Gastrointestinal Physiology Section 1 Functions and Regulation of the GI Tract: 1. List the major major organs within the GI system and overall functions of the GI GI system. - GI tract: tract: mouth, mouth, esophagu esophagus, s, stomac stomach, h, small small intest intestine, ine, large intestine, intestine, rectum rectum and anus - Ac Acces cessor sory y glands: glands: saliv salivary ary gland glands, s, liver, liver, gallb gallblad ladder der and and pancrea pancreas s 2. Differentiate between between ingestion, ingestion, digestion, digestion, absorption, absorption, metabolism, metabolism, secretion, and excretion - Ingestio Ingestion: n: take take food food into into the the body body by swallo swallowin wing g or absorb absorbing ing it. it. - Digestion: Digestion: process process of breaking breaking down down food by by mechani mechanical cal or or enzymati enzymatic c action action in the stomach and intestines - Ab Abso sorpt rptio ion: n: pass pass into into the the bod body y from from the the GI GI - Metabo Metabolism lism:: chemi chemical cal proce process ss occurri occurring ng within within a body body to mainta maintain in life - Secret Secretion ion:: substan substance ces s produce produces s by cells cells or gland glands s are move moved d into the the GI - Excr Excret etio ion: n: remo removal val from from the the body body.. 3. Review Review histologi histological cal features features of the the wall of the GI tract - Four Four hist histol olog ogic icall ally y def define ined d regio regions ns:: Mucosa: consists of single layer o epithelium that is highly folded. The epithelium is frequently invaginated to form tubular exocrine glands o Submucosa: connective tissue layer with major blood and lymph vessels. Also has large number of ganglion cells forming the Meissner’s plexus o Muscularis externa: contains major smooth muscle (peristalsis); inner circular and outer longitudinal Serosa: thin connective tissue through which the major vessels and o extrinsic nerve enter 4. Compare and contrast smooth and and striated muscle muscle with respect to structure, excitation contraction coupling, and cellular mechanism of contraction. Comparison between Smooth and Straited Muscles. - Cell Cell bundl bundles es in SM have have diver diverse se orien orienta tati tion ons s due due to the lack lack of a disc discre rete te muscle origin and insertion. - Cont Contrac racti tile le filam filamen ents ts are arrang arranged ed irregu irregular larly ly (no (no sarco sarcome mere res) s) – this this allo allows ws forc force e gene genera rati tion on over over a wide wide rang range e of mus uscl cle e leng length ths s (ter (term med “len “lengt gth h adaptation”). There are large numbers of actin filaments attached to dense bodies and it is mainly through interconnections of these dense bodies that the force of contraction is transmitted from cell to cell. - Smoot Smooth h muscle muscle contai contains ns both both actin actin and myosin myosin filam filament ents. s. It does does not contain contain the normal troponin complex that is necessary in the control of skeletal muscle contraction. - Cont Contrac racti tion on of smoo smooth th musc muscle le requi require res s confo conform rmat atio iona nall alte alterat ratio ion n of myosin head wher wherea eas s with with stria striate ted d musc muscle le ther there e is movem movemen entt of the the tropo troponi ninntropomyosin complex on the actin filament.
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The The Sarc Sarcop opla lasm smic ic Reti Reticu culu lum m is not not orga organi nize zed d into into a T-tu T-tubu bule le sy syst stem em.. The The caveoli caveoli which which represent represent invaginations invaginations of the smooth muscle membrane membrane are analogous to T tubules in striated muscle - Smooth muscle can contrac ract for for lon long perio riods at low lev levels of ener nergy consumption and low myosin cross bridge recycling rates. Contraction: - Smoot Smooth h muscle muscle activit activity y is control controlled led by nerve nerves, s, circulat circulating ing hormo hormones nes,, by stretch of the muscle and other tissue factors. - In both both calci calcium um is key key to contra contracti ction, on, when when cell cellular ular leve levell is high high enough enough 2+ contractile protein interact. When extracellular Ca enters it can trigger the release of Ca2+ from internal sources. - Once Once calciu calcium m binds binds to to calmo calmoduli dulin n they they both both activat activate e MLCK MLCK whic which h phosphorylates myosin which interacts with actin causing contraction.
