Increasing the protein content of a meal increases acid
secretion. This occurs for two reasons. First, protein ingestion
increases the concentration of peptides in the lumen of the stom-
ach. These peptides, as we have seen, stimulate acid secretion.
The second reason is more complicated and reﬂ ects the effects
of proteins on luminal acidity. Before food enters the stomach,
concentration in the lumen is high because there are few
buffers present to bind any secreted hydrogen ions; therefore,
the rate of acid secretion is low because high acidity inhibits acid
secretion. The protein in food is an excellent buffer; however, as
protein enters the stomach, the H
concentration decreases as
binds to proteins. This decrease in acidity removes the inhi-
bition of acid secretion. The more protein in a meal, the greater
the buffering of acid, and the more acid secreted.
We now come to the intestinal phase that controls acid
secretion—the phase in which stimuli in the early portion of
the small intestine inﬂ uence acid secretion by the stomach.
High acidity in the duodenum triggers reﬂ exes that inhibit
gastric acid secretion. This inhibition is beneﬁ
cial because the
digestive activity of enzymes and bile salts in the small intes-
tine is strongly inhibited by acidic solutions. This reﬂ ex limits
gastric acid production when the H
concentration in the duo-
denum increases due to the entry of chyme from the stomach.
Acid, distension, hypertonic solutions, solutions con-
taining amino acids, and fatty acids in the small intestine
reﬂ exly inhibit gastric acid secretion. Thus, the extent to
which acid secretion is inhibited during the intestinal phase
varies, depending upon the volume and composition of the
intestinal contents, but the net result is the same—balancing
the secretory activity of the stomach with the digestive and
absorptive capacities of the small intestine.
The inhibition of gastric acid secretion during the intes-
tinal phase is mediated by short and long neural reﬂ exes and
by hormones that inhibit acid secretion by inﬂ uencing the
four signals that directly control acid secretion: ACh, gastrin,
histamine, and somatostatin. The hormones released by the
intestinal tract that reﬂ exly inhibit gastric activity are collec-
and include secretin and CCK.
summarizes the control of acid secretion.
Pepsin is secreted by chief cells in the form of an inactive pre-
cursor called pepsinogen. Exposure to low pH in the lumen
of the stomach causes conversion of pepsinogen to pepsin by
cleavage of acid-labile linkages. This reaction is faster when pH
is lower; in fact, it is almost instantaneous when pH<2. Once
formed, pepsin itself can act on pepsinogen to produce more
The synthesis and secretion of pepsinogen, followed by
its intraluminal activation to pepsin, provides an example of
a process that occurs with many other secreted proteolytic
enzymes in the gastrointestinal tract. Because these enzymes
are synthesized in inactive forms, collectively referred to as
any substrates that these enzymes might be able
to act upon inside the cell producing them are protected from
digestion, thus preventing damage to the cells.
Pepsin is active only in the presence of a high H
tration (low pH). It is irreversibly inactivated when it enters
the small intestine, where the bicarbonate ions secreted into
the small intestine neutralize the hydrogen ions.
The primary pathway for stimulating pepsinogen secre-
tion is input to the chief cells from the enteric nervous sys-
tem. During the cephalic, gastric, and intestinal phases, most
of the factors that stimulate or inhibit acid secretion exert the
same effect on pepsinogen secretion. Thus, pepsinogen secre-
tion parallels acid secretion.
Pepsin is not essential for protein digestion because in
its absence, as occurs in some pathological conditions, protein
can be completely digested by enzymes in the small intestine.
However, pepsin accelerates protein digestion and normally
accounts for about 20 percent of total protein digestion. It is
also important in the digestion of collagen contained in the
connective tissue matrix of meat.
An empty stomach has a volume of only about 50 ml, and
the diameter of its lumen is only slightly larger than that
of the small intestine. When a meal is swallowed, however,
the smooth muscles in the fundus and body relax before the
arrival of food, allowing the stomach’s volume to increase to as
much as 1.5 L with little increase in pressure. This
is mediated by the parasympathetic nerves to the
stomach’s enteric nerve plexuses, with coordination provided
by afferent input from the stomach via the vagus nerve and by
the swallowing center in the brain. Nitric oxide and serotonin
released by enteric neurons mediate this relaxation.
Enteric neural activity
Gastric phase stimuli:
amino acids & peptides
Cephalic and gastric phases controlling acid secretion by the
stomach. The dashed line and
indicate that an increase in
acidity inhibits the secretion of gastrin and that somatostatin
inhibits the release of HCl. HCl inhibition of gastrin and
somatostatin inhibition of HCl are negative feedback loops limiting
overproduction of HCl.