Small Intestine Physiology - PDF

SPEAKER 0 Hello everyone. My name is Seley and welcome to this learning session on the physiology of small intestine. The learning outcomes for this session are to describe the physiology and secretion of small intestine, to describe the completion of the digestive processes in the small intestine,...

SPEAKER 0 Hello everyone. My name is Seley and welcome to this learning session on the physiology of small intestine. The learning outcomes for this session are to describe the physiology and secretion of small intestine, to describe the completion of the digestive processes in the small intestine, and to describe the mechanisms of absorption of the digestive products of lipids, carbohydrates and proteins. We will also look at special mechanisms regulating the absorption of calcium, iron and some vitamins. We will explain symptoms of malabsorption and acid base balance in the digestive system. And finally, we will look at the secretions of the exocrine pancreas in respect to its composition, function and production. So the small intestine consists of three segments that you, the duodenum, the jejunum and the Ilium. It is the longest GI tract organ which is about seven metres long from the pylorus of the stomach to the colon. It has a diameter of about 3 to 4cm, which gives it a very large absorptive surface area of about 4500m². So the duodenum is the shortest segment of the small intestine, which is about 28cm long. It receives the digestive content from the stomach. It encircles the pancreas and receives pancreatic juice from it, and it receives the bile from the gallbladder. So most of the digestion occurs in this part, and all components are in their simplest form, such as amino acids, monosaccharides and emulsified fatty acids. So the jejunum is two fifth of the small intestine and this is the main site of absorption. So we've said that the duodenum is the main site of digestion and the jejunum is the main site of absorption. So what do we mean by these terms? So digestion refers to processes by which ingested molecules are broken down into smaller one by digestive enzymes, and these enzymes are either secreted into the lumen of the GI tract or they reside on the luminal surface of the GI tract. And absorption refers to processes by which molecules are transported through the epithelial cells that line the GI tract and then they enter the blood or the lymphatic system. So the mucosa of the small intestine is arranged in these plicae circles. And we have about 800 of these plicae circulars in the small intestine. So here you can see an enlarged of these plicae and the largest plicae are found in the lower part of the duodenum and they decrease in size along the small intestine and they are absent in the lower part of the ileum So these places are constituted of projections that are called villi. So these intestinal villi are projections of the mucosa into the lumen and they are in direct contact with the chyme from the stomach. So these villi are covered by an epithelium of entero sites that are the cells of the small intestine. And these are connected by tight junctions. So these interocytes are polarised cells and on their apical membrane they are covered with these microvilli that form the brush borders. And on their basolateral side, they are facing the blood circulation or the lymphatic circulation. So other components of the villi are the goblet cells that secrete mucin, which is a protective mucus to protect the small intestine. And we also have crypt cells on the villi that include stem cells which are important for renewal of these enterocytes. So on the Villi, we also have endocrine cells that secrete intestinal hormones such as secretin and cholecystokinin. So these brush borders play an important role in digestion as they have brush border enzyme on them that are important for digestion of disaccharides and peptides. These brush borders are also important for absorption as they contain receptors and transport proteins for ions, glucose and amino acids. So the small intestines receive digestive products from the stomach, which is very acidic and hypertonic. And this triggers the release of several hormones digestive enzymes, water and mucus from the small intestine itself, as well as from the exocrine pancreas or the exocrine liver. So although some digestion has already started in the stomach, but the products cannot be absorbed. So therefore in the small intestine, acidity is corrected by the release of bicarbonate ions from the pancreatic secretion and digestion is completed by the release of several enzymes. And these enzymes come from three sources. They either come from the small intestine itself or the exocrine pancreas or the exocrine liver. In the hypotonicity of the chyme is corrected by osmotic movement of water across the wall of the duodenum which is permeable to water and mucus that protects the duodenum from acidity of the incoming chyme. So in the small intestine, mucus is secreted by Brunner's glands in the