5. Review Review histolo histologica gicall features features of of transporting epithelia. - Leaky Leaky epit epithe heli lium um:: low low resis resista tanc nce, e, can’t build large potential difference. Seen in proximal renal tubule, small intestine, gallbladder, and choroid plexus. They have high water permeability - Tigh Tightt epit epithe heli lium um:: high high elec electri trica call resistance, do build up significant transepithelial potential differences. Generally these are not important in transport 6. Provide Provide general general cellula cellular r models models of fluid absorption and secretion. Absorption = movement movement of substances substances into the blood stream. An example example is a Na+ channel in tight epithelia, but can also be Na+/H+ exchange or a Na+ cotransporter. Absorption is characterized characterized by passive Na+ entry at the apical apical membrane and active Na+ extrusion at the basolateral membrane. membrane. In tight
epithelia the movement of Na+ through apical membrane channels create a flow of positive charge from the lumen to the interstitium that induces a lumennegative transepithelial potential difference. This is the driving force for passive Cl- absorption across the tight junction. (paracellular) vs Na+ was transcellular Secretion = movement of substance out of the blood. Transport is not the simple reverse of absorption. It centers on Cl- movement, rather than Na+. The electrochemical gradient for Na+ is still of key importance to drive secondary active Cl- uptake at the basolateral membrane. This results in an intracellular Clactivity above electrochemical equilibrium. Secretion is initiated by opening Clchannels in the apical cell membrane. The resulting Cl- current provides Cl- flux and also generates a lumen negative transepithelial potential difference, which drives passive paracellular Na+ secretion. *Clinical: Cystic Fibrosis notable failure of airway and pancreatic duct secretory epithelia, due to loss of the apical membrane Cl- channel = thick mucus, obstruction
7. Describe neural, endocrine, and paracrine modes of control and give examples of each. CCK – an example of endocrine control Enteroendocrine cells have apical microvilli which have receptors that o “taste” the gut lumen. I-cells (CCK secreting) detect long-chain fatty acids and products of protein digestion which results in the release of hormone from granules located at the basal part of the cell. Hormones are secreted by exocytosis and enter the blood capillaries supplying the intestinal mucosa. GI hormones then pass through the liver via the hepatic portal vein, then into the systemic circulation. •
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Serotonin, somatostatin, and histamine – examples of paracrine control o Serotonin is present in large quantities w/i enterochromaffin (EC) cells. In response to mechanical stimulation of the gut wall EC cells release serotonin. It’s effects are generally excitatory, resulting in increased intestinal motility and secretion. Serotonin exerts its effects largely through interactions with the ENS. o Somatostatin – peptide produced by D-cells. It may be released into the blood and act as a hormone, or a paracrine mediator. It is potent inhibitor – it inhibits pancreatic secretion, gastric secretion and motility, gallbladder concentration and nutrient absorption. Somatostatin is also a vasoconstrictor (used to treat GI hemorrhage). Histamine – present in mast cells and enterochromaffin-like cells (ECL) o in the stomach mucosa. Local release of histamine in stomach is important for stimulatory effects on gastric acid secretion. In the event of local infection or injury, mast cell degranulation may occur resulting in vascular effects including local edema and vasodilation. For neural example see #8
8. Describe the intrinsic and extrinsic innervations of the GI tract. The intrinsic innervation of the GI tract is through the enteric nervous system (ENS). The ENS is a “mini-brain” and initiates patterns of the GI activity by functioning autonomously without extrinsic activity. It is arranged anatomically into nerve networks in the myenteric and submucosal plexuses. The myenteric plexus is primarily involved with control of motility and innervates the longitudinal and circular smooth muscle layers. The submucosal plexus mainly innervates the glandular epithelium, intestinal endocrine cells, and submucosal blood vessels to control intestinal secretion. The ENS uses Ach, amines (serotonin), purines (ATP), gases (NO), and peptides (GUT-BRAIN peptides).
