Greetings. Today, we're going to talk about digestion and absorption. The learning objectives we want to explain are as follows: First is the mechanisms of digestion and absorption and identify where they occur within the GI tract. Second thing we want to talk about is the absorption of water and where this occurs along the GI tract. The last is the underlying mechanism for diarrhea and its causes. As you recall, the digestive tract or the GI tract, gastrointestinal tract, starts at the mouth and then extends as a tube called the esophagus. This enables very rapidly delivery of food materials into the stomach. In the stomach, we encounter acid. This acid starts to act on the food materials degrading the protein materials. In so doing, it makes what's called an acidic chyme. The acidic chyme leaves the stomach at a very slow rate to enter into the duodenum. The reason that there is a slow rate is that this acidic chyme, has a very low pH. It enters into the duodenum, the first part of the small intestine. This area does not have a barrier that's resistant to acid. If acid is delivered to the beginning of the duodenum, we could get erosion of that epithelium. By having the acidic chyme squeezed out of the stomach is very small dollops, that is in about three or four milliliters at a time, then the acid as it arrives in the duodenum can be neutralized. We want to have a slow emptying of the stomach. It usually takes about four hours to empty the stomach. The second thing that can slow entry of food coming into the duodenum, into the first part of the small intestine, is a fatty meal. If you think about it, when you have a fatty meal, the fat tends to not be soluble in water. It tends to float on top of an aqueous solution. If you have a pan of water and you add vegetable oil or you add olive oil to it, the oil tends to form a little puddle up on the surface of that water. The same thing is happening in your stomach. The stomach contains HCl which is aqueous. As the acidic chyme is removed from the stomach, the fat floating on the surface of the chyme is one of the last things to be removed from the stomach. The third thing that makes a very slow exiting of material from the stomach into the duodenum, the first part of the small intestine, is if you engest a hypertonic solution. The stomach walls are not permeable to water. You could actually drink pure water. That doesn't affect the movement of water across the stomach walls. You could have very high hypertonic solutions coming into the stomach, such as a Coke cola. If you drink a Coke or Pepsi Cola or some type of soda, this hypertonic solution is fine in the stomach. But in the small intestine, the walls are permeable to water. At all times, the lumen of the intestine, in fact, all of the small intestine and the large intestine are isotonic to the cells. It's kept at 300 milliosmoles at all times. Water will move across the cells, from the blood space, across the cells, and into the lumen, and from the lumen towards the blood, to maintain this isotonicity. If we add a hypertonic solution into the duodenum, and we do so very quickly, what will happen is that a lot of water will move into the lumen as well. This extra volume will stretch the walls to the duodenum. It will be very painful. The only type of pain that you perceive from the GI tract is stretch. You can cut it, you can burn it, but you don't recognize pain. However, if you stretch the walls, then it's a painful response. So, we deliver the acidic chyme then very slowly from the stomach, emptying the stomach over four hours. The acidic material enters into the beginning of the small intestine, which is the duodenum. Now the small intestine is built in such a way that we have essentially ten meters of tubing. The first ten inches is the duodenum. Then we have five meters of jejunum and five meters of ileum. The tube itself has an aqueous environment within the lumen of the tube. It is within that aqueous environment that we are going to have digestion. We will break down the food materials within the lumen, and then we move these materials across the cells, i.e., absorb the materials across the cells. Both of those processes take time. Therefore, the movement of the chyme or the food materials through this particular area of the body is going to be slow. It'll be over a period of two to four hours to move the materials through the intestine. The small intestine is where we have digestion and absorption. Next we enter the large intestine, which I will refer to as the colon. That is where we have absorption, predominately of water and electrolytes. Note that delivery of engested food material is not regulated as it enters into the small intestine. In addition other materials and fluid are added from the accessory glands. These are first secreted and then delivered into the lumen of the small intestine where digestion occurs. What are some of these secreted materials? The first of these is added when we have carbohydrates arriving into the duodenum. The epithelium of the duodenum recognizes that carbohydrates are present within the lumen. They send a signal which is a hormone. More than one, but in this particular case, the glucagon-like peptide-1. Glucagon-like peptide-1 works on the pancreas, on the islets of the pancreas. As you recall, the islets of the pancreas have an endocrine function. They will to