NROSCI 1070-2070

1. NROSCI 1070-2070 November 10, 2014 Gastrointestinal 1

2. Function of the GI System • The digestive system has two primary roles: • Digestion, or the chemical and mechanical breakdown of foods into small molecules that can absorbed, or moved across the intestinal mucosa into the bloodstream. • In order to accomplish these functions, the secretion of enzymes, hormones, mucus, and paracrines by the gastrointestinal organs is needed. • Motility, or controlled movement of materials through the digestive tract is also required.

3. Challenges of the GI System • Almost 7 liters of fluid must be released into the lumen of the digestive tract per day to allow for digestion and absorption to occur. Clearly, most of this fluid must be reabsorbed or dehydration will occur. • Furthermore, the inner surface of the digestive tract is technically in contact with the external environment; for this reason, protective mechanisms are needed. In part, these mechanisms must protect against the secretions of the GI tract, including acid and enzymes.

4. Anatomy of the GI System

5. Anatomy of the GI System • The organs involved in digestion and absorption include: 1. Salivary glands 5. Liver 2. Esophagus 6. Pancreas 3. Stomach 7. Large intestine 4. Small intestine • In addition, 7 sphincters control the movement of material and secretions between the organs. • The total length of the GI tract is about 15 feet, of which 13 feet are comprised of intestine. • The processed material within the GI tract is referred to as chyme.

6. Wall of GI Tract • The wall of both the intestines and stomach is similar, in that it contains four (or five) layers: • Mucosa • Submucosa • Muscle layer (sometimes divided into 2 layers) • Serosa

7. Wall of GI Tract • The mucosa is composed of epithelial cells, the lamina propria (connective tissue), and muscularis mucosa (specialized smooth muscle). • The mucosa has a number of specializations to increase surface area. • Within the stomach, these occur as folds called rugae. • Within the small intestine, a number of fingerlike projections, or villi, are present. The individual cells on the villi have further specializations that increase surface area; these specializations are called microvilli. • In addition, invaginations (called gastric glands in the stomach and crypts in the intestine) exist in the GI tract. These invaginations are lined with secretory cells.

8. Multiple Secretory Cells are Present • As an example, the stomach contains the following secretory cells: • Mucus-secreting cells • Parietal cells (secrete hydrochloric acid) • Chief cells (secrete pepsin) • G cells (secrete the hormone gastrin) • Enterochromaffin cells (secrete histamine) • D Cells (secrete somatostatin) • A multiplicity of secretory cell types are also present in the small intestine

9. Wall of GI Tract • The submucosal layer contains large blood vessels and lymph vessels, and the submucosal plexus, a major component of the enteric nervous system. • The muscle layer of the gut is composed of two layers of smooth muscle: an inner circular layer and an outer longitudinal layer. • Contraction of the circular layer decreases the diameter of the lumen • Contraction of the longitudinal layer shortens the tube • Between the two layers of muscle is the myenteric plexus, another component of the enteric nervous system • The outer serosa forms the wall of the GI tract. It is an extension of the peritoneal membrane that lines the abdominal cavity. Sheets of mesentery connect with the serosa to hold the intestines in place.

10. GI Smooth Muscle • The cells in each bundle of smooth muscle are linked by gap junctions; therefore, electrical signals travel easily from cell to cell. Thus, a layer of GI smooth muscle forms a syncytium, in that an action potential elicited anywhere in a bundle will evoke a contraction of all surrounding muscle cells. • Three types of electrical activity are important in control of contraction of gastrointestinal smooth muscle: 1. Slow waves 2. Spikes 3. Resting membrane potential • Most gastrointestinal contractions occur rhythmically, and the slow waves play a key role in controlling these contractions.

11. GI Smooth Muscle • Slow waves are slow oscillations that occur at different frequencies at different points in the gut (3/minute in the body of the stomach to 12/minute in the duodenum). These slow waves are presumably due to cycling changes in activity in the Na+-K+ pump. The slow waves mainly reflect the entry of sodium into the smooth muscle cell, and do not cause muscle contraction (calcium triggers smooth muscle contraction).