The extrinsic innervation of the GI tract – The Gut-Brain axis – although the ENS is capable of independent activity, it is modulated by the CNS. Anatomical connections between the ENS and CNS are via extrinsic nerves from the parasympathetic and sympathetic divisions of the ANS. The flow of info is bidirectional between the CNS and GI tract, giving rise to the concept of a gut-brain axis. PSNS – efferent nerve stimulation (mostly from vagus n) generally causes excitation. Most fibers exert their effect by ending on ganglia w/i the ENS therefore give “command signals” to ENS. The vagus n. is particularly important in control of the upper GI tract (esophagus, stomach, duodenum, gallbladder, and pancreas). PSNS outflow to secretory epithelial cells is universally excitatory. PSNS to gut smooth muscle has parallel inhibitory and excitatory fibers. Excitatory neurotransmitters = Ach and substance P; inhibitory neurotransmitters = NO and ATP. VIP is inhibitory to SM but excitatory to secretory enterocytes. PSNS also contains sensory afferent fibers from the GI tract that transmit sensations such as non-painful distension and nausea. SNS – generally acts to antagonize parasympathetic excitatory effects, with NE acting on alpha2-presynaptic receptors to inhibit Ach release by parasympathetic nerves. Other efferent sympathetic fibers mediate vasoconstriction to reduce intestinal blood flow. SNS also convey sensory afferents from the GI wall to the CNS, conveying sensations of pain and nausea. 9. Name the major GI hormones and the location of the endocrine cells that secrete them. Describe the main stimuli for secretion of each hormone and their main physiological actions. Name Loc of endocrine Main stimuli for Physiological cells that secrete secretion actions them -Incr secretory activity of G-cells of gastric amino acids, Gastrin stomach antrum distension of -trophic (growth stomach by food, promoting effect) on vagus nerve activity stomach mucosa via GRP -inhibited by H+ in the lumen of the •
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Cholecystokini n
I-cells of duodenum and jejunum
stomach and by somatostatin Fatty acids, monoglycerides, small peptides and amino acids
Secretin
S cells of duodenum
Acid and amino acid
Ghrelin
X-cell, secreted from body of stomach
Hypoglycemia and low body weight
Motilin
M-cell in distal stomach and small instestine
An ill-defined clock exists within the ENS that determines the interval btw meals and prompts motilin secretion when appropriate
GIP (Glucose-
Small intestine
Secreted in response to fat and glucose in the small intestine
L-cells of the gut mucosa of SI
Secreted in response to glucose in the SI lumen
dependent Insulinotropic Polypeptide)
Glucagon-like Peptide-1 (GLP-1)
-contraction of gallbladder and relaxation of sphincter of oddi -stimulates pancreatic enzyme secretion -potentiates secretininduced pancreatic bicarb secretion -stimulates growth of the exocrine pancreas -inhibits gastric emptying -incr bicarbonate secretion by pancreas and biliary system, thereby neutralizing acid delivered to the duodenum and stomach -this allows digestive enzymes in the SI to operate at optim pH -inhibits acid production by stomach -potenet stimulator of food intake and growth hormone release -secretion is highest in the interdigestive period -stimulates a pattern of contraction seen in the distal stomach and SI btw meals (MMC – migrating motor complex) -acts on neurons within the ENS to being the MMC contractions -when given in large doses causes inhibition of motor and secretory activity in the stomach -in smaller doses it promotes the secretion of insulin -promotes insulin secretion and inhibits glucagon secretion by pancreatic islet cells.
10. Explain what is meant by Cephalic, Gastric, and Intestinal phases of the GI tract regulation. The integrated response to a meal causes three phases of gastric secretion – cephalic, gastric, and intestinal phases. Cephalic phase describes the results of anticipation, sight, smell, and taste of food. Gastric and intestinal phases refer to
events occurring as a result of food being present in the stomach and intestines, respectively.
