Funds of Phys - Lecture 8 Notes PDF

Lecture 8 - GI Lectures (part 1) GI physiology = the process by which you obtain nutrition Two general processes involved: Secretion & Absorption Water, Ions, & enzymes are secreted to help you break down food. The latter yields nutrients, ions, and water which are absorbed. The byproducts are elimi...

Lecture 8 - GI Lectures (part 1) GI physiology = the process by which you obtain nutrition Two general processes involved: Secretion & Absorption Water, Ions, & enzymes are secreted to help you break down food. The latter yields nutrients, ions, and water which are absorbed. The byproducts are eliminated (excreted). You cannot transport water without transporting ions. Enzymes & nutrients are almost always transported with ions. Enzymes need water to help break down nutrients (I.e. R1–R2 + H2O —-> R1OH + R2H (hydrolytic)) Carbohydrates & proteins are hydrophilic (polar/charged) Lipids are hydrophobic (do not like the aqueous medium) How can we absorb lipids in an aqueous medium? Lipids are broken down differently in the GI system than hydrophilic substances The teeth & stomach break down food The stomach acid sterilizes the food (breaks down any ingested bacteria) The salivary, gastric, pancreatic, liver and intestinal secretions help to further break down food into the nutrients you need. The small intestine’s absorptive processes are used to extract or absorb whatever nutrients are beneficial to the body. In order for food/nutrients to move from one region of the GI to another you need the smooth muscle to contract & push the food along the GI system. The nerves & hormones control the speed of those smooth muscle contractions, the speed of secretions, and the speed of absorption. Finally, the large intestine processes the unwanted byproducts & gets rid of the waste. There is also quality control: the mouth - spit. The esophagus, stomach, small intestine vomit. The small & large intestine - diarrhea. If you cut the GI tract crosswise, it has 4 anatomical layers: the innermost layer is the mucosa. The mucosa consists of epithelium, lamina propia (connective tissue), and muscularis mucosae (muscle). On top of the mucosa is the Submucosa. The submucosa consists of connective tissue containing most major nerves & blood vessels (it also has a lot of immune cells). On top of the mucosa is the muscularis externa (smooth muscle that lines the lumen of the GI tract). The muscularis externa consists of the longitudinal muscle & circular muscle. Within these muscle layers are two groups of nerves: the myenteric plexus (between the longitudinal & circular muscle) & the submucosal plexus (below the circular muscle, in the submucosa). The most superficial layer is the Serosa (connective tissue) which is on top of the longitudinal muscle (muscularis externa). ***Remember: the lumen is the food side (the inside of the GI tract). The serosa is the blood side. If something is absorbed, it is moving from the lumen to the blood. If something is secreted, it is moving from the blood to the lumen. The parasympathetic nervous system usually stimulates motor & secretory activity of the GI tract. Primarily through the vagus nerve (medulla oblongata) & pelvic nerves (sacral spinal cord). The sympathetic nervous system usually inhibits motor & secretory activities of the GI system. Primarily through the prevertebral sympathetic ganglia (celiac, superior mesenteric, inferior mesenteric). Small intestine absorbs about 78% of water. The large intestine absorbs 21%. The stool contains about 1% (higher than that is diarrhea, anything lower leads to constipation). One of the most important functions of saliva is to maintain pH (~7) in the oral cavity (chemical buffer). Saliva also starts the process of digestion & kills bacteria. Saliva is a secretion from the oral cavity or more specifically from the salivary glands. Composition of saliva: Aqueous component (the ions) - sodium, potassium, magnesium, chloride, bicarbonate, phosphate. Organic component (the enzymes) - urea, ammonia, uric acid, glucose, lipids free amino acids, proteins. Effect of flow rate on aqueous components of saliva: the concentration of ions in saliva is a function of flow rate —> the greater the flow rate the greater the concentration of Na+, Cl-, & HCO3-. The opposite effect for K+: the greater the flow rate the less K+ present in saliva. Of the ions, the most important is HCO3- because it regulates the pH of saliva. Since the concentration of HCO3- changes with flow rate of saliva, then the pH of saliva also changes with flow rate —> the greater the flow rate, the greater (more basic, more HCO3-) the pH (the