duodenum, which is a very rich in alkaline fluid. And it's function is obviously to protect the small intestine against acidity and protect it from the enzymes as well. And secondly, about 1.5L water is secreted by the wall of small intestine into its lumen. And one of the reasons for this secretion is to correct the hypertonicity of the chyme And secondly, the intestinal epithelial cells secrete ions into the lumen and water flows by osmosis. So overall, there is a large net absorption of water from the small intestines. As all this water will be absorbed into the blood, but also other secretions such as the salivary secretion, the gastric, the hepatic and the pancreatic secretion as well as the ingested water, all are absorbed into the blood. So the small intestine also secretes several hormones. And first of all, we have motilin that stimulates migrating motor complexes or MMCs via the enteric and autonomic nervous system. So these MMCs are inter digestive patterns of motility, and these are different from the gastric motility. So these MMCs happen between meals, and the function of them is to sweep the GI tract of the indigestible debris, and we recognise them as the rumbling tummy. And the second hormone on the list is the Vaso active intestinal peptide, which the name suggests it increases blood flow to the GI tract. And third hormone on this list is the gastric inhibitory peptide which we've seen in the previous session, that it inhibits gastric secretion and stimulates insulin secretion. So finally, we have the two important hormones of the small intestine which are CCK and secretin. And we've seen in the previous session that they inhibit gastric motility and secretion, and they also act coordinately to control both pancreatic and biliary secretion from the liver. So one question for you is what causes the secretion of CCK? And also what causes the secretion of secretin? If you could have a go at these questions and you will see the answers at the end of the slides. So let's look at the role of these intestinal hormones in regulating pancreatic and biliary secretions. So the exocrine pancreas and the liver are both major glands that secrete substances that flow along ducts to the small intestine. So let's see how this control is brought about. So the small intestine secretes the hormones CCK and secretin and secretin stimulates the pancreas to release bicarbonate ions that flow through the ducts into the duodenum. secretin also stimulates the liver to to release a complex solution known as bile that flows into the gallbladder that sits under the liver. So we will learn more about the liver and bile production in another learning session on liver physiology. So the other hormone, called the CCK, stimulates the pancreas to release digestive enzymes, and these enzymes are flown through the duct into the duodenum. So cck also stimulates the gallbladder to contract or squeeze to release a bile into the duodenum through its ducts. So this figure gives you a schematic overview of where nutrients are absorbed along the GI tract, such as carbohydrates, proteins, lipids, minerals, vitamins and water. So nutrition are mostly broken down in the lumen of the GI tract by various secretions of the stomach and the pancreas. And in the intestinal lumen nutrition are in the enterocytes, which are the absorptive cells of the intestine. So these enterocytes have a very large surface area as they contain the brush borders or the microvilli along their apical membrane. So additional broken down of the nutrients occur at these brush borders as that's the case for small peptides, disaccharides and triglycerides. These molecules can then enter the cells through the transport proteins that are located on these brush borders, and they also exit the cell through the basolateral membrane and they can enter the blood circulation. So we will look at the digestion and absorption of each of these dietary components in the next few slides. So first of all, let's have a look at the digestion and absorption of fats in the small intestine. So for digestion and absorption occurs entirely in the small intestine and the main enzyme involved is the pancreatic lipids. So dietary fats are broken down into small particles in the stomach by the virtue of gastric acid, in the mixing action of the stomach, and they are delivered to the duodenum at the controlled rate. And once they are in the duodenum, they are mixed with the emulsifying agent that consists of bile, salt and phospholipids. These are the components of bile that comes from the liver. So these Emulsifying agents are polar molecules that form clusters around these triglycerides and form these emulsion droplets. So the role of this emulsification is to convey the fat in a very small particles to make them sufficiently water soluble so they can remain in the lumen of the duodenum. They also provide a large surface area for the water soluble fat digestion enzymes to work on them. So these triglycerides are then digested by the pancreatic enzyme pancreatic lipase