Section 2 Mouth, Salivary Glands, and Esophagus: 1. Describe functions of chewing. - Reduces particle size of food and increased exposure to saliva. - Lubricates food for swallowing and aids carb digestion via salivary amylase. - Taste receptors stimulated 2. Outline functions of saliva. - 70% produced by submandibular glands, 25% from parotid glands, and 5% from sublingual glands. - Maintains oral pH of 7 at rest - When stimulated the glands produce a slightly alkaline fluid - Functions: lubrication (moisten, mucins), protection, (lysozyme, lactoferrin, IgA) and digestion (alpha-amylase, lingual lipase) 3. State which digestive enzymes are present in saliva, their substrates and digestion products. - Alpha-amylase: starch - Lingual lipase: fats 4. Describe electrolyte composition of saliva and how it changes with flow rate. Explain salivary flow rate curves based on transport properties of the acinus and striated ducts. - Primary secretion formed by acini is isotonic and has a composition close to plasma - At low flow rates the saliva is hypotonic, at high flow rates it has an osmolality approaching that of plasma - Contraction of myoepithelial cells helps to move fluid out of the blind-ended acini into the striated ducts via the intercalated duct. Striated duct: reabsorbs NaCl o Ducts have low permeability, this is what cuases the saliva to become o hypotonic - Flow rate curves come about due to the length of time the duct has to modify the primary
5. Outline control mechanisms for production of saliva - Autonomic system is the sole mechanism of control, parasympathetic is the most important - parasympathetic outflow is via glossopharyngeal and facial nerves - direct innervation of local blood vessels by parasympathetic nerves causes vasodilatation by local release of vasodilator metabolites and kallikrein o causes glands to grow - only hormonal effect on saliva secretion is increased ductal Na+ absorption and K + secretion in response to aldosterone. 6. Describe swallowing sequence and identify voluntary and involuntary components. - Voluntary stage: where food is shaped into a bolus, collected on the tongue and pushed into the pharynx. The tongue is raised against the hard palate to create the pressure gradient that forces the food into the pharynx and beyond. - Involuntary stage: once food enters the pharynx, the nasopharnyx is closed by the soft palate and contraction of the superior pharyngeal constrictor. Closure of glottis, elevation and forward displacement of the larynx and deflection of the food bolus by the epiglottis, together prevent food entering the airway. The UES relaxes to allow the bolus to enter the esophagus. Breathing is stopped during these steps. - Swallowing is coordinated by a center in the reticular formation. The oral and pharyngeal component of swallowing is controlled solely by extrinsic nerves, neurologic damage can adversely affect this phase of swallowing. 7. Identify the normal resting esophageal pressure and explain why it varies with the respiratory cycle. Normal esophageal pressure is: UES = +40 mmHg, mid-esophagus = -5 mmHg, LES = +20 mmHg, stomach = +5 mmHg. 8. Describe the origin and consequence of the high basal tone found in the upper and lower esophageal sphincter. 9. Contrast anatomical and functional characteristics of the upper, middle, and lower parts of the esophagus. The esophagus can be divided anatomically into an upper third surrounded by striated muscle and a lower two thirds consisting of smooth muscle. Physiologically, the esophagus has 3 functional zones. The upper zone is closely related to the pharyngeal musculature and consists of striated muscle. The middle zone consists of smooth muscle and the lower zone constitutes the lower esophageal sphincter.
