NROSCI 1070-2070 November 12, 2014 Gastrointestinal 2 Clinical Note • Inhibition of GI enzymes can be used therapeutically • An example is Xenical (orlistat), which reversibly inhibits lipases and prevents lipids from being absorbed. • Xenical is used to treat obesity. • What major side effect would you expect to be associated with this drug? Clinical Note • Lactase levels decease in most individuals as they age, resulting in inability to digest milk sugar (lactose intolerance) • Between 30 and 50 million Americans are lactose intolerant. Certain ethnic and racial populations are more widely affected than others. As many as 75 percent of all African Americans and American Indians and 90 percent of Asian Americans are lactose intolerant. The condition is least common among persons of northern European descent. Other GI Secretions • In addition to digestive enzymes, mucus is secreted by specialized cells in the stomach, small intestine, and colon. – This viscous secretion is composed primarily of glycoproteins that are collectively called mucins. – Mucus functions to form a protective lining over the GI mucosa and to lubricate the contents of the gut. – Mucus is secreted by globlet cells in the stomach and intestine. – The release signals for mucus include parasympathetic innervation, a variety of neuropeptides found in the enteric nervous system, and cytokines from immune cells. – Infections of the gut enhance mucus secretion as the digestive system attempts to protect itself. Other GI Secretions • Another secretion that aids in digestion is bile, a non-enzyme solution secreted by liver cells. • The key components of bile are: salts for fat digestion, bile pigments (e.g., bilirubin, a breakdown product of hemoglobin), and cholesterol. – The bile salts are formed by the combination of bile acids (steroid detergents with polar side chains) with amino acids. • Bile is secreted into the hepatic ducts that lead to the gall bladder. During a meal, contraction of the gall bladder sends bile into the duodenum through the common bile duct. • Bile acts as a surfactant, that allows fats to form small droplets that have a large surface area for digestion. • Bile salts are not altered during fat digestion, and are reabsorbed and taken through the hepatic portal system back to the liver. Other GI Secretions • Hydrochloric acid is released by parietal cells in the stomach. H+, which is derived from CO2 and water (this reaction is catalyzed by carbonic anhydrase), is actively pumped into the stomach in exchange for K+. • Bicarbonate ion, another product of the reaction, then diffuses into the extracellular fluid and blood in exchange for Cl-. • Acid secretion by the stomach is needed to denature proteins so they can be digested. Stomach enzymes work best at low pH. Other GI Secretions • Bicarbonate ions are formed in the pancreas from CO2, which combines with water under the influence of carbonic anhydrase to form carbonic acid. In turn, the carbonic acid dissociates to form HCO3- and H+. • The bicarbonate is pumped from the pancreas into the lumen by secondary active transport in exchange for Clions. • H+ is pumped into the blood, also by secondary active transport in exchange for Na+. • The secretion of HCO3- into the lumen of the small intestine neutralizes stomach acid and assures that the environment remains alkaline. Control of GI Secretions • Hormones play the predominant role in the control of GI secretions. • In fact, the first hormone every discovered was a GI hormone (secretin). • Many gastrointestinal hormones are generally recognized, or have been proposed. Those that we will focus on in this course include: Gastrin Cholecystokinin (CCK) Secretin Vasoactive Intestinal Peptide (VIP) Enteroglucagon Somatostatin Gastric Inhibitory Protein (also called Glucose-Dependent Inslinotropic Hormone or GIP) Control of Gastrin Secretion • Gastrin is synthesized by G cells in the stomach antrum, and its secretion is triggered by peptides and amino acids in the lumen of the stomach and by parasympathetic influences on the enteric nervous system. • Its targets are Enterochromaffin cells in the stomach (which release histamine) and parietal cells in the stomach (which release HCl). • Acid secretion in the stomach is thus triggered both directly and indirectly by gastrin release, as the secretion of histamine from Enterochromaffin cells also enhances gastric acid secretion. • Histamine in itself does not generally induce HCl secretion, but it greatly potentiates the effects of Gastrin on the parietal cells. • Activity of the parasympathetic nervous system can also induce acid secretion by Parietal cells. • Gastrin release is inhibited by somatostatin release from D cells in the stomach. As will be discussed below, this release is induced by the presence of large amounts of stomach acid. CCK & secretin release from the intestine have a similar effect. Summary of Stomach Secretions Summary of Stomach Secretions Clinical Note • A massive drug market exists to limit gastric acid secretion • One strategy is to block the histamine receptor on parietal cells (e.g., cimetadine [Tagament], ranitidine [Zantac-75], famotidine [Pepcid]) • Another treatment has been inhibitors of the ATP-ase (H+/K+ ATPase) that pumps H+ out of the parietal cells (e.g., omeprazole [Prilosec] and lansoprazole [Prevacid]). Clinical Note • The original use of anti-acid therapies was to treat peptic ulcers, damage to the stomach lining • However, in the 1980s it was discovered that most peptic ulcer patients all had a chronic infection of their stomach wall by the bacterium Helicobactor pylori. • Apparently, enzymes secreted by this bacterium break down the mucus layer. • The “latest and greatest” drugs