12. GI Smooth Muscle • Spike potentials occur when voltage-gated channels that pass calcium and sodium open. • The opening of these channels allows calcium to enter the smooth muscle cell, which induces contraction. • These channels have slow kinetics, which results in very long-lasting spikes. • Thus, if the resting membrane potential is sufficiently depolarized, the spike potentials will occur at the crest of the slow waves. • In other words, control of resting membrane potential is all important in determining whether gastrointestinal smooth muscle cells will contract.

13. GI Smooth Muscle • • Hyperpolarization of GI smooth muscle cells can be induced by: • Norepinephrine and epinephrine (e.g., the effects of the sympathetic nervous system) • Depolarization of GI smooth muscle cells can be induced by: • Muscle stretch • Acetylcholine (released by cells of enteric nervous system) • Some specific gastrointestinal hormones

14. The Enteric Nervous System • Two “plexuses” of nerve cells comprise the enteric nervous system of the gut. • The first plexus is in the submucosal layer • The second plexus is between the longitudinal and circular smooth muscle (myenteric plexus) • These nerve cells receive innervation by the sympathetic and parasympathetic nervous system, but can function without this input. • The enteric nervous system plays the fundamental role in neural control of GI function.

15. Evidence that the Enteric Nervous System is a “Little Brain” • The neurons of the enteric nervous system release more than 20 neurotransmitters and neuromodulators, many of which are identical to molecules found in the brain. These neuro-transmitters are sometimes called “non-adrenergic, non-cholinergic” to distinguish them from the “traditional” autonomic neurotransmitters: norepinephrine and acetylcholine. • The support cells of neurons in the enteric nervous system are more similar to the astroglia of the brain than to the Schwann cells of the peripheral nervous system • The capillaries that surround ganglia within the enteric nervous system are not very permeable and create a diffusion barrier that is similar to the blood-brain barrier of cerebral blood vessels • Reflexes resulting from stimulation of sensory receptors in GI tract can be integrated and elicited entirely within the enteric nervous system. Thus, the enteric nervous system must have the “sophistication” of coordinating these responses.

16. Organization of the Enteric Nervous System • In general, the enteric nervous system is organized into two sheets: the submucosal plexus and the myenteric plexus. • The submucosal plexus mainly regulates secretory functions and vasomotor control, whereas the myenteric plexus mainly regulates motility. • In reality, the cell bodies in the submucosal and myenteric plexus are concentrated into ganglia, with interganglionic fiber tracts interconnecting them.

17. Organization of the Enteric Nervous System • The submucosal and myenteric layers appear to largely subserve different functions: the submucosal layer participates in regulating secretion and blood flow whereas the myenteric layer is involved in motility. • However, there also seems to be coordination between these functions. There is good electrophysiological evidence that submucus neurons receive cholinergic and non-cholinergic excitatory input and non-cholinergic inhibitory inputs from myenteric neurons. • Similarly, a population of submucus neurons project to the myenteric plexus. • The precise role of these interconnections in influencing GI function is currently unknown.

18. Function of the Enteric Nervous System • In large part, the enteric nervous system serves as a “pattern generator” for the carefully coordinated sequence of contractions that results in motility. By relinquishing this control to the periphery, the central autonomic systems do not have to worry about coordinating this activity. In large part, the pacemaker system in the heart or the brainstem respiratory pattern generator serve a similar role. • One clear response that the enteric nervous system produces is the “migrating action potential complex” (or “migrating motor complex”) which propagates through both normal gut and that removed from the body and placed in a tissue bath. Many hours after eating a meal, when the digestive system is not influenced by chemical inputs from the lumen, this special pattern of activity propagates through the stomach and small intestine about once every 90 min. Because this response involves a contraction that sweeps through most of the digestive tract, it must be precisely coordinated. The occurrence of this response, which apparently takes place to sweep debris out of the gut, shows the extent of influences of the enteric nervous system. • Propulsive and mixing contractions can also take place in the isolated gut, suggesting that the enteric nervous system also controls these responses.