10. Compare and contrast primary and secondary esophageal peristalsis. Swallowing induces a wave of peristalsis known as primary peristalsis. If this is insufficient to move a bolus all the way to the stomach, distension of the esophageal wall by a remaining bolus induces a secondary peristalsis, which is repeated until the bolus enters the stomach. Contrast motility defects in the lower esophageal sphincter that is 11. responsible for heartburn and achalasia. Acid reflux: Acid reflux from the stomach occurs physiologically. The problem is when the LES is not working properly. Acid in the esophagus is neutralized by saliva and also induces secondary peristalsis to rapidly return to the stomach. If LES function is diminished and reflux occurs chronically, a patient has GastroEsophageal Reflux Disease (GERD). Symptoms include pyrosis (heartburn) and mucosal damage. Achalasia: (“absence of relaxation”) is a disorder with its origin in the ENS, affecting esophageal smooth muscle. There is a loss of peristalsis and a failure of the LES to relax properly. Patients have great difficulty swallowing, frequently aspirate food, and suffer malnourishment. Section 3 The Stomach 1. Describe the motor patterns of the stomach following ingestion of a meal.
1 – Fasted state 2 – Receptive relaxation & accommodation – ingestion of meal requires proximal stomach to relax so relaxation and accommodation occur to allow food to enter the stomach and store it without causing a rise in intragastric pressure – mediated by vago-vagal reflexes. 3 – Peristalsis begins – once food is ingested, proximal stomach exhibits slow sustained contractions that gradually press food into the distal stomach. Tonic contraction of the proximal stomach determines intra-gastric pressure, which is the main determinant of the gastric emptying of liquids. 4 – Retropulsion – contractions of the distal stomach serve to grind food (trituration) and to mix it with gastric juice. The powerful contractile waves seen at this time = “antral systole” and food is broken down by retropulsion in which food is forcefully reflected back from the pyloric sphincter into the stomach. 2. List the endocrine and exocrine secretions of the stomach, their cells of origin, and their functions. Name Cells of origin Functions
HCl Pepsinogen
Mucus Exocrine Secretions
Gastric mucosa
Bicarbonate Intrinsic Factor Gastric Lipase Water Endocrine Secretions
Gastrin Somatostatin
Antrum
-Denatures proteins, helping digestion -Cleaves pepsinogens -Proenzymes that are cleaved to produce active proteolytic pepsins -Lubricates ingested solids, helping gastric motility -Forms part of gastric mucosal barrier against acid and pepsin attack -Forms part of the gastric mucosal barrier -Forms complex with vit B12 in small intestine -Needed for vit B12 absorption in ileum -Contributes to triglyceride hydrolysis -Dilute and dissolve ingested food Stimulates acid production Inhibits acid production
3. Contrast the electrolyte composition of gastric juice with plasma and explain how this relationship changes with secretory rate. The composition of gastric juices changes with secretion rate. At all rates it is approximately isotonic with plasma. At low flow rates it resembles interstitial fulid while at high rates is becomes a solution primarily of HCl. This change is explained by the two component model. At rest, the gastric juice compromises a non-oxyntic component derived from paracellular diffusion of interstitial fluid and secretions of mucus cells. This produces a basal alkaline fluid of constant composition and low volume. As oxyntic cells are stimulated the non-oxyntic fluid is gradually diluted with HCl/KCl until the final [Na+] is only about 5mM. Pure oxyntic fluid is slightly hyperosmotic. This model is important since patients
suffering from prolonged vomiting, or nasogastric suction, may lose large amounts of gastric juice.
4. Provide a model explaining the cellular basis of gastric acid secretion and the generation of the alkaline tide. The alkaline tide refers to a condition, normally encountered after eating a meal, when stomach acid is released into the stomach causing a temporary increase in pH of the blood. The active transporter H+/K+ ATPase is used to pump the H+ out of the cell up an immense concentration gradient. K+ secretion via luminal membrane K+ channel provides the K+ needed by the H+/K+ ATPase to pump H+ out of the cell. OH- inside the cell produced along with H+ is neutralized by combining it with CO2 to form bicarbonate. Most of the CO2 comes from oxyntic cell metabolism. The HCO3 produced leaves the cell in such quantity that the gastric venous plasma becomes alkaline = post-prandial alkaline tide. Clenters the cell against in concentration gradient by coupling its entry with the exit of HCO3. Secretion of Cl- via a channel results in the formation of a large negative electrical potential in the stomach lumen. This is important to reduce the overall electrochemical gradient up which H+ needs to be transported. It can be thought of as “trapping” H+ in the lumen and thus contributes to the barrier function against acid self-attack of the mucosa.
