithelial folds are immature epithelial cells that continually

795
Unit XII  Gastrointestinal Physiology

divide to form new epithelial cells. These in turn spread out- is absorbed as disaccharides and almost none as larger
ward over the luminal surfaces of the intestines. While still ­carbohydrate compounds. By far the most ­abundant
in the deep folds, the epithelial cells secrete sodium chloride of the absorbed monosaccharides is glucose, usually
and water into the intestinal lumen. This secretion in turn is accounting for more than 80 percent of carbohydrate
reabsorbed by the older epithelial cells outside the folds, thus
calories absorbed. The reason for this is that glucose is
providing flow of water for absorbing intestinal digestates.
the final digestion product of our most abundant carbo-
The toxins of cholera and of some other types of diarrheal
bacteria can stimulate the epithelial fold secretion so greatly that hydrate food, the starches. The remaining 20 percent of
this secretion often becomes much greater than can be reab- absorbed monosaccharides is composed almost entirely
sorbed, thus sometimes causing loss of 5 to 10 liters of water and of galactose and fructose, the galactose derived from milk
sodium chloride as diarrhea each day. Within 1 to 5 days, many and the fructose as one of the monosaccharides digested
severely affected patients die from this loss of fluid alone. from cane sugar.
Extreme diarrheal secretion is initiated by entry of a sub- Virtually all the monosaccharides are absorbed by an
unit of cholera toxin into the epithelial cells. This stimulates active transport process. Let us first discuss the absorp-
formation of excess cyclic adenosine monophosphate, which tion of glucose.
opens tremendous numbers of chloride channels, allowing Glucose Is Transported by a Sodium Co-Transport
chloride ions to flow rapidly from inside the cell into the
Mechanism.  In the absence of sodium transport through
intestinal crypts. In turn, this is believed to activate a sodium
the intestinal membrane, virtually no glucose can be
pump that pumps sodium ions into the crypts to go along
with the chloride ions. Finally, all this extra sodium chloride absorbed. The reason is that glucose absorption occurs in
causes extreme osmosis of water from the blood, thus pro- a co-transport mode with active transport of sodium (see
viding rapid flow of fluid along with the salt. All this excess Figure 65-8).
fluid washes away most of the bacteria and is of value in com- There are two stages in the transport of sodium
bating the disease, but too much of a good thing can be lethal through the intestinal membrane. First is active transport
because of serious dehydration of the whole body that might of sodium ions through the basolateral membranes of the
ensue. In most instances, the life of a cholera victim can be intestinal epithelial cells into the blood, thereby deplet-
saved by administration of tremendous amounts of sodium ing sodium inside the epithelial cells. Second, decrease of
chloride solution to make up for the loss. sodium inside the cells causes sodium from the intestinal
Active Absorption of Calcium, Iron, Potassium, lumen to move through the brush border of the epithelial
Magnesium, and Phosphate.  Calcium ions are actively cells to the cell interiors by a process of secondary active
absorbed into the blood, especially from the duodenum, transport. That is, a sodium ion combines with a trans-
and the amount of calcium ion absorption is exactly con- port protein, but the transport protein will not transport
trolled to supply the daily need of the body for ­calcium. the sodium to the interior of the cell until the protein also
One important factor controlling calcium absorption is combines with some other appropriate substance such as
parathyroid hormone secreted by the parathyroid glands, glucose. Intestinal glucose also combines simultaneously
and another is vitamin D. Parathyroid hormone activates with the same transport protein and then both the sodium
vitamin D, and the activated vitamin D in turn greatly ion and glucose molecule are transported together to the
enhances calcium absorption. These effects are dis- interior of the cell. Thus, the low concentration of sodium
cussed in Chapter 79. inside the cell literally “drags” sodium to the interior of the
Iron ions are also actively absorbed from the small cell and along with it the glucose at the same time. Once
intestine. The principles of iron absorption and regula- inside the epithelial cell, other transport proteins and
tion of its absorption in proportion to the body’s need for enzymes cause facilitated diffusion of the glucose through
iron, especially for the formation of hemoglobin, are dis- the cell’s basolateral membrane into the paracellular space
cussed in Chapter 32. and from there into the blood.
Potassium, magnesium, phosphate, and probably still To summarize, it is the initial active transport of
other ions can also be actively absorbed through the intes- sodium through the basolateral membranes of the intesti-
tinal mucosa. In general, the monovalent ions are absorbed nal epithelial cells that provides the eventual motive force
with ease and in great quantities. Conversely, bivalent for moving glucose also through the membranes.
ions are normally absorbed in only small amounts; for Absorption of Other Monosaccharides.  Galactose is
example, maximum absorption of calcium ions is only transported by almost exactly the same mechanism as glu-
1/50 as great as the normal absorption of sodium ions. cose. Conversely, fructose transport does not occur by the
Fortunately, only small quantities of the bivalent ions are sodium co-transport mechanism. Instead, fructose is trans-
normally required daily by the body. ported by facilitated diffusion all the way through the intes-
tinal epithelium but not coupled with sodium transport.
Absorption of Nutrients Much of the fructose, on entering the cell, becomes
phosphorylated, then converted to glucose, and finally
Carbohydrates Are Mainly Absorbed transported in the form of glucose the rest of the way into
as Monosaccharides the blood. Because fructose is not co-transported with
Essentially all the carbohydrates in the food are absorbed sodium, its overall rate of transport is only about one half
in the form of monosaccharides; only a small fraction that of glucose or galactose.