19. Influences on the Enteric Nervous System • The enteric nervous system and its target tissues receive inputs from the sympathetic and parasympathetic nervous systems, which influence motility, secretion and blood flow. Perhaps these influences are analogous to the sympathetic and parasympathetic influences on the pacemaker system of the heart (which serve to regulate rate, but not pattern of activity). • The parasympathetic influences to the upper GI tract are mediated by the vagus nerve. In contrast, the distal half of the colon is innervated by the sacral division of the parasympathetic nervous system. The postganglionic parasympathetic neurons are components of the enteric nervous system. • The sympathetic nervous system mainly influences motility through inputs to the enteric nervous system, but to some extent through direct influences on smooth muscle cells.

20. Influences on the Enteric Nervous System • Many afferents originating in the gastrointestinal tract influence central nervous system activity. These afferents can be activated by irritation of the gut mucosa, distension of the gut, or the presence of specific chemical substances in the gut. • Some of these afferents are “local,” in that their cell bodies and terminations are in the enteric nervous system. • Some of these afferents also make connections in prevertebral sympathetic ganglia. • In other cases, the cell bodies are in the dorsal root ganglia; the axons of these afferents course in sympathetic nerves. • Other gastrointestinal afferents course in the vagus nerve to the brainstem; their cell bodies are in the nodose ganglion.

21. Influences on the Enteric Nervous System • A number of hormones affect gastrointestinal motility; some of these agents also affect secretion. • Cholecystokinin is secreted by “I” cells in the mucosa of the small intestine, mainly in response to breakdown products of fat. This hormone causes the expulsion of bile from the gall bladder into the stomach. In addition, it inhibits stomach motility, so that food is emptied from the stomach into the intestine more slowly. • Secretin is secreted by “S” cells in the mucosa of the duodenum, in response to gastric acid released by the stomach. It acts to inhibit motility throughout the GI tract. • Gastric inhibitory peptide, secreted by the mucosa of the upper small intestine, is similar to cholecystokinin in that it slows emptying of materials from the stomach. • The hormone gastrin, which is released by cells in the antrum of the stomach in response to the presence of certain foods and stomach distension, has a mild stimulatory effect on stomach motility.

22. Motility and Secretion in the GI System

23. Motility: Types of Contractions in the GI System • There are three major types of contractions of gastrointestinal smooth muscle: 1) Tonic, sustained contractions (mainly in sphincters). 2) Peristaltic contractions (move food forward in GI tract) 3) Segmental contractions (responsible for mixing food with GI secretions and pushing it against the wall of the mucosal layer)

24. Motility: Peristaltic and Segmental Contractions

25. Motility: Mastication & Deglutition • Mechanical digestion of food begins in the oral cavity with chewing. The lips, tongue and teeth contribute to mastication of food, creating a softened mass that can be easily swallowed. Mastication is an important process, as it increases the surface area of food that will be exposed to digestive enzymes. • Swallowing (deglutition) occurs in three stages: • A voluntary stage, which initiates the swallowing process • An involuntary pharyngeal stage. • An esophageal stage.

26. Motility: Mastication & Deglutition • The voluntary stage of swallowing involves the moving of food into the pharynx by the actions of the tongue.

27. Motility: Mastication & Deglutition • The involuntary pharyngeal stage of swallowing is triggered by the stimulation of receptors near the opening of the pharynx, whose axons terminate in nucleus tractus solitarius. • Stimulation of these receptors evokes a coordinated response that involves outflow along cranial nerves 5, 9, 10 and 12. • Contraction of pharyngeal muscles causes closing of the glottis, the opening between the pharynx and larynx, so that no materials move into the airway. At the same time, respiration is inhibited and the upper esophageal sphincter relaxes.

28. Motility: Mastication & Deglutition • The esophageal stage of swallowing has two components: primary peristalsis and secondary peristalsis. • Primary peristalsis is a continuation of the swallowing reflex that began in the pharynx. • Secondary peristalsis is initiated by distention of the esophagus by a large bolus of food, which triggers reflex contractions. • The afferents that evoke secondary peristalsis send their axons through the vagus nerve, which also carries the efferent outflow from the brainstem to the esophagus. • The musculature of the upper third if the esophagus, like that of the pharynx, is striated muscle, which is controlled bythe vagus nerve. • The lower two-thirds of the esophagus contains smooth muscle, whose activity is mainly controlled by the enteric nervous system. • Thus, even if the vagus nerve is sectioned, swallowing can occur if food reaches the lower part of the esophagus.