secrete insulin into the blood. The glucagon-like peptide-1 does not cause the secretion of insulin but it potentiates the secretion of insulin. It allows the insulin to be released from the beta cells. The second of these signals coming from the duodenal epithelial cells is in response to fat and peptides. When peptides, remember in the stomach we started the dissection of protein into peptides. The peptides now are delivered to the duodenum. These peptides cause the duodenum to secrete a hormone which is called cholecystokinin or CCK. The cholecystokinin also works on the pancreas, but it works on the exocrine cells of the pancreas. These exocrine cells secrete inactive enzymes into a duct. The duct then delivers the inactive enzymes directly into lumen of the duodenum. The inactive enzymes are called zymogens. When they arrive in the duodenum, a protease called trypsin, can activate all of the zymogens, all of these inactive enzymes which arrive from the pancreas. The second effect that the CCK has is on the gall bladder. The gall bladder is a storage site for bile, a detergent like molecule, synthesised by the liver. The liver secretes bile continuously. It is stored within the gall bladder. When needed, then, CCK causes contraction of the gallbladder. This expels the bile directly into a duct which then delivers the bile to the duodenum. The bile, as we'll talk about in a few minutes, is a detergent that's necessary for the digestion of the fats. Last is the arrival of acids. When an acidic chyme enters into the duodenum, then the epithelial cells secrete the hormone, secretin. We have all ready talked about how secretin mediatess negative feedback to the antral portion of the stomach where it inhibits the secretion of gastrin by the G-cell. Secretin also acts in the pancreas. In the pancreas it causes the duct cells of the pancreas to secrete bicarbonate. This bicarbonate is used the neutralize the acidic chyme that's coming into the lumen of the duodenum. In addition the bicarbonate makes an alkaline environment. It is this alkaline environment that's necessary for the optimal activity of all of the pancreatic enzymes which are used to degrade the food materials. These enzymes include proteases, lipases, and nucleases. They are able to degrade all the materials which are coming into the body as foodstuffs. So let just look at this exocrine pancreas cell for a second. The exocrine pancreas cell as I said secretes its zymogens into a duct. It looks a little bit like an eye dropper. You have the bulb at one end of the eye dropper and you have the duct cells coming off from that. The exocrine cells shown here are in a cluster or a ball. These are called acinar cells. They function as exocrine cells. The cholecystokinin, the hormone coming from duodenum, will cause these cells to secrete the zymogen granules. The zymogen granules are these little red dots that I’ve indicated here on the top of the cells. The zymogen granules, are simply vesicles chock full of inactive enzymes. These vesicles will move up to the plasma membrane surface and then secrete all of the zymogens (or inactive enzymes) out of the cells. The zymogens enter into the duct. As I said, they become activated once they reach the duodenum. The second effect that will occur is that Secretin will cause secretion of bicarbonate. It is from the duct cells and not these cells. These are the cells which line the ducts. These cells secrete bicarbonate. The bicarbonate is also delivered to the duodenum. It is used to neutralize the acidic chyme and to make an alkaline environment in the lumen. The enzymes delivered into lumen, and are activated at their optimal pH. All right, so now let's consider what's happening within the GI tract itself. In particular what's happening within the duodenum and in the jejuneum, the next segment of the small intestine. This is where we have most of the digestion of materials occurring within the lumen. Subsequently we start to absorb digested materials across the epithelial cells which line this area. There's two points to remember about these epithelial cells. One, is that there are big folds of these cells which are called villi. In addition there are small folds on the surfaces of these cells. These smaller folds are called microvilli. The folds, both the villi and the microvilli, increase the absorptive area of this region. All through the small intestine, there is a very large absorptive area. It is the size of a doubles court for tennis. What's located on the luminal surfaces of these cells are transporters. We have all different types of transporters. But I want to talk about a couple of important ones. The first one is the glucose- sodium co-transporter. This is called the SGLT. The SGLT is the salt-glucose transporter. This transporter moves glucose into the interior of the epithelial cells. The digestion of carbohydrate releases glucose. Now the glucose molecules and sodium move into these epithelial cells. As the glucose enters into the cell it's transported across the cell to the opposite side to the basal surface. There it exits the cell via a GLUT transporter. We have a GLUT transporter sitting on the basal cell surface. On the apical cell surface, we have a co-transporter, the sodium-glucose co-transporter. The ability of these cells to bring glucose into the cells and across the cells and into the intersitium