into mono glycerol and free fatty acids. So then these mono glycerides and free fatty acids are formed into a structure called micelle that consists of a bile, salt, fatty acids, mono glycerides and phospholipids all clustered together with their polar ends facing the surface of the micelle and the nonpolar end forming the core of the micelle. So these micelles are in a similar structure to the emulsion droplets, but they are smaller in size, so they're able to diffuse into the epithelial cells. So these micelles can diffuse into unstirred layer next to the epithelial cells of the small intestine. And a key property of the micelles is that they keeps breaking down and reforming. So once a micelle breaks down, its content is released and they can be absorbed into the epithelial cells of the small intestine. So it is important to note that it is the individual lipids that are released from the micelles. They are absorbed into the epithelial cells and the bile salt that forms the casing of the micelle will remain in the gut and that will be reabsorbed. And we will revisit this in a session on liver physiology. So now during the passage into the epithelial cells, these monoglycerides And fatty acids are synthesised into triglycerides. And inside the cells, these triglycerides are packaged into these droplets surrounded by membranes, and they are called chylomicrons. So these chylomicrons can be transferred across the basolaterl membrane. As they are bigger in size, they cannot be absorbed into the blood capillary. So they are passed on into lacteal, which is a lymphatic capillary. So these chylomicrons are carried away into the lymphatic system and eventually they'll be absorbed into the venous blood. So this figure gives you a big picture of the movement of absorbed nutrition into the blood or the lymphatic circulation. So this figure depicts the villus structure in the wall of small intestine, and you can see that the other digestion products such as amino acids and monosaccharides, are directly absorbed into the blood circulation from where they flow into the hepatic portal vein. So the chylomicrons that include the triglycerides are bigger in size, so they cannot enter the blood circulation. So therefore they enter the lacteal, which is the lymphatic capillary. So they are carried away from the gut into the lymphatic system and from where they can enter the venous side of the blood circulation. So now let's look at the digestion of carbohydrates and absorption of monosaccharides in the small intestine. So carbohydrate intake typically consists of two thirds of starch and one third of disaccharides, which consists of sucrose and lactose. So starch digestion begins in the mouth with the salivary enzymes, amylase and carbohydrate digestion and absorption of monosaccharide is completed in the small intestine. So here you have the written summary of the steps that occur in digestion of carbohydrates and absorption of monosaccharides, and we will follow it on the diagram on the next slide. So this diagram gives you a brief overview of carbohydrate, digestion and monosaccharide absorption in the small intestine. So you can see that starch digestion starts in the mouth by the release of salivary amylase from the salivary glands, and it's completed in the small intestine by the release of pancreatic amylase. So the digestion of starch by these two amylase gives you the disaccharide maltose and short chain branches of glucose that are further digested by the enzyme glycosidase. So this gives you free glucose that can be absorbed from the brush borders or the microvilli of the small intestine into the intestinal epithelial cells. So if you remember from the learning session on carbohydrates and lipids from our diet, we get the three disaccharides that are maltose lactose and sucrose. So they line up the microvilli of the small intestine and they can be further digested into the monosaccharides using the enzymes that resides on these brush borders, as we've mentioned before. So on these brush borders, we also have transport proteins that can transport these monosaccharides into the epithelial cells of the small intestine. And on the basolateral membrane, we also have transport proteins that can further transport these monosaccharides into the blood circulation. So we will cover these transport proteins on the next slide. But before moving on, another question for you to think about is how are these disaccharides that I mentioned, sucrose, lactose and maltose made and name the sugars that make these disaccharides sucrose, lactose and maltose? So if you could write your answers down and you will find the answer in the end of the slides. So looking at the transport of these monosaccharides across the intestinal epithelium. So here we have the intestinal epithelial cells and on the luminal membrane or the apical membrane, we have the membrane transporters. And that can transport these monosaccharides into the cell. So we have the monosaccharides, glucose and galactose that enter the cell by