5. Explain how gastric secretion is stimulated during the interdigestive, cephalic, gastric and intestinal phases. - Interdigestive: gastric secretions continues at about 15% of maximal producing, the characteristic low pH of the stomach contents at rest. - Cephalic: mediated by the vagus nerve. The thought of a meal is sufficient to increase acid production. Afferent signals pass up the vagus nerve to the vagal nucleus and down the efferent vagal fibers to the stomach. There are two ways that gastric acid secretion is stimulated during this phase: o release of Ach by nerve terminals on oxyntic cells post-ganglionic vagal efferent’s ending on G-cells release GRP causing o gastrin release. Note that during this phase gastrin secretion is suppressed when intragastric pH is below 3. Gastric: acid secretion during this phase accounts for 50% of the response to a meal. When food enters the stomach there is a rise in pH to about 6, this causes more gastrin secretion to occur. Distension of the
stomach is also a key stimulus during the gastric phase as it activates the vago-vagal reflex and the ENS. Long loop vago-vagal reflexes operate, where the efferent pathway is very similar to that described for the cephalic phase. Short reflexes within the ENS also support the same activation mechanisms, since cutting the vagus does not abolish neurally mediated acid production. Intestinal: partially digested peptides and amino acids in the proximal part of the small intestine activate the duodenal G cells to produce gastrin. 5-10% of the total gastric secretion comes from this phase. 6. Describe negative feed back mechanisms that inhibit secretion of gastric acid. - 1 hour after ingestion of a meal, gastric acid secretion is at max and most of the meal has entered the small intestine. - Once the pH falls below three the G cells are inhibited by H+ concentration. - Lowered pH also activates D cells to release somatostatin which inhibits gastrin release. - Lowered pH also directly inhibits oxyntic cells. - The presence of acid, fatty acids, and hyperosmotic fluids in the small intestine all stimulate the release of hormones from endocrine cells that inhibit gastric function – called enterogastrins. o secretin is the main one. o GIP: released in response to glucose and fatty acids and can inhibit oxyntic cells CCK: released in response to protein and fat o digestion products and reduces motility rather than acid production.
7. Describe how pepsinogen secretion is controlled and what factors are important for its conversion to pepsin. Pepsinogens are proenzymes that are cleaved and activated when pH drops below 5. The pepsin produced then autocatalyses conversion of pepsinogen to pepsin. 8. Explain what is meant by the gastric mucosal barrier and indicate the main agents known to disrupt it. This is one layer involved in the protecting the mucosa from erosion. It is effective at neutralizing acid due to the bicarbonate that gets trapped in the mucus gel. Note that the tight junctions are the most important factor preventing back diffusion of H+.
Certain agents can disrupt this barrier including ethanol, bile salts or asprin/indomethacin. Disruption can be associated with gastritis and after time, ulcers.
Pancreas and Biliary System: 9. Explain what primary and secondary bile acids/salts are and indicate their relative abundance in human bile. Hepatocytes synthesize and secrete the primary bile acids, cholic acid and chenodeoxycholic acid. Most of these bile salts are conjugated to glycine or taurine to produce glycocholate and taurocholate, respectively. This conjugation makes them more soluble. Primary bile salts undergo bacterial modifications in the gut lumen. 10-20% undergo deconjugation and are reabsorbed in the small intestine and reconjugated in the liver to be secreted again. During this process dehydroxylation may occur to create secondary bile acids (cholic deoxycholic acid; chenodeoxycholic acid lithocholic acid).
