1. NEURAL REGULATION
The sympathetic and parasympathetic nervous systems, as well as the enteric nervous system,
mediate gastrointestinal activities. Sympathetic nervous system fibers, arising in the thoracic and
lumbar regions of the spinal cord, innervate all areas of the gastrointestinal tract. Generally,
norepinephrine, released from the nerve endings, acts on smooth muscle of the digestive tract to
inhibit activity. Sympathetic efferent neurons, for example, decrease muscle contractions and
constrict sphincters to diminish gastrointestinal motility. In contrast, the parasympathetic nervous
system typically stimulates the digestive tract promoting motility (peristalsis), gastrointestinal
reflexes, and secretions. For example, the facial and glossopharyngeal nerves stimulate saliva
production, and the vagus nerve, which innervates the esophagus, stomach, pancreas, and proximal
colon, stimulates gastric acid secretion, among other processes. The nervous system of the
gastrointestinal tract is referred to as the enteric (relating to the intestine) nervous system. The
system includes millions of neurons and their processes embedded in the wall of the gastrointestinal
tract beginning in the esophagus and extending to the anus. The enteric nervous system, which is
connected to the central nervous system largely through the vagus nerve and other pathways out
of the spinal cord, can be divided into two neuronal networks, or plexuses: the myenteric plexus (or
plexus of Auerbach) and the submucosal plexus (or plexus of Meissner). The location and actions of
these two p lexuses are given here:
Myenteric Plexus
Lies in the muscularis externa between longitudinal and circular muscles of the muscularis propia
Controls peristaltic activity and gastrointestinal motility
Submucosal Plexus
Lies in the submucosa (mostly in the intestines)
Controls mainly gastrointestinal secretions and local blood flow
Impulses, either stimulatory or inhibitory, are sent from the enteric nervous system to the smooth
circular and l ongitudinal muscles of the gastrointestinal tract. The m yenteric plexus controls
peristalsis, and when this plexus is stimulated, gastrointestinal activity generally i ncreases. The s
ubmucosal plexus typically controls s ecretion r elease, receiving information from stretch receptors
and gastrointestinal e pithelial cells in the i ntestinal wall. Also under control by the enteric nervous
system is the regulation of gut motility by the migrating myoelectric or motility complex, described
in the “Regulation of Gut Motility and G astric Emptying” s ection of this chapter.
The enteric nervous system also affects gastrointestinal reflexes, called enterogastric reflexes.
Reflexes are an involuntary response to stimuli and in the gastrointestinal tract affect secretions,
blood flow, and peristalsis as well as other processes involved in digestion. Two examples of
enterogastric reflexes include the ileogastric reflex and the gastroileal reflex. With the ileogastric
reflex, gastric motility is inhibited when the ileum becomes distended. With the gastroileal reflex,
2. ileal motility is stimulated when gastric motility and secretions increase. Other r eflexes a ffect the
small and large intestines. For example, the colonoileal reflex from the colon inhibits the emptying
of the contents of the ileum into the colon. The intestinointestinal reflex diminishes intestinal
motility when a segment of the intestine is overdistended
REGULATORY PEPTIDES
Factors influencing digestion and absorption are coordinated, in part, by a group of gastrointestinal
tract molecules called regulatory peptides or, more specifically, gastrointestinal hormones and
neuropeptides. Regulatory peptides affect a variety of digestive functions, including gastrointestinal
motility, intestinal absorption, cell growth, and the secretion of digestive enzymes, electrolytes,
water, and other hormones.
Some of the regulatory peptides—such as gastrin, cholecystokinin, secretin, glucose-dependent
insulinotropic peptide (GIP), and motilin—are considered hormones. In fact, many of the hormones
can be categorized together (and called families) based on their amino acid sequences. Some
regulatory peptides are termed paracrines and neurocrines. When released by endocrine cells,
paracrines
diffuse through extracellular spaces to their target tissues rather than being secreted into the blood
(like hormones) for transport to target tissues. Some paracrines affecting the gastrointestinal tract
include somatostatin, glucagonlike peptides, and insulin-like growth factor.
The functions of regulatory peptides with respect to the gastrointestinal tract and the digestive
process are numerous and have been addressed to varying degrees in the sections on regulation of
gastric and intestinal secretions and motility. Most, but not all, hormones and peptides have
multiple actions; some are strictly inhibitory or stimulatory, whereas some mediate both types of
responses. More than 100 regulatory peptides are thought to affect gastrointestinal functions. Table
2.2 summarizes some of the functions of a few of these peptides.
Gastrin, secreted into the blood primarily by enteroendocrine G-cells in the antrum of the stomach
and proximal small intestine, acts mainly in the stomach. Gastrin release occurs in response to vagal
stimulation, ingestion of specific substances or nutrients, gastric distention, hydrochloric acid in
contact with gastric mucosa, and the effects of local and circulating hormones. Gastrin principally
stimulates the release of hydrochloric acid, but it also stimulates gastric and intestinal motility and
pepsinogen release. Gastrin also stimulates the cellular growth of (that is, has trophic action on) the
stomach and both the small and large intestines.