secondary active transport using sodium glucose, transporter one SGLT1. And this transport is coupled by sodium moving inwards with glucose or galactose, and sodium is moving down its concentration gradient and the concentration gradient is maintained by the sodium potassium atpase on the basoateral membrane and fructose enters the cell by facilitated diffusion using glucose transport five or glut five. So once these monosaccharides are in the cell, they can be transported out of the cells across the basolateral membrane using facilitated diffusion via glucose transporter two or glut 2 So if you would like to remind yourself of these membrane transporters, you had a learning session in Welcome week on membrane transport so you could visit that. Now let's look at the digestion of proteins and absorption of amino acids and oligo peptides in the small intestine. Here you have a summary of the steps that occur during this digestion and absorption process and we will follow it on the diagram in the next slide. So we've seen in the learning session on digestive system that protein digestion starts in the stomach by the enzyme pepsin and hydrochloric acid, and it's completed in the small intestine. So in the stomach, protein is broken down by hydrochloric acid and pepsinogen into polypeptides. And once they arrive in the small intestine, these polypeptides are broken down by the pancreatic enzyme trypsin, chymotrypsin and carboxy peptidases and to di in tri peptides. So these di and tri peptides arrive at the brush borders or the microvilli of the small intestine, and they are further broken down into amino acids by the brush border enzymes. So on these brush borders, we have transport proteins that are able to transport these amino acids inside the cells and from inside the cells. They use the transport proteins on the basolateral membrane to cross the basoateral membrane into the portal vein. And we will look at these transport proteins in the mechanism of amino acid transport in the next slide. So how are these amino acids, di and tri peptides transported across the intestinal epithelium? So here we have the intestinal epithelial cell with its luminal membrane and its basolateral membrane that contains these transport proteins that transport amino acids into the cell and as well as out of the cell across these basolateral membranes so they can be absorbed into the blood circulation. Now, when we look at the amino acids, specific sodium co transporters are responsible for the active transport of amino acids that is linked with the inward movement of sodium ions into the cell. Since sodium is transported down its concentration gradient, this provides the energy for the movement of amino acids that go up their concentration gradient. So despite the action of the brush border enzymes, a lot of ingested proteins are absorbed by the intestinal epithelial cells in their di and tri peptide forms. And these are transported by a separate proton dependent transporter that transports these di and tri peptides. So once they are inside the cells, they are further digested by peptidases into free amino acids. So from the cytosol amino acids from both sources are then further transported by facilitated diffusion across the basolateral membrane and only a small amount of di and tri peptides are transported unchanged. So let's look at the transport of calcium across the intestinal epithelium. So here we have the intestinal epithelial cell, again with its luminal membrane that contains the calcium channel that helps the entry of calcium into the cell. And on the basolateral membrane, we have two calcium transporters that mediate the transport of calcium out of the cell, so only a small fraction of ingested calcium is absorbed into the small intestine and it can be absorbed in all segments of the small intestine. But in particular the duodenum and the jejunum are more active in absorbing calcium and they can absorb calcium against a greater than 10 fold concentration gradient. So calcium moves down its concentration gradient through the calcium channel into the cell. And once it's in the cytosol of the cell, it can bind to this calcium binding protein called calbindin. And the amount of calbindin in the cytosol correlates with the capacity of the cell to absorb calcium. Now looking at the basolateral membrane, we have these transporters that can transport calcium out of the cell into the blood circulation. So calcium absorption is stimulated by vitamin D3, which is a hormone, and you will cover this hormone more in block four. So vitamin D3 does a number of things, such as increasing the abundance of calcium channel on the luminal membrane, increasing the amount of calbindin in the cell cytosol, as well as increasing the activity of the calcium transporters on the basolateral membrane, which all brings about the stimulation of calcium absorption. So now let's look at the transport of iron across the intestinal epithelium. The normal daily Western diet contains about 10 to 20% of iron, and it comes in two