Outline mechanism of the bile acid secretion by hepatocytes. 10. 95% of the bile acids arriving in the intestine are reabsorbed (via Na +-bile acid cotransporter), these acids return to the liver-via the portal vein. Bile acids that become deconjugated are largely unionized and reabsorbed by simple diffusion in the jejunum due to their higher lipid permeability. Typically, around 0.2g of bile acids is excreted in feces each day. This is replaced by new synthesis of primary bile acids by the liver. The rate limiting step in secretion of bile acid is the transport across the canalicular membrane via facilitated diffusion. Explain what is meant by the amphipathic properties of bile acids 11. and predict how this property assists the digestion of fats. Contrast the physical state of emulsion with a micellular solution. Bile acids are amphipathic which means a portion is polar and a portion is nonpolar. The polar outer shell interacts with water and the hydrophobic inner region interacts with insoluble fatty acids, and cholesterol.
In mixed micelles the other amphipathic molecules (phospholipids and monoglycerides) line up with their polar heads facing outwards and their tails facing the hydrophobic code. The mixed micelle is more efficient at dissolving other hydrophobic molecules. Thus, micelles are in a true solution unlike emulsions.
Define the enterohepatic circulation 12. of bile acids. The total bile acid pool is about 3.5g which is not enough to assimilate the lipid content of a typical meal, Therefore, bile acids are recycled, with the total bile acid pool secreted approximately twice during each meal and around 6-8 times a day. This is achieved by enterohepatic circulation of bile acids.
13. Discuss factors which govern the rate of bile flow and the rate of synthesis of new bile acids. Outline the effects of CCK and secretin on secretion and delivery of bile to the duodenum Regulation of bile acid synthesis in hepatocytes is mainly governed by their delivery from the intestine via portal blood. High delivery rates in sinusoidal blood causes stimulation of bile fluid secretion, but also inhibits synthesis of new bile acids. 14. Outline the functions of the gallbladder and the control of gallbladder motility. During the interdigestive phase the tone of the sphincter of Oddi is increased and the wall of the gallbladder is relaxed – this promotes flow of hepatic bile into the gallbladder. More than 50% of the hepatic bile flow enters the gallbladder during the interdigestive period. Between meals bile is secreted constantly and the volume produced can greatly exceed the small volume of the gallbladder. This difference is accounted for by the NaCl and water reabsorption by epithelial cells lining the gallbladder. During a meal the bile flow rate is at its highest. The cephalic phase causes gradual contraction of the gallbladder which is mediated by cholinergic vagal nerves. Once the meal is in the intestine a powerful signal for gallbladder contration comes from CCK release. CCK also relaxes the sphincter of Oddi, which is the key event that allows pancreatic and biliary secretion to enter the duodenum and digest the meal.***** 15. Describe the processes of bile pigment synthesis, modification of secretion. Predict changes in plasma bile pigment concentrations in jaundice with pre-hepatic and post-hepatic causes. About 2% of biliary solids are bile pigments. The major pigment is bilirubin which is derived form the breakdown of hemoglobin in macrophages by heme oxygenase. Bilirubin is insoluble and is therefore transported bound to albumin.
The liver takes up free bilirubin and transports it to the endoplasmic reticulum where it is conjugated with glucuronide via glucuronyl transferase. This is called conjugated bilirubin and is water soluble – it can now be transported across the canilicular membrane. Half of this is delivered to the intestine and excreted unaltered. Intestinal bacteria is reabsorbed and returned to the liver in the portal vein. Much of the urobilinogen is processed again by the liver and delivered to the GI tract. In the colon the urobilinogen is metablized by bacteria into stercobilin. Some of the urobilinogen escapes hepatic uptake and enter systemic circulation. At the kidneys this is filtered into the urine and oxidized to urobilin. Below is a pictorial representation.