on the opposite side is driven by the sodium gradient that's within the cells. This process is called secondary active transport. Secondary active transport occurs because on the basal surface of the cells, we have our sodium-potassium ATPase. As the sodium enters the cell, the sodium-potassium ATPase extrudes it from the cell. This action keeps the gradient very low within the cell for sodium. The presence of the SGLT, once it was discovered, has now enabled individuals to become rehydrated very quickly from a dehydrated state. An example of this action is as follows: There is a team, a football team, called the Gators. This is a Florida football team. These individuals, the team players, were playing in the hot sun. The coach was worried that they were getting dehydrated. He wanted to have a very fast way that he could rehydrate his players. So he went to the nephrologist at the medical center that was nearby and asked them what substance he should give to his players to rehydrate them quickly. The substance, of course, was salt, glucose, and water. That mixture was then called Gatorade. It became a commercial product. The school now has a patent on Gatorade. The Gatorade uses the SGLT to rehydrate the body quickly. There are other transporters that are located on these cells. That's what's indicated here. We have simple amino acids. We degrade the proteins into amino acids. These amino acids, all different types of amino acids, are then moved with co-transporters into the cells into the epithelial cells. They again cross the cell and are extruded at basal surface with a transporter. The amino acids exit the cells, enter into the blood, and are delivered to the liver. This is again is a secondary active transport. Where the sodium concentration within the cells is kept low by the sodium potassium ATPase which has not been shown here but as you all know is present on the basal surfaces Of all cells. Recall that sodium is extruded by the sodium potassium ATPase as a primary active transport. When it is coupled to an amino acid co-transporter, then the process is called the secondary active transport of the amino acid. There is also another way that amino acids can get across these cells. This process moves di-peptides and/or tri-peptides. They bind to a co-transporter, as well. That's what's shown here. This co-transporter is called the PEPT transporter. The PEPT transporter uses a proton instead of sodium. As the proton enters into the cells because of its low gradient, then the peptides move into the cells. They piggyback onto the co-transporter. Once inside the cell they are degraded to amino acids.The simple amino acids then leave at the basal surface by the simple transporters for amino acids. Again, this is a secondary active transport. As we're moving all of these materials, these nutrients across these cells. We're also moving ions across the cells, and we're moving water. We have to maintain isotonic conditions within the gut lumen. That is done by moving water. So as we move these materials, water is also traversing the cells. It is taken up into the body during feeding. What about fats? Fats are different. I told you, fats will be the last thing to leave the stomach, because they float on top of the acidic chyme. Eventually late after feeding, the fats enter into the duodenum. The fat droplets as they enter into the duodenum are combined with bile. The bile is our detergent. The bile is the molecule that comes from the liver via the gall bladder. It was stored in the gall bladder, and then delivered when needed. The bile causes the fat droplets to break into small droplets. This increases the surface area of the droplet. By increasing the surface area of the droplet, a co-lipase, a protein, can bind to this droplet in high number. Then the lipase, the enzyme that will cleave these molecules these fats, can act. We break the fat down into free fatty acids and monoglycerides. There is also free cholesterol. And these molecules can enter into the cells mostly by simple diffusion, but there are also transporters that move this material into the cells. Once they're inside the cells, the cell resynthezizes the triglycerides. It combines these fats, the triglycerides and the cholesterol with proteins to form what are called chylomicrons. Chylomicrons are very large particles. The chylomicrons are not able to pass across the plasma membrane. The chylomicrons are secreted by the cell at the basal surface. They enter into the interstitial space. The chylomicrons are so large that they cannot get across the epithelium that lines the blood vessels. Instead the chylomicrons enter into the lymphatic circulation. They enter into the lymphatic circulation because the epithelium, the cells that line the lymphatic vessels are more leaky than those of the blood vessels. These large molecules, these large particulars are able to go across at this region. They enter through the lymphatic drainage. The lymphatic drainage (lymph) then will come back to the heart. The chylomicrons move into the blood circulation at the heart, and then they are delivered to the liver. So that's absorption of fat. Now we reach the ileum. Note that most of the absorption is occurring within the small intestine. The ileum is the primary site where we move water across the epithelial cells. So, water and nutrients, electrolytes, and so forth are