lower the flow rate, the lower (more acidic, less HCO3-) the pH). Ion composition of saliva relative to the plasma (important to know): When comparing Na+ & Cl- concentrations in the saliva to the plasma, the saliva is actually hypotonic (less Na+ & Cl-) as compared to the plasma at any flow rate. When looking at potassium, K+ is higher in the saliva than in the plasma at any flow rate. As for HCO3-: at low flow rates (low HCO3-), the plasma contains more HCO3-. But, at high flow rates (high concentration of HCO3- in the saliva), the saliva is hypertonic (has more HCO3-) than the plasma. The most important organic components in saliva are the enzymes. I.e, alpha-amylase which digests starch by breaking down alpha 1-4 linkages (it is only active at pH 4-11 —> activity is reduced in the stomach). Another enzyme in the saliva is lingual lipase which hydrolyzes (breaks down) triglycerides (pH optimum = 4.5-5.5 —> continues to function in the stomach & proximal intestine). This enzyme can catalyze reactions with lipids without the help of bile salts. The oral enzymes are not very important in the break down of nutrients unless you have pancreatic insufficiency or cystic fibrosis (if you didn’t have these enzymes you would be fine). The salivary glands are primarily regulated by egg the sympathetic nervous system. Certain events (chewing, smell, etc.) stimulate a group of neurons called the salivatory nucleus in the medulla which leads to the release of acetylcholine (via parasympathetic system - cranial nerves 9 & 7). Acetylcholine binds to M3 receptors of the salivary gland cells that lead to the production of secondary messengers IP3 & Ca2+. This leads to secretion of saliva, contraction of smooth muscle cells that line the salivary gland, vasodilation, increased metabolism, & overall growth of the salivary gland. This pathway is inhibited by sleep, fatigue, dehydration, fear, & drugs (I.e. drugs that block acetylcholine binding) The salivary nervous system also positively stimulates salivary secretion (transient & minor regulator of salivary secretion). The superior cervical ganglion is stimulated & leads to the release of norepinephrine. NE binds to Beta-adrenergic receptors on the cells of the salivary gland & lead to camp release which leads to salivary secretion (etc.). Stomach & Pancreas: The pancreas neutralize the acid that your stomach secretes. One of the most important functions of the stomach is secretion of the intrinsic factor required for intestinal vitamin B-12 absorption. All of the functions of the stomach are: autoclave (high acidity), mechanical digestion, protein hydrolysis (pepsin breaks down dietary protein), food storage (the stomach relaxes when food is present (receptive relaxation), secretion (intrinsic factor), quality control (second panic button - vomiting) There are three regions of the stomach: the fundus (top), corpus (middle/body), and the antrum (bottom). The regions of the stomach have gastric pits of glands —> the cell population depends on gland location. The cardiac/fundic regions contains: the surface mucous cells which secrete mucus & bicarbonate. The mucus neck cells also act as stem cells (produce more cells). If the mucus neck cells migrate upwards they become the surface mucous cells (secrete H2CO3 & mucus). If the mucus neck cells migrate downwards, they morph into different cell types. The parietal cells that secrete acid & intrinsic factor. The ECL cells that secrete histamine The chief cells which secrete pepsinogen (an enzyme) The gastric pit found in the antrum (antral gland) contain: Surface mucous cells (secrete mucus & HCO3) & mucus neck cells (stem cells) The D cells (in the lower part of the antral pit) which produce somatostatin (secretion that goes into the bloodstream) The G cells secrete gastrin Unknown cells that secrete prostaglandin Composition of the luminal gastric secretions: Aqueous components: mostly HCl Organic components: Pepsinogen (secreted by chief cells - converted to pepsin at pH < 5. Hydrolyzes dietary protein). Intrinsic factor - protects vitamin B12 from digestion & facilitated absorption of B12 in the small intestine. Mucus - protection (secreted by surface mucous cells) Composition of aqueous gastric secretions changes as function of secretion rate: Basal secretion in the stomach is primarily made up of Na & Cl (Na levels are less than in the plasma, Cl levels are more than in the plasma & K levels are greater than in the plasma). The basal secretion is hypotonic to the plasma (due to less Na). When stimulated (consuming food), the stomach secretions are mostly made up of HCl (activate chief & parietal cells). The