Cholecystokinin (CCK), secreted into the blood by enteroendocrine I-cells of the proximal small
intestine and by enteric nerves, principally stimulates secretion of pancreatic juice and enzymes into
the duodenum. It also stimulates gallbladder contraction, which facilitates the r elease of bile into
the duodenum, and to a limited extent, it stimulates gastric motility
Secretin, secreted into the blood by enteroendocrine S-cells found in the proximal small intestine,
is secreted in response to the release of acid chyme into the duodenum. Secretin acts primarily on
pancreatic acinar cells to stimulate the release of pancreatic juice and enzymes into the intestine.
Secretin is thought to stimulate pepsinogen release but inhibit gastric acid secretion. It may also
3. inhibit motility of most of the gastrointestinal tract, especially the stomach and proximal small
intestine.
Motilin, a peptide secreted by enteroendocrine M-cells of the duodenum and jejunum, stimulates
gastric and duodenal motility, gastric and pancreatic secretions, and gallbladder contraction.
Glucose-dependent insulinotropic peptide (GIP), previously called gastric inhibitory peptide, is
produced by enteroendocrine K-cells of the duodenum and jejunum and primarily stimulates insulin
secretion. GIP also inhibits gastric secretions and motility.
Peptide YY, secreted by enteroendocrine cells of the ileum, inhibits gastric acid and pancreatic juice
secretions and inhibits gastric and intestinal motility.
Enteroglucagon, secreted by the ileum, inhibits to a minor extent gastric and pancreatic secretions.
Amylin, secreted by the pancreatic cells and gastric and intestinal endocrine cells, delays gastric
emptying and i nhibits postprandial glucagon secretion.
Paracrine-acting substances usually work by entering secretions. Three examples of paracrine-acting
peptides are:
Somatostatin, synthesized by pancreatic Δ (D) cells and intestinal cells, appears to mediate the
inhibition of gastrin release as well as the release of GIP, secretin, VIP, and motilin and thus inhibits
gastric acid, gastric motility, pancreatic exocrine secretions, and gallbladder contraction.
Glucagon-like peptides are secreted by enteroendocrine L-cells of the ileum and colon and by the
nervous system. These peptides decrease gastrointestinal motility and increase proliferation of the
gastrointestinal tract; they also influence glucagons and insulin secretion.
Insulin-like growth factors, also secreted by endocrine cells of the gastrointestinal tract, increase
proliferation of the gastrointestinal tract.
Four examples of neurocrine peptides are:
Vasoactive intestinal polypeptide (VIP) is present in central and peripheral neurons. It is not thought
to be present in intestinal endocrine cells. VIP is thought to stimulate intestinal secretions, relax
most gastrointestinal sphincters, inhibit gastric acid secretion, and s timulate the release of
pancreatic secretions.
Gastrin-releasing peptide (GRP), also called bombesin, released from enteric nerves, stimulates
gastrin release as well as other peptides like cholecystokinin, glucagon-like peptides, and
somatostatin.
Neurotensin, produced by neurons and N-cells of the small intestine mucosa (especially the ileum),
has no physiological role in digestion at normal circulating concentrations; however, neurotensin
has multiple actions in the brain.
Substance powder (P), another neuropeptide found in nerve and endocrine cells in the
gastrointestinal tract, increases blood flow to the gastrointestinal tract, inhibits acid secretion,
increases motility of the small intestine, and binds to pancreatic acinar cells associated with enzyme
secretion.
4. In addition to effects on gastrointestinal tract secretions and motility, many hormones and peptides
influence food intake. Ghrelin, for example, a peptide secreted primarily from endocrine cells of the
stomach and small intestine, stimulates food intake. Plasma concentrations of ghrelin typically rise
before eating (e.g., a fasting situation) and decrease immediately after eating, especially
carbohydrates. Ghrelin also stimulates expression of neuropeptide Y. Neuropeptide Y also
stimulates eating, but inhibits secretion of gastric ghrelin and insulin. Neuropeptide Y is typically
effective as long as leptin concentrations are relatively low.
Leptin is secreted mainly by white adipose tissue and the amount secreted is proportional to fat
stores. Leptin suppresses food intake and inhibits neurons from releasing neuropeptide Y and
agouti-related protein, with the net effect of suppressing these appetite-stimulating peptides.
Leptin is known to work in conjunction with α melanocyte stimulating hormone (α-MSH).
Specifically, leptin’s ability to inhibit food intake is based, at least in part, on α-MSH’s stimulation of
MC4 receptors primarily in the hypothalamus. Corticotropin-releasing factor (CRF) also is involved
in leptin’s suppression of food intake.
Some of the other hormones that control gastrointestinal tract secretions also have been shown to
affect food intake. Cholecystokinin and gastrin-releasing peptides are thought to serve as satiety
factors. Thus, the various mediators of the digestive process work in concert to stimulate and inhibit
food intake and to break down and absorb the nutrients.