for treatment of peptic ulcer are aimed at destroying this bacterium. Intrinsic Factor & Pernicious Anemia • In addition to acid, parietal cells release intrinsic factor • Intrinsic factor is essential for the absorption of Vitamin B12 • Lack of intrinsic factor results in pernicious anemia, as this vitamin is required to produce red blood cells Control of CCK Secretion • CCK is a hormone released by endocrine cells in the small intestine. Interestingly, it also appears to be a neurotransmitter in both the enteric nervous system and the brain. • CCK release is stimulated by the presence of fatty acids and some amino acids in the duodenum. • CCK acts on the gall bladder to induce contraction, and the release of bile into the small intestine (makes sense, as bile acts to emulsify fats). • CCK also acts in the stomach (presumably on parietal cells) to reduce acid secretion; another effect is to reduce gastric motility. These effects also make sense, because the small intestine can only digest small amounts of fat at a time (and this response acts to slow stomach emptying). • CCK also acts to stimulate bicarbonate secretion from the intestine and to enhance peristalsis in the small intestine. • Finally, the hormone is a primary stimulant for pancreatic enzyme secretion. Control of Secretin Secretion • The hormone secretin has some of the same effects as CCK. • Like CCK, it is secreted by endocrine cells in the small intestine. • Secretin release is stimulated by acid in the small intestine. • The effects of this hormone include: a stimulation of bicarbonate secretion from the pancreas, bile secretion from the liver, a stimulation of pepsinogen release in the stomach, and an inhibition of gastric acid secretion. • Gastric emptying is also inhibited by this hormone. Control of VIP Secretion • Vasoactive Intestinal Peptide (VIP) is both a hormone and a neurotransmitter. • In the gut, it is produced by cells in the enteric nervous system. • The factors leading to VIP release are unknown, but obviously the release is the result of activity in the enteric nervous system. • VIP acts to stimulate somatostatin release from D cells in the stomach, stimulate bicarbonate release from the pancreas, and to decrease motility. Control of GIP Secretion • GIP is released from endocrine cells in the small intestine. • Although this hormone was once thought to inhibit gastric acid secretion (hence its original name, gastric inhibitory peptide), the main role attributed to it today is the stimulation of insulin release from beta cells of the pancreas (hence its new name of glucose-dependent insulinotropic peptide). • The main trigger for the release of GIP is glucose and amino acids in the small intestine. • The role of GIP in controlling acid secretion is now debated, as the concentration needed to produce this effect is extremely high. Control of Enteroglucagon Secretion • Another hormone released from endocrine cells in the small intestine is Enteroglucagon. • This hormone may act together with GIP, as it stimulates insulin secretion from the beta cells of the pancreas. • It is released when glucose is present in the small intestine. Control of Somatostatin Secretion • A final GI hormone is somatostatin, which is released from D-cells of the stomach. • This hormone is not well understood, but seems to inhibit gastric acid, pepsin, pancreatic enzyme, and bicarbonate secretion. • Its release appears to be triggered by acid in the stomach and perhaps by the hormone VIP. What Happens During a Meal? • Digestion has traditionally been divided into three phases: a cephalic phase, a gastric phase, and an intestinal phase. – The cephalic phase is due to the effects of the brain on the enteric nervous system, and begins when a person anticipates eating. During the cephalic phase, the parasympathetic nervous system induces the G cells to produce gastrin, the Enterochromaffin cells to release histamine, and the parietal cells (directly) to release HCl. In addition, Pepsinogen is induced to be released from chief cells. – The gastric phase begins when food enters the stomach. The stimulants for initiation of the gastric phase include distension of the stomach and the presence of proteins and amino acids in the lumen. Initially, the distention induces vago-vagal reflexes that result in stomach relaxation to allow a large meal to enter. Then, the nervous system induces motility to begin. Acid and pepsinogen release are also reinforced during the gastric phase. – The intestinal phase of digestion occurs when chyme begins to enter the small intestine. Feed-back then occurs to the stomach to restrict gastric motility and to slow the release of materials into the intestine. The Intestinal Phase of Digestion Summary: Control of Secretion Blood Supply to • Virtually all of the blood leaving the GI the GI Tract tract travels through the hepatic portal vein and through the liver. • Within the liver, reticuloendothelial cells that line the liver sinusoids remove bacterial and other large material that may enter the general blood stream from the GI tract. • Most of the non-fat, water soluble nutrients absorbed from the gut are also transported to the liver sinusoids. Here, liver cells absorb and store many of the nutrients. • Much intermediate processing of these nutrients also occurs in the liver. • Non—water-soluble, fat-based nutrients are almost all absorbed by the liver lymphatics and then conducted to the blood via the lymphatic system. Control of GI Blood Flow • Under normal conditions, the blood flow in each area of the gastrointestinal tract as well as in each layer of the gut wall is directly related to the level of local activity. – For example, blood flow to the intestinal