H+ levels are much higher in the lumen of the stomach as compared to the plasma when producing gastric juice (HCl). Thwe high level of H+ in the stomach translates to a very low pH ( if [H+]is greater than 140 mM, then your pH is less than 1). The secretion of H+ into the lumen of the stomach requires a lot of energy (the plasma is neutral & thus has a low concentration of H+). So how do we overcome the H+ gradient in plasma vs. lumen? Molecular mechanisms of HCl secretion: Parietal cells have lots of mitochondria because spend a lot of ATP. A byproduct of high metabolic rate is CO2. The parietal cell takes CO2 + H2O and converts it to H2CO3 & later into HCO3- + H+ with the help of the enzyme carbonic anhydrase II (CAII). The proton (H+) is then transported into the lumen of the stomach through a K/H+ exchanger (brings K+ into the cell from the lumen & H+ into the lumen from inside of the cell) on the apical surface (side facing the lumen) of the parietal cell. The HCO3- goes to the basolateral side (side of the cell facing the blood stream) & gets into the bloodstream through a HCO3-/Cl- exchanger (brings Cl- into the cell, takes HCO3- out of the cell). “Alkaline tide” —> occurs when you are actively eating and bringing a lot of proton into the lumen, you are creating a lot of HCO3 as a byproduct & that HcO3 gets brought to the bloodstream (if you measure the pH if the bloodstream, it becomes more alkaline (basic) than 7.4. HCl secretion by parietal cells: 3 factors stimulate the production of acid in parietal cells: histamine (ECL), gastrin (G cells) , & acetylcholine (vagus nerve - parasympathetic) Somatostatin (D cells) inhibits the production of acid in parietal cells by reducing of cAMP (inhibits acid production). Drugs like omeprazole (proton pump inhibitors or acid pump antagonists or potassium channel blockers) also inhibit the production of acid by parietal cells. ACh, histamine, & gastrin can each individually produce acid but if you add them together can lead to potentiation (increased acid releasing rate). ECL cells are the most potent regulators of parietal cell secretions. If you have too much acid or protons —> the protons can signal D cells to produce somatostatin and decrease acid release (somatostatin inhibits HCl release by reducing cAMP concentrations in parietal cells). Factors that release HCl also lead to the release of pepsinogen from chief cells (pepsinogen needs low pH to be turned into active enzyme pepsin). Most ulcers (90% in the duodenum & 70% gastric) are caused by the bacteria Helicobacter pylori (acid resistant bacteria). Aspirin inhibits (irreversibly) COX-1. COX-1 is an enzyme that is required for prostaglandin (PG) synthesis & that produces thromboxanes. Aspirin thus leads to reduced levels of PGE-2 & PGI-2 & of thromboxanes (can lead to blood clots. PhD are inhibitors of acid secretion so if they are not around you develop ulcers due to too much acid production. Pancreas: We are discussing the exocrine function of the pancreas (the endocrine function is not involved with the GI system) The pancreatic islets make insulin & glucagon (endocrine) Acinar cells produce enzymes & the duct cells (in the pancreatic duct) produce bicarbonate (to neutralize acid) Composition of the pancreatic secretions: The aqueous component is bicarbonate (most important) produced by the duct cells Organic components are the enzymes produced by the acinar cells: Amylases (starch), lipases (fats), proteases (proteins - zymogens), & ribonucleases (DNA & RNA from food) Composition of aqueous components changes with secretion: Flow rate is low when you are not eating & fast when you are actively eating. At basal rates (at rest), the aqueous components consist of Na & Cl mostly. Concentration of HCO3 & Cl is less than in the plasma while Na & Cl concentrations are similar to the plasma. For the pancreatic secretions, Na & K concentrations are stable throughout no matter the flow rate. Na+ is high in pancreatic secretions both at rest & during eating. On the other hand, K concentration is low at rest & during active eating. Stimulated (during active eating): pancreatic secretions are mostly Na+ & HCO3 (HCO3 increases when stimulated). While the Cl- concentration decreases during active eating. In the pancreas during stimulation of secretion (increased flow rate): the sum of the anions (Cl + HCO3) is always equal to the sum of the cations (Na + K) In pancreatic juice the osmolality (summed concentration of ions) does not change with flow rate but pH increases (more HCO3) as flow rate increases. Molecular mechanisms, HCO3 secretion by pancreatic duct (duct cells): In the duct