being reabsorbed or absorbed across the ileum. The amount of secretions that we have added to the GI tract is as much as 7 liters. Seven liters have been added to the GI tract. We started with 2 liters of food. Now we have to reabsorb the 7 liters of fluid before it arrives at the colon. That 7 liters of fluid is taken up predominantly along the GI tract in the jejunum and the ileum. The ileum also is a site where we remove the bile from the lumen and take it back up into the body. There is a receptor, which recognizes the bile. The bile is then recycled back to the liver via the blood. If you recall, the ileum also has a receptor for intrinsic factor, which was secreted by the parietal cells. This is the carrier for vitamin B12. The ileum is the site where that carrier and vitamin B12 are taken up into the body. That leaves the large intestine. So what happens within the large intestine? We had two liters of food coming into the stomach. We then add seven liters of secretions along the small intestine. We re-absorbed seven liters back into the body. That leaves about two liters of material to be delivered to the large intestine. There is two liters of material, non-digested material, that's going to be delivered to the colon or the large intestine. The function of the colon is to concentrate that material. At the statr ofhe colon is a very watery type of feces. Normally only about 200 milliliters or 500 milliliters of feces is excreted per day. So the 2 liters entering into this region, will be concentrated by removing water. Water will move from the lumen of the colon across the cells, which are lining the colon, and into the blood. This occurs under normal conditions. Recall that water moves by osmosis. Here there is movement of ions from the lumen, that is from the luminal surface. IOns move from the luminal contents to the opposite side of the cells. As sodium moves across these cells, water follows the sodium. We are moving both sodium and chloride across these cells. Now what happens under condition where not all of the nutrients have been reabsorbed? For instance, there is a situation, called lactose intolerance in which an individual, myself included, delivers the sugar lactose to the colon. Lactose is present in milk products, such as ice cream. It is not digested by the small intestine, because the enzyme that can cleave this disaccharide into small simple sugars is missing. The lactose is delivered to the colon. But the colon has no transporters for nutrients. So as this material, a sugar, enters into the colon. The sugar is osmotically active. Consequently instead of water moving from the lumen of the colon, across the epithelium to enter into blood, the lactose, is now holding the water within the lumen. We now have water being held in the lumen due to the presence of lactose. That will cause far more water to be present within the lumen of the colon, and instead of having a concentrated feces, we now will have a very watery, dilute feces that could be 500 milliliters or more. That of course you all know as diarrhea. When we lose a lot of water from the colon, you're also losing a lot of bicarbonate at the same time. So the loss of water, large amounts of water by diarrhea will cause the body to also lose bicarbonate. There's one other thing I want to talk about, and then we're going to come back to the idea of diarrhea. The last thing I want to talk about is the water absorption in the fasting state. This can occur all through the small intestine,and in the large intestine. It's also occurring within the gallbladder. This is how you concentrate the bile within the gallbladder. This process is called the "standing water gradient". As I told you, there is an isotonic solution in the lumen of the small intestine. Let's say this is the small intestine. We have an isotonic situation on the interstitial side. So the problem is how do you move water from an isotonic state to an isotonic state? As you all recall, water moves by osmosis. It moves when there is a gradient for water. And under these conditions, we do not have a gradient for water. So how does the cell generate a gradient for water? It does so by locating sodium, potassium ATPases along the lateral surfaces of the cells. We have the first epithelial cell here and the second here. They are held together by a tight junction, which is a seal which does not allow the luminal content to cross directly into the interstitial space between the cells. That means that as you're pumping the sodium out from these lateral surfaces as well as from the baso-lateral, from the base of these cells, then a gradient is generated in which a high concentration of sodium is between the cells. This is very local pocket containing a high concentration of sodium. This will draw water from the lumen of the cell across and out to these lateral surfaces. The water now has a gradient. Water moves from a lower concentration of sodium to a high concentration of sodium between the cells. AS water moves, it dilutes the sodium between the cells. nOte that there is an increase in the volume in that region. An increase in volume mean higher pressure between the cells. eventually the pressure in this space pushes the fluid into the interstitium at the base of the cell and into the blood. The "standing water gradient" then allows the movement of water to cross the cells. This occurs