796
 Chapter 65  Digestion and Absorption in the Gastrointestinal Tract

Absorption of Proteins as Dipeptides, Direct Absorption of Fatty Acids into the Portal
Tripeptides, or Amino Acids Blood.  Small quantities of short- and medium-chain fatty
As explained earlier in the chapter, most proteins, after acids, such as those from butterfat, are absorbed directly
into the portal blood rather than being converted into trig-

U n i t X II
digestion, are absorbed through the luminal membranes
of the intestinal epithelial cells in the form of dipeptides, lycerides and absorbed by way of the lymphatics. The cause
tripeptides, and a few free amino acids. The energy for of this difference between short- and long-chain fatty acid
most of this transport is supplied by a sodium co-trans- absorption is that the short-chain fatty acids are more water-
port mechanism in the same way that sodium co-trans- soluble and mostly are not reconverted into triglycerides by
port of glucose occurs. That is, most peptide or amino acid the endoplasmic reticulum. This allows direct diffusion of
molecules bind in the cell’s microvillus membrane with a these short-chain fatty acids from the intestinal epithelial
specific transport protein that requires sodium binding cells directly into the capillary blood of the intestinal villi.
before transport can occur. After binding, the sodium ion
then moves down its electrochemical gradient to the inte-
rior of the cell and pulls the amino acid or peptide along Absorption in the Large Intestine:
with it. This is called co-transport (or secondary active Formation of Feces
transport) of the amino acids and peptides (see Figure
65-8). A few amino acids do not require this sodium About 1500 milliliters of chyme normally pass through
co-transport mechanism but instead are transported by the ileocecal valve into the large intestine each day. Most
special membrane transport proteins in the same way of the water and electrolytes in this chyme are absorbed in
that fructose is transported, by facilitated diffusion. the colon, usually leaving less than 100 milliliters of fluid
At least five types of transport proteins for transport- to be excreted in the feces. Also, essentially all the ions
ing amino acids and peptides have been found in the are absorbed, leaving only 1 to 5 mEq each of sodium and
luminal membranes of intestinal epithelial cells. This chloride ions to be lost in the feces.
multiplicity of transport proteins is required because of Most of the absorption in the large intestine occurs in
the diverse binding properties of different amino acids the proximal one half of the colon, giving this portion the
and peptides. name absorbing colon, whereas the distal colon functions
principally for feces storage until a propitious time for
feces excretion and is therefore called the storage colon.
Absorption of Fats
Earlier in this chapter, it was pointed out that when Absorption and Secretion of Electrolytes and
fats are digested to form monoglycerides and free fatty Water.  The mucosa of the large intestine, like that of the
acids, both of these digestive end products first become small intestine, has a high capability for active absorption
dissolved in the central lipid portions of bile micelles. of sodium, and the electrical potential gradient created by
Because the molecular dimensions of these micelles are absorption of the sodium causes chloride absorption as
only 3 to 6 nanometers in diameter, and because of their well. The tight junctions between the epithelial cells of the
highly charged exterior, they are soluble in chyme. In this large intestinal epithelium are much tighter than those of
form, the monoglycerides and free fatty acids are carried the small intestine. This prevents significant amounts of