cell cytosol, you have CO2 that combines with H2O & with the help of carbonic anhydrase (CA) turns into H2CO3 & later to HCO3- + H+. The HCO3- is brought into the lumen of the pancreatic duct by an HCO3-/Cl- exchanger on the apical surface of the duct cell (takes Cl- into the cell & HCO3- out of the cell into the lumen). The Cl- is recycled by the CFTR channel on the apical surface which takes the Cl- out of the cell back into the lumen to be used by the HCO3-/Cl- exchanger again The byproduct of the reaction is H+ which is brought into the blood side through a Na/H exchanger on the basolateral side of the duct cell (takes Na into the cell & H+ out of the cell). Cystic fibrosis leads to a mutation of the CFTR channel (prevents the release of HcO3 from pancreatic duct cells & this are unable to neutralize the stomach acid). The negative lumen of the duct cell generated by Cl- & HCO3- is neutralized by the paracellular transport of Na+ & K+ through the tight junctions between the duct cells into the lumen of the pancreatic duct. Water follows the ions (osmotic pressure) and thus moves from the blood side to the duct lumen. Secretin (hormone released by cells in the duodenum) in eased the secretion of the aqueous (bicarbonate) component of the pancreatic secretions. The stimulus for secretin release is acid (HCl) in the duodenal lumen. Secretin is made by S cells in the duodenum CCK is made by I cells in the duodenum Liver & Gallbladder: do not make hormones - the main digestive function is to make bile to break down fats (fat digestion). Liver cells are called hepatocytes. The hepatocytes empty into the bile duct. Bile is synthesized by the hepatocytes. The common hepatic duct extends into the cystic duct which empties into the gall bladder & the common bile duct which fuses with the pancreatic duct. The sphincter of oddi separates the pancreatic duct/common bile duct from the small intestine. The bile produced by the hepatocytes is stored in the gallbladder & released during meals. The sphincter of oddi is closed during normal conditions (but the hepatocytes continue making bile & storing it in the gallbladder). The bile has aqueous & organic components. The aqueous component is bicarbonate (produced by the bile duct cells) making the bile basic. The organic components of bile are mostly bile acid, cholesterol, phospholipids, bile pigments, proteins. Bile acids = detergent. They are amphipathic molecules (hydrophobic & hydrophilic sides), highly polar, made up of cholesterol, OH groups, & amino acids. Bile acids are important for the emulsification of lipids which allows efficient break down by lipolytic enzymes. If you consume food rich in fat, the fat will sequester itself in the aqueous environment. With bile salt/acid you emulsify the fat & break it down into smaller droplets (to increase the surface area to volume ratio so that lipases can more efficiently break the fat down). The lipases (pancreatic enzymes - they are hydrophilic so site of action is the surface of fat globules) digest along with the bile salts further digest the insides of these droplets which liberates fatty acids & monoglycerides. Bile acids are also important for Micelle formation. Organic components of bile: Cholesterol - very hydrophobic, can only exist in the insides of these micelles. Phospholipids - have a polar head & fatty acid tails. & Bile pigments product of the degradation of hemoglobin (bilirubin). Bile pigments: bilirubin from broken down blood cells will go to the liver. In the hepatocytes, bilirubin is linked to glucoronic acid by the UDP glucuronyl transferase. Conjugated bilirubin can be excreted in the urine or go to the small intestine. In the small intestine, conjugated bilirubin gets turned into a more hydrophilic urobilinogen by bacteria (so that it is not completely recycled back in the enterohepatic circulation). Some urobilinogen enters enterohepatic recirculation. But most urobilinogen is turned into stercobilin by the bacteria in the colon - which is then excreted in the feces. How bile moves from gall bladder to gut lumen: Between the meals, the VIP (vasoactive intestinal peptide) inhibits gallbladder contraction. The gallbladder is relaxed & accumulates bile. The sphincter of oddi is closed. During a meal: nutrients arrive in the duodenal lumen - the I cells are stimulated to make CCK which is released to the bloodstream and the extracellular fluid. In the extracellular fluid, there are Vagal afferents that have CCK-1 receptors —> CCK binds and the afferent nerve sends a message to the dorsal vagal complex in the brain. The brain via the vagus nerve sends efferents to release ACh onto