forms. So the haem iron is contained in animal products and the free iron is contained in vegetables. So why do we want to absorb iron from the diet? Well, iron is essential for normal health, the oxygen binding component of haemoglobin, and it's the key component of the active site of many enzyme. So the absorption of free iron and haem iron both into the intestinal epithelial cells is mediated by two separate mechanisms. Now let's look at the absorption of iron in the intestinal epithelial cells. So here we have the intestinal epithelial cells with its luminal membrane that contains the two mechanisms of iron absorption. So Haem iron is absorbed through receptor mediated endocytosis and it's further digested into Fe 3+ inside the cell. So this Fe3+ is then further reduced into Fe2+ plus in the cytosol of intestinal epithelial cells. But free iron is first reduced into Fe 2+ and then it enters the cell through the DMT1 transmembrane protein. So inside the cell we have Fe2+ from both sources. And some of these Fe2+ will exit the cell through the transmembrane protein called Ferroportin-1. And the remaining of these Fe2+ will enter a intracellular pool inside the cell where it binds to a molecule called ferritin. And we will look at that in a bit more detail in the next slide. So looking at the regulation of ion absorption into the epithelial cells, we have said that dietary ion is absorbed by two mechanisms and from both mechanisms we have Fe2+ ion inside the cytosol. So these Fe2+ ions use ferroportin1 to cross the basolateral membrane and they are absorbed into the blood circulation. So the remainder of this Fe2+ iron joins a intracellular pool and make a complex with iron binding protein ferritin. So ferritin limits the amount of free iron that is available to be transported out of the cell. So the iron that binds to ferritin will be later lost from the body when the intestinal mucosa is shed. So in cases when body's iron levels are low, for example, in blood loss or haemorrhage, the body has a mechanism by which it increases the level of iron absorption by increasing the activity of ferroportin-1. So ferroportin activity will be increased. So more iron is absorbed into the blood and less will be available to join the ferritin pool and be lost from the body. So let's look at the absorption of vitamins across the intestinal epithelium. So we have fat soluble vitamins and water soluble vitamins, fat soluble vitamins. Follow the pathway for fat absorption, as we have seen earlier in the session. And anything that interferes with fat absorption will also interfere with the absorption of fat soluble vitamins and water soluble vitamins are absorbed by diffusion, facilitated diffusion or active transport. Another vitamin that uses a special way of transport system is vitamin B12. So vitamin B12 is released by the actions of pepsin and hydrochloric acid in the stomach, and it binds to a protein called Protein R that is released by the salivary glands and also by the stomach. So it forms a complex with protein R and it's transported to the duodenum as a complex. We also have intrinsic factor that is released in the stomach and it moves down into the duodenum in the duodenum. This protein R and B12 complex is degraded by the pancreatic enzymes, and vitamin B12 is released where it can bind to the intrinsic factor that we have. And this intrinsic factor of vitamin B12 complex moves down to the ileum or terminal ilieum. So on the brush borders of the terminal ileum, we have a special receptors that mediate receptor mediated endocytosis of vitamin B12 and intrinsic factor and releases vitamin B12 into the cell that can move through the basolateral membrane and can be absorbed into the blood. So a question for you to think about is the name, the cell type and the location that releases intrinsic factor. So have a go at this question. Write your answers down and you can see the answer at the end of the slides. So malabsorption is defined as difficulty in digestion and absorption of nutritions from food substances so it can arise from failure or deficiency of any of these four processes, such as the pancreatic enzyme secretion, absorption, brush, border enzyme function or bile secretion. So malabsorption can arise from failure of digestion, process or impaired absorption of certain fats, sugars or proteins. Or it can be a general malabsorption of food that can be the result of a broad spectrum of diseases. And a few of them are listed in this table. So, for example, coeliac disease is a condition where the lining of the small intestine becomes sensitive to gluten as a result of damage to the mucosa of the duodenum and jejunum. So this makes it unable to absorb a number of substances, including fat. So another example of malabsorption is the resection of ileum that causes Crohn's disease. So remember, vitamin B12 is also absorbed in the Ileum, but also bile salts, which is essential for fat digestion and absorption are absorbed in conserved in the body. So removal of ileum makes you unable