Overview of Control Mechanisms
The digestive system is
controlled by a fascinatingly complex interaction between extrinsic and
intrinsic hormones, the extrinsic and intrinsic nervous systems, and a unique
electrical control system. Recent increases in our understanding of the neural
and hormonal regulatory systems have shown that many of the neurotransmitters
crucial to functioning of the CNS are also found in the gut. In fact, many were
first identified in the gut and then shown to also exist in other organs,
including the brain.
Effective, well-organized contractions throughout the tubular digestive
system are of critical importance to digestion and absorption in the mixing and
propelling of intraluminal contents. As in other muscles, contractions result
from cell membrane depolarizations that are recorded as action potentials.
These membrane changes are responsible for effective electromechanical coupling
by opening calcium channels that stimulate actin-myosin interactions. To cause
coordinated, circular contractions that will effectively move luminal contents,
these depolarizations must occur around the lumen. This is made possible by an
electrical syncytium that preferentially creates simultaneous depolarizations
around the lumen. Depolarizations occur in a rhythmic fashion from electrical
pacemaker potentials created by the interstitial cells of Cajal. These paced
depolarizations, which facilitate coordinated contractions around the lumen,
are known as slow waves. They are not seen in the esophagus or fundus of
the stomach but first develop in the upper body of the stomach at a frequency
of three cycles per minute. Gastric paced slow waves progress down the stomach
and end at the pyloric sphincter. In the small intestine, the rate of slow
waves created by the pacemakers is higher in the duodenum (17 to 18 cycles per
minute) than the jejunum and even slower in the ileum (14 to 16 cycles per
minute). This gradient of slow wave frequency contributes to the proximal to
distal movement of luminal contents. The progressive movement of slow waves
from the proximal to the distal lumen also permits peristalsis to occur in a caudal direction. Slow wave
frequencies in the colon are more complex and less uniform but are generally
thought to occur at three to six cycles per minute.
Slow waves result in forceful mixing or peristaltic contractions only in the presence of
stimuli that result in further cell membrane depolarizations that create an
action potential. The presence of an electrical syncytium favoring circular
depolarizations around the lumen permits a circular contraction to be produced from the stimulus that creates the action
potential. Thus, slow waves control spatial relationships and directions of
movement of gastric and intestinal luminal contractions that were created by
action potentials that created electrical responses. Action potential stimulation
may originate from extrinsic hormones, extrinsic neurotransmitters, intrinsic
hormones, or intrinsic neurotransmitters.
Extrinsic
Endocrine System
Extrinsic hormones that have a broad influence on all organ systems also
affect the gut; they include thyroid hormones, adrenocorticotropic hormone, corticosteroids,
mineralocorticoids, corticotropinreleasing factor, and leptin. Leptin is a CNS
hormone that has a primary role in influencing digestion by reducing food
intake and modulating the metabolism of nutrients. The complex role of hormones
in the regulation of appetite and satiety is discussed in Plates 1-56 and 1-57.
Both deficiencies and excesses of thyroid hormones may lead to gut malfunction.
Patients with hypothyroidism often complain of constipation and loss of
appetite. If the disorder progresses to myxedema, motility dysfunction can
develop throughout the digestive system, with impaired peristalsis and
contractility.
Corticotropin-releasing hormone has a major role in the physiologic
response to stress. Levels of this hypothalamic hormone increase during actual
stressful events, as when a person is facing a traumatic situation, but also
during events that are not inherently stressful but are perceives as stressful.
The latter situation leads to challenges in diagnosing and managing functional
bowel disorders.
Extrinsic Nervous System
The previous theory that digestive system functions are primarily
regulated by the autonomic nervous system and, thus, the CNS is overly
simplistic. The influence of the autonomic nervous system is mediated by a
balance of the stimulatory effects of the para-sympathetic nervous system and
inhibitory effects of adrenergic
neurons in the sympathetic nervous system.