the wall of the gall bladder which stimulates the wall of the gall bladder to contract. The CCK released into the bloodstream goes to the gall bladder as a hormone & stimulates the muscles of the wall of the gall bladder to contract (smooth muscle contraction). At the same time, Nitric Oxide (NO) & VIP are released on the sphincter of Oddi so that it can relax & open. The contents of the gall bladder (bile) can now be released into the small intestine. How bile is recycled: Enterohepatic circulation The amount of bladder that is stored in the gallbladder is insufficient to digest all the fat in a typical diet & the body solves that problem by recycling bile. Once the bile acids have emulsified fats to help in the digestion (duodenum), the micelles form & fat absorption occurs (in the jejunum). Then they arrive at the ileum (last portion of the small intestine), where the bile acids are actively absorbed & return to the liver via the portal circulation. This process occurs during a meal & it’s called enterohepatic circulation. The gallbladder is not involved! Coordination of secretion: Regulation with the central nervous system = long or vagovagal reflexes Or short/local reflex (anything that does not involve the CNS) Control of secretion: There are three phases named after the site of receptors initiating secretory processes: 1. Cephalic phase (in the brain) - I.e. thinking about food/smell food. Occurs before food enters the stomach. 2. Gastric phase - when food enters the stomach & stimulates chemo- & mechanoreceptors. 3. The intestinal phase - food enters the duodenum & activates the chemo- & mechanoreceptors in the mucosa. 1. Cephalic phase: Thinking/Smelling food The salivary glands is always under neural or autonomic nervous system control (throughout all three phases controlling secretion). Long/vagovagal pathway. Gastric secretion during the cephalic phase: (no food in the stomach yet). After smelling/thinking about food, a vagus nerve efferent neuron will release acetylcholine (ACh) onto the parietal cells, mucus neck cells, & chief cells leading to the release of their respective molecules. The vagus nerve also releases acetylcholine onto interneurons that lead to the release of GRP (gastrin releasing peptide). GRP binds to G cells leading to gastrin release. The gastrin leads to more HCl release by binding to parietal cells. The gastric secretion during the cephalic phase is under both long/vagovagal reflex control & endocrine (local) control. During the cephalic phase, your stomach can produce up to 30% of the total response of the stomach cells to a single meal. Pancreatic secretion during the cephalic phase: the long pathway is a weak stimulant for pancreatic secretion. Thinking/smelling food leads to the release of ACh in to interneuron that stimulates the release of GRP which then leads to gastrin release from G cells in the stomach. The gastrin (which is a cousin of CCK, normally binds CCK-2 or CCK-beta receptor on parietal cells) binds by low affinity to the CCK-1/CCK-alpha receptor (specialized for binding of CCK) on the pancreatic acinar cells. This local gastrin confuses the acinar cells into releasing low volume & high protein content secretion. Gastrin also stimulates afferent nerves that connect to the vagus which leads to the release of ACh onto acinar cells (long vagovagal pathway). At this point, the secretion is low fluid because there is no secretin being released yet (have not eaten anything yet). 2. Gastric Phase: Food enters the stomach Salivary secretion = regulated by the autonomic nervous system Gastric secretion = food distends the stomach & stimulates mechano/stretch receptors. Distension of the stomach activates the stretch receptors which send a signal (afferent) to the brain which then sends an efferent signal that releases acetylcholine to activate the parietal cells (mucus cells & chief cells are also activated). Through the local (short) pathway, stretch receptors (distension) also lead to the release of ACh at the parietal cells. Additionally, Distension leads to the release of ACh at the G cells (locally). The ACh can also act as an afferent signal (to the brain) which sends another efferent signal & releases ACh at an interneuron. The interneuron leads to GRP release onto G cells which will then release gastrin. Gastrin acts as a local signal to bind to parietal cells & lead to more acid release. Chemoreceptors are also present in the stomach: I.e, G cells detect partially digested peptides & release gastrin. Gastrin stimulates the parietal cells into making HCl & chief cells into making pepsinogen. Pancreatic secretions in the gastric phase: The response of the pancreas to the gastric phase mirrors its response to the cephalic phase (release of gastrin affecting the acinar cells). Gastrin confuses the CCK-1 receptors in the afferent nerves of the vagus & in the basolateral membrane of the acinar cells. 