to the surfaces of the microvilli of the intestinal cell brush back-diffusion of ions through these junctions, thus allow-
border and then penetrate into the recesses among the ing the large intestinal mucosa to absorb sodium ions far
moving, agitating microvilli. Here, both the monoglycer- more completely—that is, against a much higher concen-
ides and fatty acids diffuse immediately out of the micelles tration gradient—than can occur in the small intestine.
and into the interior of the epithelial cells, which is possi- This is especially true when large quantities of aldoster-
ble because the lipids are also soluble in the epithelial cell one are available because aldosterone greatly enhances
membrane. This leaves the bile micelles still in the chyme, sodium transport capability.
where they function again and again to help absorb still In addition, as occurs in the distal portion of the small
more monoglycerides and fatty acids. intestine, the mucosa of the large intestine secretes bicar-
Thus, the micelles perform a “ferrying” function that is bonate ions while it simultaneously absorbs an equal
highly important for fat absorption. In the presence of an number of chloride ions in an exchange transport process
abundance of bile micelles, about 97 percent of the fat is that has already been described. The bicarbonate helps
absorbed; in the absence of the bile micelles, only 40 to 50 neutralize the acidic end products of bacterial action in
percent can be absorbed. the large intestine.
After entering the epithelial cell, the fatty acids and Absorption of sodium and chloride ions creates an
monoglycerides are taken up by the cell’s smooth endo- osmotic gradient across the large intestinal mucosa, which
plasmic reticulum; here, they are mainly used to form in turn causes absorption of water.
new triglycerides that are subsequently released in the
form of chylomicrons through the base of the epithelial Maximum Absorption Capacity of the Large
cell, to flow upward through the thoracic lymph duct and Intestine.  The large intestine can absorb a maximum of
empty into the circulating blood. 5 to 8 liters of fluid and electrolytes each day. When the

797
Unit XII  Gastrointestinal Physiology

total quantity entering the large intestine through the ileo- Barrett KE, Keely SJ: Chloride secretion by the intestinal epithelium:
cecal valve or by way of large intestine secretion exceeds ­molecular basis and regulatory aspects, Annu Rev Physiol 62:535, 2000.
Black DD: Development and physiological regulation of intestinal lipid
this amount, the excess appears in the feces as diarrhea. absorption. I. Development of intestinal lipid absorption: cellular events
As noted earlier in the chapter, toxins from cholera or in chylomicron assembly and secretion, Am J Physiol Gastrointest Liver
certain other bacterial infections often cause the crypts Physiol 293:G519, 2007.
in the terminal ileum and in the large intestine to secrete Bröer S: Amino acid transport across mammalian intestinal and renal
10 or more liters of fluid each day, leading to severe and ­epithelia, Physiol Rev 88:249, 2008.
Bröer S: Apical transporters for neutral amino acids: physiology and
sometimes lethal diarrhea. pathophysiology, Physiology (Bethesda) 23:95, 2008.
Bacterial Action in the Colon.  Numerous bacteria, especially Bronner F: Recent developments in intestinal calcium absorption, Nutr Rev
67:109, 2009.
colon bacilli, are present even normally in the absorbing
Daniel H: Molecular and integrative physiology of intestinal peptide trans-
colon. They are capable of digesting small amounts of cel-
port, Annu Rev Physiol 66:361, 2004.
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