to absorb vitamin B12, which can result in pernicious anaemia. And it will also give the patient impaired ability to digest fat and absorb it as they become deficient in bile salt. So the next malabsorption that we will look at is lactose intolerance that results from deficiency in the enzyme lactase. So lactose intolerance and diet results and symptoms ranging from mild discomfort to severe diarrhoea. So on both sides in this diagram, you can see the small intestine. And just to cast your mind back to when we talked about the absorption and digestion of carbohydrates and the small intestine, we mentioned that lactose is further digested by the enzymes on the brush border into the monosaccharides. So this enzyme is lactase that's responsible for converting the disaccharide lactose into the monosaccharides, glucose and galactose that are further absorbed into the epithelial of small intestine and absorbed into the blood. So when we look on the right side of the diagram, this is a patient with lactose intolerance and. The absence of the enzyme lactase in this patient results in failure of metabolising lactose into the monosaccharides. So lactose will move down into the large intestine and it will be digested by the bacteria in the large intestine into the resulting monosaccharides. So as we don't have transporters on the walls of large intestine, these monosaccharides are not able to be absorbed into the blood. So they will be further digested by the bacteria of the large intestine that will produce gas, which will distend the colon and cause discomfort. And also the fermentation products will cause fluid movement across the walls into the lumen of the large intestine by osmosis. And hence this will produce diarrhoea. So symptoms of malabsorption could be intestinal. That is manifestation that results from dysfunction in the intestine or it can be extra intestinal. That is when gastrointestinal signs are moderate or absent. But there are other signs of lack of nutrition absorption, so symptoms can differ between children and adults and children. We tend to see clear gastrointestinal symptoms that include fatty stool which results from malabsorption of lipids. And if malabsorption is not detected or treated on time, the constant lack of nutrition can lead to failure to thrive. So other examples of symptoms are vomiting. Constipation. As well as weight loss. So in adults, we see less of a gastrointestinal symptoms except for lipids in the stool. So other signs are fatigue, depression and malabsorption can also be associated with anaemia, specifically pernicious anaemia due to absorption of vitamin B12 in the small intestine and also loss of bone minerals issues with reproductive system or skin issues. So however, malabsorption can take time to develop depending on the type of nutrition that is not absorbed. So let's look at the role of acid base balance in the digestive processes. You will cover acid base balance in more details in block two and the key role that the kidneys and the lungs play in the dynamic control of it. So the GI tract has also influence on the acid base homeostasis. As large amounts of protons and bicarbonate ions are crossing the membrane of the walls of the GI tract organs, as well as the accessory organs such as the pancreas and the liver. Only a small amount of alkali will be lost in the stool. And however, disruption to the normal function of the gut can overwhelm this acid base homeostasis and this can lead to vomiting and diarrhoea. So vomiting leads to what's known as metabolic alkalosis, which is due to losses of acids from the body, whereas metabolic acidosis is due to loss of fluid, especially bicarbonate ions in the faeces. So we have already talked about the secretions of the exocrine pancreas several times in this session. And because of the important role they play in the physiology of small intestine in regards to the digestion, in absorption of nutrition, we will look at it in more details. So the pancreas is an elongated organ that sits behind the stomach and it has both exocrine and endocrine functions. And in this session we will focus on its exocrine function. So the human pancreas weighs less than 100g, and yet it secretes about one litre of pancreatic juice, which is about ten times its own mass. So this figure gives you an idea of the arrangements of the cells in the pancreas. So we have these acinar cells that are connected to a network of ducts that drain into the duodenum, and we have the endocrine cells, which are the cells of the islet of Langerhans, and they are scattered between the acinar cells. So the cells in the duct cells form the main secretory cells of the pancreas, where the acinar cells secrete enzymes and duct cells secrete alkaline, which are the main component of the pancreatic juice. So the pancreatic juice consists of alkali, which is a aqueous component, rich in bicarbonate ions that is secreted by the duct cells. So if it wasn't for the neutralising capacity of this component, the high acidity of the chyme coming