3. Intestinal Phase: Food has reach the intestine Salivary secretions are still regulated solely by the autonomic nervous system Gastric secretions: at pH greater than 2-3 parietal cells are stimulated to produce acid. At pH lower than 2-3, acid production is inhibited. Distension of the duodenum stimulates gastrin (g cells in the duodenum) & enterooxyntin (enhances acid secretion by parietal cells) from mechanoreceptors. There are also chemoreceptors in the duodenum that lead to the release of gastrin (form g cells in the duodenum) & enteroxyntin (from unknown cells). Inhibitory effects on gastric secretions during the intestinal phase: Towards the end of a meal, you have less food in your stomach so the amount of acid being made is still very high. So there is less food to buffer the acid as you empty the stomach. At this point the chyme entering the duodenum is highly acidic & once the acid enters the duodenum the S cells detect it (stimulated by the excess H+ in the duodenum lumen). The S cells release secretin which will go into the pancreas make tons of bicarbonate (by the pancreatic duct cells). The secretin also inhibits gastrin release by G cells (& so consequently stops gastrin from inducing more acid release from parietal cells). Secretin stops acid twice: neutralizes the acid (with the bicarbonate production from duct cells) & stops gastrin release from G cells (stops stimulation of acid release from parietal cells). Less Distension of the duodenum leads to less stimulation of mechanoreceptors & less release of enteroxyntin (less stimulation of parietal cells = less acid production) The fat in the food also stimulates the I cells (chemoreceptors) to produce CCK which will bind to acinar cells (either CCK-1 receptors) which will lead to the release of enzymes. (Remember: CCK also stimulates the afferent cells of the vagus nerve which goes to the brain which the tells efferents to release ACh onto acinar cells & lead to more enzyme release). Excess gastric acid (no food remaining in the stomach): excess acid is detected by the D cells in the stomach which stimulates the release of somatostatin. Somatostatin inhibits the G cell (stops it from making gastrin & leading to more acid release). Somatostatin also inhibits the parietal cell from making protons. Interactions: the D cell releases somatostatin which inhibits the G cell directly. Somatostatin is also stimulated by protons to inhibit the parietal cell. Additionally, Somatostatin inhibits histamine release by ECL cells (most potent stimulator of the parietal cell). Protons also inhibit the G cell directly. Digestion & Absorption: The small intestine has 3 regions (from proximal to distal): Duodenum, Jejunum, Ileum. Bile acids & Vitamin B-12 are reabsorbed at the ileum. Secretion = digest food to absorbable units (nutrients) Absorption of hydrophilic nutrients across membranes requires transporters It is easy to digest (break down) proteins & carbohydrates but it is difficult to absorb them (due to them being hydrophilic they cannot cross the lipid bilayer without the help of transporters) Carbohydrate digestion: mostly done by pancreatic amylase (occurs in the lumen of the small intestine). After break down with numerous enzymes, the end product of carbohydrate digestion is glucose. Glucose is co- absorbed into the cells with Na+ by SGLT-1 transporters (on the apical side of the epithelial cells). Sucrose is digested by a brush border enzyme called sucrase (breaks sucrose into glucose & fructose). Fructose is brought into the cell by GLUT-5 transporter (on apical membrane). Lactose is broken down into glucose & galactose by a brush border enzyme called lactase. Glucose & galactose can be co- absorbed into the cell with Na+ by the SGLT-1 transporter (on the apical side of the cell). In the basolateral membrane: glucose, galactose, & fructose go from the cytosine to the blood side by a transporter on the basolateral surface called GLUT-2. Enterocytes are the cells lining the intestine What is lactose intolerance? Lactase is present in all humans as babies but it is lost in adulthood. (Congenital Lactase deficiency is rare) The majority of adult humans cannot digest lactose. The phenomenon of “lactase persistence” is now increasing in all populations (more and more humans are not losing lactase - they are tolerant to lactose bc milk is more present in our foods).