29. Motility in the Stomach • The activity of the enteric nervous system also causes the relaxation of the lower esophageal sphincter when a bolus of food approaches. The tight closing of this sphincter is needed to prevent reflux of acid from the stomach into the esophagus. • When food enters the stomach, it stimulates receptors, and through a “vasovagal reflex” induces relaxation of the stomach wall so the stomach can be distended with food. The contractions of the stomach are mainly weak, and for the purpose of mixing food with stomach secretions. At the antrum of the stomach, contractions are more intense, and aid in stomach emptying. • With each slow wave some materials are pushed through the pyloric sphincter into the duodenum. Typically, the pyloric sphincter is only partially contracted, which allows liquid materials to pass along. The degree of constriction of the pylorus can be increased or decreased by nervous and hormonal signals. • Motility in the stomach is influenced most prominently by hormonal factors: gastrin release from the stomach has a stimulatory effect, whereas cholecystokinin, secretin and gastric inhibitory peptide release from the duodenum inhibit stomach motility.

30. Motility in the Small Intestine • Both mixing and propulsive contractions occur in the small intestine. These contractions occur no more rapidly than a rate of 12/minute, the frequency of occurrence of slow waves in the small bowel. • The rate of motility is influenced by distension of the intestine, which effects the excitability of cells of the enteric nervous system. • A number of hormones released from the small intestine also modestly enhance motility in the small intestine. • Irritation of the bowel wall or central nervous system influences can induce the enteric nervous system to rapidly empty the digestive system. This “peristaltic rush” helps to remove toxins when they are present. • The ileocecal valve permits one way movement of materials from the small intestine into the colon. Its physical structure of overlapping “lips” assists with this process.

31. Motility in the Large Intestine • The regulation of motility in the colon is similar to that in the small intestine. • The main functions of the colon are to absorb water from residual products of digestion and to store the material until elimination. • Mixing contractions, which are called haustrations in the colon, can be very intense, but are needed to expose the fecal material to the intestine wall to permit reabsorption of water. • Strong propulsive movements occur in the distal part of the colon to force feces into the rectum.

32. Defecation • Elimination of wastes is usually triggered by the entry of material into the rectum. • Afferent signals affect the enteric nervous system of the distal colon, causing propulsive movements of further materials towards the anus. • The enteric nervous system also causes the relaxation of the internal anal sphincter. • At the same time, afferents whose cell bodies are in the sacral dorsal root ganglia evoke a conscious sensation of a filled rectum. These inputs can induce a voluntary relaxation of the external anal sphincter, which is composed of striated muscle. • Thus, both conscious and autonomic activity is required for defecation to take place.

33. Secretion in the GI Tract • As noted previously, about 7 liters of secretions enter the GI system per day, as summarized in the following table: • Most of this fluid most be reabsorbed or dehydration will occur. Most of the absorption occurs in the small intestine, although some occurs in the colon. • Only about 0.15 L of water per day are lost in the feces.

34. Secretion: Digestive Enzymes • Digestive enzymes are secreted by exocrine glands (salivary glands and the pancreas) or by epithelial cells in the stomach and small intestine. • These enzymes are proteins, and are packaged by the Golgi apparatus into secretory vesicles and stored within the cell until needed. • On demand, they are released into the extracellular space by exocytosis. • Some of these enzymes become mixed with chyme, and others are attached to the brush border (microvilli) on the epithelial cells.

35. Secretion: Digestive Enzymes • Some digestive enzymes are secreted in an inactive proenzyme form, and must be activated by other agents. • Amongst these enzymes are pepsinogen in the stomach and the pancreatic enzymes chymotrypsinogen, procarboxypeptidase, procolipase, and prophospholipase. • These pancreatic enzymes are converted to their active form by trypsin, a conversion product of the pancreatic enzyme trypsinogen. • Trypsinogen is converted to trypsin through the actions of the brush border enzyme enteropeptidase (also known as enterokinase).

36. Question for Discussion • Why are some GI enzymes released in an inactive form?

37. Table of GI Enzymes