from the stomach would inactive the pancreatic enzymes in the small intestine. And secondly, we have a complex mixture of digestive enzymes secreted by the acinar cells. And each of these enzymes digests a particular component of the diet. So we have enzymes such as the pancreatic amylase, which is important for breakdown of starch. We have pancreatic lipase, which is important for digestion of fat. And we also have peptides that are important for protein digestion. And it's important to note that these peptides are trypsin, chymotrypsin and carboxy peptides, and they are secreted in their inactive precursor forms. So another question for you to think about is name another enzyme of the digestive system that was released in its inactive form. Name the cell type and the location of that enzyme. So have a go at this question. Write your answer down and you will see the answer at the end of the slides. So let's look at the activation of pancreatic enzyme precursors. So the enzymes that are secreted by the acinar cells of the pancreas and their precursor form are called zymogens and they are activated in the duodenum. So let's see how this activation is brought about as the duodenum doesn't have a acidic environment like the stomach. So we have this enzyme called entero kinase in the duodenum that is embedded in the luminal plasma membrane of the intestinal epithelial cells. And it's a proteolytic enzyme that splits a peptide from the precursor enzymes that brings about their activation. So it releases the active form. So another enzyme that acts as a proteolytic enzyme is trypsin. Once it's activated by entero kinase, it can act on the other enzyme as a proteolytic enzyme to bring about their activation as well. So this is another function of trypsin in addition to digesting ingested proteins and peptides. So another question for you to think about is what is the endocrine functions of pancreas? So if you could have a go at this question, write your answers down and you could see the answers at the end of the slides. So let's look at the mechanism of bicarbonate secretion from pancreatic duct cells. So we saw in the session on acid secretion that the movement of ions across the luminal and basal membrane resulted in secretion of hydrogen ions and chloride ions into the lumen of the stomach. Well, the mechanisms of bicarbonate secretion from the pancreatic duct cells into the pancreatic duct lumen which empties into the lumen of the duodenum is analogous to that, except the direction of the hydrogen ion and bicarbonate ions are reversed. So let's have a look. So the hydrogen ion and bicarbonate ion are produced from water and carbon dioxide in the cytosol of duct cells in the presence of the enzyme carbonic anhydrase. So that releases hydrogen ions and bicarbonate ions into the cytosol. And the net effect of the pumps on both sides is that hydrogen ions are actively transported across the basolateral membrane and ultimately absorbed into the blood and bicarbonate ions are secreted into the lumen of the pancreatic duct. So let's look at the control of these pancreatic secretions. So we've said that the pancreatic enzymes and alkali are secreted by two distinct cells and the enzymes are secreted from acinar cells, and the alkali are secreted by the pancreatic duct cells, and these secretions are controlled separately. So first of all, let's look at the control of enzymes by the acinar cells. So there are two agonists that play important role in this control, which are the intestinal hormone CCK and the neurotransmitter acetylcholine, which is released by the vagus nerve. And the nerve activity is triggered by the taste and smell of the food, which is called the vegal reflex, but it's also activated by the signals from the stomach. And so the secretion of alkali is stimulated by another intestinal hormone secretin and its effects are potentiated by these two agonists, cck and acetylcholine. So similar to cck, Acetylcholine is not sufficient to stimulate alkali secretion, but it can potentiate the effect of secretin in stimulating alkali secretion by vagal tone, which is a constant vagal discharge that releases low levels of acetylcholine. So in summary, we've looked at the structure, function and secretion of small intestine. We've looked at the digestion and absorption of fats, carbohydrates and proteins in the small intestine. We also looked at digestion and absorption of calcium, iron and vitamins in the small intestine. We also looked at acid base balance in the digestive system in respect to metabolic acidosis and alkalosis. We also looked at some symptoms of malabsorption and the diseases that cause malabsorption. And finally we looked at the mechanisms of pancreatic secretion into the small intestine. If you would like to read on any of these topics or would like to clarify anything, I recommend this chapter that you can directly access from clinically key. And if you have any specific question, I'm more than happy to help you with that. So thank you very much for your attention.