HORMONAL FACTORS INFLUENCING GASTRIC ACTIVITY
The stomach has multiple functions, which include digestion, secretion of acid, storage of food, and absorption. It is also involved in the regulation of appetite and satiety. Gut peptides play a major role in each of these diverse functions by modifying secretion, motility, and appetite regulation. More than 100 bioactive peptides have been discovered and function in autocrine, paracrine, or neurocrine ways. Five peptides, gastrin, CCK, secretin, somatostatin, and motilin, directly influence gastric activity and are described here in more detail.
Gastrin is produced mainly in the G cells of the gastric antrum in response to a meal or a high gastric pH. G cells are tightly regulated by gastrin-releasing peptide, somatostatin, and vagal inputs from the parasympathetic nervous system. Gastrin is a major media- tor of gastric acid secretion and acts by inducing the secretion of histamine, which, in turn, stimulates hydrochloride secretion. The most common cause of elevated gastrin levels is use of acid-suppressive medications, specifically proton pump inhibitors, which inhibit somatostatin release (a potent inhibitory stimulus) from the antral D cells. Other important causes of hypergastrinemia include the atrophic gastritis often associated with H. pylori infection and Zollinger-Ellison syndrome. The latter is a rare disorder caused by a gastrin-producing tumor commonly located in the gastrinoma triangle, bounded by the neck of the pancreas, the duodenum, and the cystic and common bile ducts. The serum gastrin in patients with a gastrinoma can be higher than 1000 pmol/L. The syndrome typically presents with peptic ulcers, diarrhea, and abdominal pain.
Cholecystokinin (CCK) is a peptide produced by the I cells of the duodenum and jejunum and belongs to the family of “brain-gut” peptides, in which the same transmitter is found in the intestine and CNS. The primary stimulus for its secretion is the presence of long-chain fatty acids, monoglycerides, or proteins in the small intestine. CCK is a potent stimulator of gallbladder contraction and also relaxes the sphincter of Oddi, which facilitates flow of bile into the intestine. CCK is a potent inhibitor of acid secretion by activating somatostatin release via CCK 1 receptors. Over the past few decades, understanding of CCK’s role in regulation of meal ingestion satiety has increased. Following post-prandial secretion, it delays gastric emptying. CCK also acts on vagal afferent nerve fibers and sends signals to the dorsal hindbrain to reduce meal size and increase the intermeal interval.
Secretin is a peptide secreted by the S cells in the duodenum and jejunum in response to a low duodenal pH. Secretin stimulates pancreatic fluid and bicarbonate secretion, leading to neutralization of acidic chyme in the intestine. Secretin also stimulates fluid and bicarbonate release from the biliary ducts, duodenal mucosa, and Brunner glands while inhibiting gastric acid release and intestinal motility.
Somatostatin is abundant in the gastrointestinal tract and pancreas, where it is produced by paracrine D cells. Somatostatin secretion is stimulated by meal ingestion and gastric acid secretion. Somatostatin is a key inhibitory peptide. It decreases endocrine and exocrine secretion, reduces gastrointestinal motility and blood flow, and inhibits gallbladder contraction and secretion of most gastrointestinal hormones.
Motilin is a peptide secreted by the M cells of the proximal small intestine. It is released in the interdigestive state and triggered by luminal alkalization and bile. On the other hand, the presence of nutrients or acid in the small intestine strongly suppresses the endogenous release of motilin in a digestive state. The motilin receptor activates the phospholipase C signaling pathway expressed in nerves and smooth muscles. Circulating motilin levels peak every 1 to 2 hours in fasting individuals. Motilin is thought to facilitate the phase III migrating motor complex, often known as the intestinal housekeeper, which is a strong contraction that begins at the lower esophageal sphincter and progresses down the gastrointestinal tract, sweeping nondigestible solid residue toward the colon and preventing colonic bacteria from migrating into the small bowel.
The motilin receptor also binds and is activated by the macrolide antibiotic erythromycin, which is used in the off-label treatment of delayed gastric emptying seen in diabetes mellitus and in patients with duodenectomy. Ho ever, its broad range of activities limits longterm use.