because of the very small, intimate concentration of sodium localized between the cells. Now Let's consider disorders of the GI tract. Some of which maybe familiar. The first is if we had delayed emptying from the stomach. This can lead to nausea, can lead to vomiting, you can feel bloated. There is a sense of pressure within the stomach. You could have heartburn. The other state is a very rapid emptying through the GI tract. Under these conditions, you can feel very weak, start to sweat, be dizzy. You get a diarrhea. So the rate of movement of materials through these different regions of the tract needs to be regulated. When we come back the next time, we're going to talk about motility all through the track. THat is how we move materials from one area to another. It is a timed movement of materials through these different regions. But let's just consider diarrhea again for a few minutes. There are two types of diarrhea. One is secretory diarrhea. In a secretory diarrhea, watery feces occurs because there's an imbalance in the distribution of ions across the intestinal epithelial cells. For instance, if we have an infection by Cholera vibrio. This bug infects in the ileum where it causes a very high concentration of chloride to be moved into the lumen of the ileum. Sodium follows the chloride to keep a balance of charges. We have now a lot of sodium and chloride sitting within the lumen of the ileum. This material is delivered to the colon. When it comes into the colon then, as we know sodium and chloride are osmotically active. They are holding water within the lumen of the colon. This overwhelms the ability of the colon to move the sodium and chloride into the body. Instead water moves across this region from the body. The result is diarrhea. With cholera, you can lose many, many, many liters of fluid very rapidly. The major problem is the dehydration of the individual. If the individual is rehydrated sufficiently over a period of two or three days where the cholera bug is active, then the patient can actually outlive the bug. The bug will die within the GI tract and the patient will be fine. So what is it that you hydrate the patient with? Well, obviously we're going to run the SGLT. You have salt, glucose, and water delivered to the patient. You can hydrate the patient rapidly enough to counterbalance the amount of diarrhea, the amount of loss of fluid due to diarrhea. The thing that you should remember is that the feces that is coming out, that is, the diarrhea, the fecal material is going to be very watery, but is always, always, always isotonic to the body. So it's going to have 300 milliosmolars, osmolar solution. The concentration of the sodium and the chloride that's within the fecal material will add up to the 300 milliosmolar. The other type of diarrhea is the one that I was alluding to, that is, lactose intolerance. This is where an individual who cannot breakdown lactose, has the osmotically active lactose delivered to the colon. This causes water to enter into the lumen of the colon. In this condition, again, the fecal material will be 300 milliosmolar because again, it's always isotonic. But when you add up the amount of sodium, that is the concentration of sodium and the concentration of chloride that's within that fecal material, it will be less than 250 milliosmolar. That occurs because of the presence of this other osmotic material, which is what's holding water and causing the diarrhea. So I want you to think about which of these two conditions could you discriminate by having an individual who has diarrhea, and you prevent that individual from either drinking or eating any material. The diarrhea will be gone from which individual under either of those two conditions? Figure out whether secretory or osmotic diarrhea would be cured by fasting. All right, what are our general concepts? The first is we have gastric emptying into the duodenum occurs slowly. It's going to occur over four hours, and it's going to be about four milliliters per squirt. This allows for the neutralization of acidic chyme as it's coming into the duodenum. Secondly, we have hormonal pathways to coordinate the secretion of bicarbonate, digestive enzymes, and of insulin into the blood. The bicarbonate and the digestive enzymes are going to move into the digestive tract that is into the lumen of the small intestine. These things bicarbonate, the digestive ezymes, and insulin are secreted by the pancreas. Also we will have secretion of bile from the bile duct, from the gallbladder. That is under the direction of CCK or cholecystokinin, a hormone. Third, we're going to have digestion of complex food to small molecules. This will occur within the lumen of the intestine. Digestion occurs outside of the cells. It occurs all along in the small intestine but predominantly within the duodenum and in the jejunum and the early portions of the ileum. And four, the small intestine is the major site for the absorption of nutrients, solutes and water. In particular, the ileum is really important for the uptake of water. Five, we have the luminal contents of the small and the large intestine isotonic at all times. That means it is 300 miliosmolar at all times. All right, so the next time we come in, we will talk about motility along the tract and how the tract is able to move materials from one compartment to another. Okay, so see you then.