Figure 48-3. Distribution of peptide hormones in the gastrointestinal tract.

Cholecystokinin (CCK) is produced in the proximal two-thirds of the small intestine by the I cells and

released into the gut lumen. It has 4 main forms (CCK-58, CCK-39, CCK-33, and CCK-8). It shares the

final five amino acids adjacent to the C-terminus with gastrin, and this accounts for its hormonal

activity. Stimulation of I cells by amino or fatty acids causes release of CCK, this in turn stimulates

contraction and emptying of the gallbladder, increases bile flow, causes relaxation of the sphincter of

Oddi, and stimulates pancreatic enzyme secretion. CCK also has trophic effects on the small intestinal

mucosa and pancreas.

Secretin, discovered as the first gastrointestinal hormone in 1902, is a 27 amino acid peptide

produced by the S cells of the duodenum and jejunum. Secretin is released into the circulation and

intestinal lumen in response to low intraluminal pH, fatty acids, and bile salts. Water and bicarbonate

are secreted by the pancreas in response to secretin. Bicarbonate is also released from the biliary ductal

epithelium and Brunner glands in response to secretin. In turn, pancreatic enzymes are released from

the pancreas. The increased pH and the presence of pancreatic enzymes aid in the digestion of lipids.

The increased pH also provides a negative feedback loop to inhibit further production of secretin.

Secretin produces a paradoxical release of gastrin in patients with gastrinomas, but does not produce

this effect on normal individuals.

Somatostatin is a peptide hormone consisting of 14 or 28 amino acids and is produced by D cells in

the pancreatic islets, gastric antrum, and duodenum. Its primary role is inhibition of other

gastrointestinal hormones and inhibition of pancreatic, biliary, and gastric secretion. In addition,

somatostatin decreases splanchnic and portal blood flow. Somatostatin is stimulated by the presence of

fat, proteins, acid, glucose, amino acids, and CCK. Octreotide, a long-acting synthetic somatostatin

analog, is used in the treatment of variceal bleeding, hormone secreting neuroendocrine tumors,

carcinoid syndrome, and enterocutaneous and pancreatic fistulas.8

Gastrin-releasing peptide, the mammalian homolog of bombesin, is a 27 amino acid peptide which is

produced by the small intestine and is released in response to vagal stimulation. It is a prostimulatory

molecule which causes the release of most gastrointestinal hormones, with the exception of secretin. It

also has a promotility effect and stimulates endothelial proliferation. Gastric inhibitory peptide or

glucose-dependent insulinotropic peptide (GIP) is a 42 amino acid peptide produced by the K cells of the

duodenum and jejunum. It is released in response to glucose, fat, protein, and adrenergic stimulation. It

stimulates secretion of insulin and inhibits gastric acid and pepsin production. Type 2 diabetics are

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resistant to the effects of GIP.

Motilin is a 22 amino acid peptide produced by the enteroendocrine cells in the duodenum and

jejunum. Release of motilin occurs during the interdigestive and fasting periods. Release may also be

related to alkalinization of the duodenum. Motilin’s main function is to stimulate the migrating

myoelectric complex. Motilin agonists such as erythromycin, are used clinically as stimulants of

gastrointestinal motility.

VIP is a 28 amino acid peptide which is produced by gastrointestinal tract neurons. It serves as a

neurotransmitter stimulating pancreatic exocrine and intestinal secretion. Conversely, it has an

inhibitory effect on gastric acid secretion. VIP is a potent vasodilator and relaxant of smooth muscle.

Neurotensin is a 13 amino acid peptide that is produced by the N cells primarily in the ileum, but also

in the proximal small intestine and colon in response to the presence of intraluminal fat. It stimulates

pancreatic bicarbonate secretion and intestinal motility. Neurotensin also serves as a trophic factor on

the small intestinal mucosa and inhibits gastric secretion.

Pancreatic glucagon and enteroglucagon are 29 and 37 amino acid peptides produced by the α-islet

cells of the pancreas and the L cells of the small intestine, respectively. Pancreatic glucagon is released

in response to low serum glucose and subsequently induces glycogenolysis, lipolysis, gluconeogenesis,

and ketogenesis. Enteroglucagon is released in response to the presence of a mixed meal and inhibits

gastric emptying and small bowel motility.

Motility

5 The coordination of movements of the gastrointestinal tract is necessary for the proper digestion of

food. Well-timed contraction and relaxation patterns are initiated in gastrointestinal nervous system

causing coordinated electrical activity and muscular movements. This may be influenced by both

internal and external factors. The small intestine has motor functions which are distinct from the other

parts of the gastrointestinal tract. The intrinsic nerves (myenteric or Auerbach plexus) provide the basis

for coordinating the circular and longitudinal smooth muscles of the small intestine. Extrinsic

sympathetic (epinephrine) stimulation slows motility while parasympathetic (acetylcholine) stimulation

increases motility.

The intrinsic electrical activity of the small intestine is based on the intestinal smooth muscle normal

resting potential. This normally is –50 to –70 mV and is maintained by Na+-K+-ATPase activity.9 The

resting potential varies by 5 to 15 mV and results in a phasic depolarization which is referred to as slow

waves, basic electrical rhythm, or pacemaker potential. These depolarizations occur at regular intervals

of approximately 11 to 13 times per minute in the duodenum and decrease to 8 to 10 times in the ileum,

but do not directly lead to muscular contractions. The electrical activity is coupled to muscular

contraction at the level of gap junctions, which are low resistance cell-to-cell connections. These gap

junctions become less regular in the midjejunum and in the distal small intestine. This causes slowing of

the frequency of contractions distally, allowing for absorption of more slowly digested intestinal

contents, including fats and bile salts.

