Control of the digestive system progresses from the head to the stomach to the small intestine as food enters and moves through the GI tract. We can distinguish three phases of control: cephalic, gastric, and intestinal. During the cephalic phase of control, receptors for the sight, smell, taste, and even the thought of food initiate reflexes that cause salivation, production of gastric juice, and gastric contractions. These responses are mediated by the Vagus nerve and prepare the GI system for the arrival of a meal. During the gastric phase of control, the meal is in the stomach. The stomach contents and volume initiate reflexes that cause production of gastric secretions and increase gastric motility. During the intestinal phase of control, the meal moves into the intestine. The intestinal contents and volume initiate reflexes that cause secretion of bicarbonate, digestive enzymes, and bile, and begin segmenting contractions in the small intestine. Inhibitory reflexes from the intestine slow gastric emptying while the intestinal contents are neutralized, digested, and absorbed. The phases of control occur in sequence only at the beginning of a meal. Once a meal is underway, the phases are simultaneous. The stomach and intestine work together, back and forth, to digest and absorb the contents of a meal. Recall that the autonomic nervous system has a two-neuron chain between the central nervous system and effector organs. These are the neurotransmitters of the autonomic nervous system. Acetylcholine is the neurotransmitter for all preganglionic fibers and for parasympathetic postganglionic fibers. Norepinephrine is the neurotransmitter for sympathetic postganglionic fibers. Many neurotransmitters found in the brain are also found in the enteric nervous system. Interneurons may use acetylcholine, serotonin, vasoactive intestinal peptide, nitric oxide, and somatostatin. Neurons that are excitatory to smooth muscle use acetylcholine and substance P. Neurons that are inhibitory to smooth muscle use vasoactive intestinal peptide and nitric oxide. Another family of neurotransmitters, the enkephalins found in nerve fibers of the mucosa and smooth muscle act to slow intestinal motility; contract the lower esophageal sphincter, pyloric, and ileocecal sphincters; and inhibit intestinal secretion. Note that acetylcholine has profound effects on the digestive system because of its widespread use by parasympathetic, sympathetic, and enteric neurons. The enteric neurons use many different neurotransmitters, some neurons releasing more than one. This results in complex actions by the GI neurotransmitters. Like parasympathetic and sympathetic nerves, hormones modulate the activity of the digestive system. Here are some characteristics of GI hormones. GI hormones are peptides. There are many peptides in the GI system. To be recognized as a hormone, a peptide must meet rigorous criteria. Some GI peptides have been found to be neurotransmitters, and others are considered candidate hormones. We will study the five currently identified GI hormones: gastrin, cholecystokinin or CCK, secretin, glucose-dependent insulinotropic peptide or GIP, and motilin. Note that each bead in the images of the hormones represents one amino acid. Individual enteroendocrine cells in the mucosa secrete the GI hormones. GI hormones are not released from endocrine glands. They are released from single cells located over large areas of the gastrointestinal mucosa. GI hormones support the function of the particular organ that releases them. Gastrin, CCK, and secretin also have trophic effects. Let’s look at each hormone to see where it is released, and to review its actions. G cells in the pyloric antrum of the stomach secrete gastrin. Gastrin stimulates hydrochloric acid secretion in the stomach, and growth of the gastric and colonic mucosae. I cells in the duodenum and jejunum secrete CCK. CCK causes the gallbladder to contract moving bile into the small intestine. It also causes the exocrine pancreas to secrete digestive enzymes into the small intestine. CCK stimulates growth of the exocrine pancreas and mucosa of the gallbladder, and inhibits gastric emptying. S cells in the duodenum secrete the hormone secretin. Secretin causes both the liver and the exocrine pancreas to secrete bicarbonate into the small intestine, and stimulates growth of the exocrine pancreas. Secretin inhibits gastric acid secretion. Because its actions reduce acidity, secretin is called “nature’s antacid.” Cells of the duodenum and proximal jejunum secrete GIP. In the presence of glucose, GIP stimulates secretion of insulin by the endocrine pancreas. During a meal, GIP causes an earlier and larger secretion of insulin than if glucose were the only stimulus for secretion of insulin. Cells of the duodenum and jejunum secrete motilin about every 90 minutes during the postabsorptive or fasting state. Motilin stimulates production of the migrating motility complex, which sweeps the contents of the small intestine toward the terminal ileum. GI hormones enter the circulatory system, not the lumen of the GI tract. Neural activity, breakdown products of foodstuffs, or distension of the GI tract cause secretion of hormones. Note that hormones are not released into the lumen of the tract. They enter the portal blood and are transported to the liver and heart before returning to the GI tract to act. Some GI hormones exhibit potentiation. Potentiation occurs when the combined action of two hormones is greater than the sum of their individual effects. For example, secretin stimulates bicarbonate released from the pancreas. When secretin levels are low, the addition of CCK produces a large increase in the secretion of pancreatic bicarbonate solution. CCK also potentiates secretin to stimulate growth of the exocrine pancreas. Note that gastrin is structurally related to CCK, and secretin is related to GIP. Lighter beads indicate identical amino acids. The structural similarities among GI hormones, and the probable presence of receptors for all GI hormones on most cells of the GI tract, account for the amazing complexity of actions of GI hormones.