Only
10% to 20% of vagal nerves are efferent, far too few to control the many
complex responses of the seven digestive organs, much less all the other
visceral organs. Direct input to gut functions by the autonomic nervous system
is important, but the system serves as the primary control system only in the
striated muscle regions of the pharynx and upper esophagus via cranial nerves
and in the rectum and anal sphincter via sacral and pelvic nerves. Sympathetic
nerves reach the gut to mediate blood flow and help to “shut down” the gut
during the fight-or-flight response via the intermediolateral column to
splanchnic nerves originating from T2 to L3. These then innervate the gut via
nerves whose bodies are in the celiac, superior mesenteric, or inferior
mesenteric ganglia.
The autonomic nervous system primarily serves to modify local gut
reflexes, but it also plays a critical role in a variety of gut reflexes and in
communicating afferent information to the brain. Medications that inhibit
cholinergic neurons are a cornerstone of treatment of spastic disorders of the
entire gastrointestinal tract. Anticholinergics are also widely used to reduce
oral secretions during endoscopy, oral surgery, or anesthesiology. The
importance of vagal stimulation of gastric secretions explains why surgical
selective vagotomy is sometimes used to manage complex ulcer disease.
The sympathetic nervous system’s fight-or-flight reflex leads to diarrhea
and contributes to functional disorders
in patients plagued by anxiety and hypervigilance. Increased sympathetic tone
during stress associated with trauma or sepsis is needed to maintain the blood
pressure and circulation but often results in a severe reduction in gut blood
flow known as a mesenteric steal. Decreased blood flow reduces metabolic
support for the intrinsic protective mechanisms of the stomach, resulting in
unopposed acid injury and severe, at times even hemorrhagic, gastritis.
Enteric Nervous System
The amazing expansion of our understanding of the intrinsic or enteric
nervous system, both experimentally and clinically, indicates that the
complexity of the system is similar to that of the CNS. The predominance of the
enteric nervous system can be best appreciated by observing the successful
function of liver, pancreatic, small bowel, and even colon transplants in the
absence of neural input from the CNS. The enteric nervous system is so crucial
for digestion that a separate section is dedicated to its description (see
Plate 1-46).
Intrinsic Endocrine System
The field of endocrinology was conceived when the first hormone, secretin,
a major hormone in the digestive system, was discovered in 1914. Our knowledge
of the digestive system’s intrinsic endocrine system’s transmitters, functions,
and molecular processing has grown exponentially since then. Gut hormones
stimulate the coordination of widely diverse functions in each of the digestive
organs to work in concert to digest and absorb food. Gut hormones achieve this
by modifying secretion, absorption, motility, and metabolism.
Gut hormones alter metabolism not only in the digestive system but
throughout the body. Insulin released from pancreatic islet cells is the best
example of this important role of gut hormones. Other gut hormones that have a
major role in modifying metabolism include glucagon, cholecystokinin, peptide
YY, insulin- like growth factor 1, and ghrelin. Ghrelin is a hormone released
from the stomach and proximal small bowel that increases food intake.
Many gut hormones influence gastrointestinal motility. Cholecystokinin
and secretin coordinate the response to food intake by altering gastric
emptying, duodenal contractions, gallbladder contractions, and contractions of
the sphincter of Oddi (relaxed) and pyloric sphincter (contractions). Perhaps
the most fascinating physiologic event of the digestive system is coordinated
emptying of the upper digestive tract during fasting. This occurs when forceful
contractions of phase III of the interdigestive motor complex, known as
the intestinal housekeeper, are initiated by the hormone motilin.
Well-defined clinical syndromes have been recognized that are due to
neuroendocrine tumors. Advances in technology have led to the recognition that
such hormone-secreting tumors are more common than previously appreciated. These
important hormone regulators of gut function and the disorders for which they
are known to be responsible are discussed in Plate 1-49. It can readily be appreciated
that the digestive system’s seven organs are regulated by a complex interaction
of the extrinsic nervous system and extrinsic hormonal system which modulates
the more reflexive “hard-wired” reflexes of the enteric nervous system and
intrinsic hormonal system. The clinician’s challenge is to determine which of
these mechanisms is at play in causing
a patient’s symptoms and disease.