Spike potentials represent a second mode of electrical stimulation of the small intestine. Spike

potentials result in rapid depolarization of the membrane potential. Repeated bursts of spike potentials

cause a short area of contraction. In contrast to the always present slow waves, spike potentials occur at

discrete time intervals. The coordination of a slow wave and a spike potential leads to the initiation,

duration, and frequency of rhythmic migratory small intestinal contractions.

During the interdigestive period between feeding, the small intestine follows a well-defined rhythmic

pattern. This pattern consists of muscular contractions that migrate from the stomach or duodenum,

continue on to the terminal ileum, and are regulated by the migrating motor complex (MMC). This

pattern can be broken down into four distinct phases. Phase I is a period of relative quiescence; phase II

is a period of accelerated irregular electrical spiking and muscular activity; phase III is a series of highamplitude rapid electrical spikes corresponding to rhythmic gut contractions; and phase IV is a period of

subsiding activity. This process occurs over a period of 90 to 120 minutes and progresses from the

proximal small bowel and terminates in the ileum. Once the MMC reaches the terminal ileum, the

process starts over again in the proximal small bowel. The circular muscles provide segmental

contraction over a 1-cm length of small intestine. These contractions occur approximately 11 to 13 times

per minute in the duodenum and decrease to 8 to 10 times in the ileum. This creates functional

compartments where prolonged exposure to the mucosa and mixing of the intestinal chyme occurs,

aiding the process of digestion and absorption. The circular muscles are also responsible for the

peristaltic waves which propagate regularly at a rate of 1 to 2 cm/sec. These regular waves may be

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interspersed with rushes of contractions followed by periods of no motor activity. This rate becomes

progressively slower in the distal small intestine. These peristaltic movements serve as a method of

propelling chyme through the length of the small intestine. The total transit time from the duodenum to

the terminal ileum is approximately 220 minutes (+/–53 minutes).10 Serum motilin levels have been

found to mirror the activity of the MMC. Exogenous motilin administration has been found to increase

MMC activity.

During and immediately following times of feeding, the intestinal movements are not rhythmic, with

complexes of peristaltic and antiperistaltic contractions. This is thought to be a disruption of the MMC

from bolus feeding. This seemingly random pattern of movements allows for effective mixing of chyme.

Hormonal changes are thought to play a role in this process. Physiologic doses of neurotensin, insulin,

gastrin, and CCK cause an alteration in the MMC similar to bolus feeding. Visual and olfactory feeding

cues can also cause a disruption of the MMC. The MMC is more significantly inhibited by fatty meals as

opposed to protein or carbohydrate meals of similar caloric value. The intrinsic nervous plexus or

Meissner plexus innervating the submucosa helps to regulate mucosal absorption and secretion, but has

no control on motility.

IMMUNOLOGY

Principles of Gut Immunology

6 The lumen of the gastrointestinal tract is connected to the outside environment and comes in direct

contact with many potentially pathogenic microorganisms. Lymphocytes, macrophages, polymorphic

granulocytes and other cells that take part in immune response are distributed throughout the whole

gut. The commensal microflora have many benefits to the host by supporting digestion and keeping the

appropriate balance among different microbial species.11 The immune system is highly effective at

responding selectively to invading pathogens, yet on the other hand tolerating a much larger number of

harmless food antigens and commensal organisms. Many bacteria, viruses and parasites are digested and

enter the small intestine every day.12 Consequently, the small intestine needs a complex defense

mechanism to battle against these exposures in different ways.13

While the immune system in the small intestine is important for host defense, other mechanisms

within the small intestine also participate in host defense. Proteolytic and lipolytic enzymes are

produced in high concentrations by extraintestinal cells in the pancreas and degrade different

pathogenic agents at an early phase of digestion. In addition, mucin is produced by the enterocytes

which is cytoprotective and inhibits bacterial growth. The small intestine can actively increase

peristalsis functions to mechanically get rid of pathogenic agents, which may be potentially dangerous

to the gut. In addition, tight junctions between epithelial cells prevent penetration of bacteria in

between cells. Potential pathogens vary greatly in size, from very small viruses that are nanometer in

size, to parasites such as helminths that are macroscopically visible and quite large. To put this into the

broader picture of evolution, a large range of defense mechanisms is essential for survival of each

individual.

The primary cellular barrier in the gut that prevents antigens from encountering the immune system

is the single layer of gut epithelium. The total surface area of the small intestine is 400 m2, due not only

to intestinal length but also due to the formation of millions of villi in the small bowel which contribute

significantly to the overall surface area.14 In the upper small intestine, the bulk of antigen exposure

comes from the diet, whereas in the ileum and colon, the additional antigenic load of an abundant and

highly complex commensal microflora is prevalent. The epithelial cells of the gut mucosa have

developed features that make the intestinal epithelium an active immunologic as well as anatomic

barrier. For example, these nonclassical immune cells express major histocompatibility complex (MHC)

class I and II molecules, consistent with their ability to participate in adaptive immune recognition of

pathogenic bacteria. Small intestinal epithelial cells also express toll-like receptors on their apical

surface that enables them to detect bacterial products and to initiate an innate immune response.

Antigen-presenting dendritic cells (DCs) also send processes between gut epithelial cells without

disturbing tight junction integrity and sample commensal and pathogenic gut bacteria.15,16 The gut

epithelial barrier therefore represents a highly flexible structure that limits antigens from entering the

systemic body.

The gut-associated immune system represents one of the largest immunologic compartments in the

body. Lymphoid tissue in the gastrointestinal tract is a major part of the whole-body immune system

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