villi increases during absorption, and blood flow to the muscle layers increases during motility. • The “local factors” affecting this blood flow are still unclear, but almost certainly include the gut peptide hormones (cholecystokinin, vasoactive intestinal peptide, gastrin, and secretin). These hormones typically induce vasodilation. • The gut receives a huge blood supply during resting conditions. This blood supply can be markedly reduced by actions of the sympathetic nervous system in cases where the blood needs to be diverted elsewhere (e.g., exercising muscles). Absorption by the GI System Absorption by GI Tract • In general, almost all nutrient absorption occurs in the small intestine; the only substances absorbed more proximally in the GI tract are lipidsoluble substances, including alcohol and aspirin. • The colon also is involved in absorbing water and ions, as well as vitamins produced by the “intestinal flora”. • Both active transport and diffusion (both simple and facilitated) are used to absorb materials in the gastrointestinal tract. + Na Absorption by GI Tract • One very important ion to be absorbed is sodium, as large amounts are lost into the lumen of the gastrointestinal tract in secretions. • Sodium is actively transported from intestinal epithelial cells into the bloodstream. • Because the epithelial cells are constantly pumping sodium into the blood, there is a concentration gradient for this ion that causes it to diffuse from the gut lumen into the epithelial cells. • The gastrointestinal tract makes use of this concentration gradient to move other substances. • The transport protein on the lumen side of the epithelial cells will only pass sodium if it combines with another appropriate substance, which is usually glucose. • Through this mechanism, glucose is moved into the epithelial cell. In other words, the initial active transport of sodium through the basolateral membrane provides the “force” that drags glucose into the epithelial cell. • A facilitated carrier for glucose exists on the basolateral membrane to move this sugar into the blood. • Similarly, co-transport mechanisms that use the Na+ gradient are mainly responsible for amino acid absorption. H2O Absorption by GI Tract • In all parts of the body, water is transported through simple diffusion. However, the concentration gradient that is set-up in the epithelial cells by the active transport of sodium at the basolateral membrane tends to “pull” water in from the lumen, and move it to the blood. Fat Absorption by GI Tract • Fats are digested to small droplets composed of monoglycerides and free fatty acids, which are called micelles. • Bile plays a critical role in this process. Fats are not soluble in water, the major constituent of chyme. However, the bile salts surround the micelle and make the fats soluble. • However, when a micelle becomes adjacent to the villi, it experiences a local acidic environment because of transport occurring at the membrane. The acidity causes the micelle to disintegrate, releasing the free fatty acids and monoglycerides that diffuse into the epithelial cell (as they are lipophilic). • Cholesterol is transported on a specific, energy-dependent membrane transporter. • Thus, micelles formed by bile are critical in transporting fats and cholesterol to the intestinal brush border for absorption; without bile the fats were pass through the colon undigested. Fat Absorption by GI Tract • Once in the cytoplasm of the endothelial cell, monoglycerides and free fatty acids move to the smooth endoplasmic reticulum, where they are re-synthesized into triglycerides. • They then combine with cholesterol and proteins into large droplets called chylomicrons. Formation of chylomicrons is necessary to solubilize the fats. • Because of their size, chylomicrons must be packaged into secretory vesicles in order to leave the epithelial cells by exocytosis. • These particles are too large to cross the basement membrane of capillaries, and are instead absorbed into lymph vessels of the intestine. • However, a few shorter fatty acids are able to diffuse across the capillary wall and into the blood. Clinical Note • A new drug, Zetia (Ezetimibe), blocks the absorption of Cholesterol from the GI tract • Zetia is effective in cases where blocking cholesterol synthesis is not adequate Absorption of Materials by the Colon • As discussed previously, considerable water and ion absorption occurs in the colon. • Furthermore, many bacteria typically live in the colon. These bacteria normally derive their energy supply by digesting cellulose, which is not broken down in the colon and stomach. An end result of this digestion are vitamin K and B12. In particular, the vitamin K production can be important, as we typically consume too little of this important substance. • These bacteria also generate gases, including carbon dioxide, hydrogen gas, and methane. Fermentation of some particular undigested foods can lead to a production of large amounts of these gases, and other foul-smelling products, which can have undesirable social consequences. • In general, movement of materials across epithelial cells in the gastrointestinal system is achieved through very similar mechanisms as used in the kidney. What Isn’t Absorbed? • Large molecules that can’t be digested (e.g., indigestible plant material such as cellulose) are eliminated as feces. • Typical, feces are composed of about 25% water and 75% solids. • The solid matter is composed, in addition to undigested foods, of dead bacteria, sloughed epithelial cells, and dried constituents of digestive juices. • The color of feces comes from derivatives of bilirubin, a breakdown product of hemoglobin that is a constituent of bile.