Small Intestine: 1. Describe segmenting and peristalic patterns of motility seen in the small intestine during the fed state and indicate their function. - Segmenting: contractions are often regular, producing a string of evenly sized segments, but can also be irregular or even isolated. They can also vary in strength. Segmentation is effective at mixing lumenal contents - Peristalsis is a reflex event in which a ring of contraction moves a bolus aborally. The major stimulus for peristalsis is mild/moderate distension of the gut wall. Requires carefully timed sequence of contractions in the longitudinal and o circular muscle layers. o Contracting segment: the circular muscle contracts, forcing the bolus forward. At this time the longitudinal muscle relaxes in this area, and the circular muscle in the immediate downstream area relaxes (known as receptive receptive relaxation). Receving segment: longitudinal muscle layer contracts to pull the bowel o wall over the bolus like a sleeve. 2. Describe the changes in osmolarity that occur in chyme as it passes form the stomach and along the small intestine. - Chyme: Semifluid material produced by the gastric digestion of food. Results partly from the conversion of large solid particles into smaller
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particles through peristalsis and the contraction of the pyloric sphincter. Fluid absorption in the small intestine is isosmotic and not subject to hormonal regulation If food is present in the upper small intestine, high epithelial water permeability ensures rapid osmotic equilibrium with plasma. After this, absorption of fluid depends on active transport of nutrients and electrolytes. Na+ is taken up at the luminal membrane driven by low intracellular concentration of Na+. There is extrusion at the basolateral surface by the Na+ pump. Fluids absorbed after a meal are generally a result of sodium and nutrient uptake These features of the intestine indicate that the osmolarity of the chyme is not changed until it reaches the colon where it is concentrated Bicarbonate in intestinal secretions protects intestinal mucosa by neutralizing any H+ present in lumen – important in duodenum and jejunum where bacteria produce acids from degradation of certain foods
3. Relate pathways by which sodium, water, iron and calcium are absorbed in the small intestine. Sodium – nutrient coupled sodium absorption, Chloride-coupled, Na+/H+exchange Water - absorbed as a result of sodium and nutrient uptake. Iron - Mostly arrives at intestine as heme, but some as ferric/ferrous iron. Divalent cation transport brings the ferrous form of iron into duodenal enterocytes. Heme has its own transport, and is then split to ferric iron using heme oxygenase. There is also a process where the cell secretes a transferring that binds the iron and brings it into the cell. Calcium - In duodenum/jejunum Vitamin D3 increases intestinal Ca2+ uptake by inducing synthesis of transport proteins. Calcium enters the cell down a steep electrochemical gradient via a Ca2+ channel 4. Describe the process of intestinal fluid secretion, indicating its physiological function and its importance in secretory diarrhea. Secretory diarrhea is caused by an increase in active secretion or inhibition of absorption. Bacterial enterotoxins activate mechanisms that cause the intestinal fluid secretion and ultinately result in secretory diarrhea. The enterotoxins incraese cAMP which opens Cl- channels, they also increase calcium which opens calcium gated Cl- channels. Chloride leaves the intestinal cells into the lumen causing Na + to follow paracellularly. Since water follows throuh osmosis, diarrhea results. 5. List the chemical classes of carbohydrate, protein and fat entering the duodenum from the stomach, and identify mechanisms mediating further digestion. Indluce pancreatic secretions and brush border enzymes. Carbohydrates: - Duodenum: Salivary amylase begins the process of digestion in the mouth, but carbohydrates of all types enter the duodenum (mono,poly,oligosaccharides) - Pancreatic Secretions: Pancreatic amylase continues the digestion of remaining
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carbohydrates Brush Border Enzymes: Brush border enzymes also digest disaccharides and oligosaccharides Carbs must be broken into a monosaccharide form in order to be absorbed by the intestines
Protein: - Duodenum: Pepsin begins digestion in stomach, proteins only partially digested - Pancreatic Secretions: Pancreatic enzymes act on the partially digested proteins: o elastase o chymotrypsin trypsin =endopeptidases, they hydrolyze internal peptide bonds o Resulting oligopeptides are then attacked by ectopeptidases which o remove one amino acid at a time o Carboxypeptidase A – works on products of chymotrypsin, elastase o Carboxypeptidase B – acts on products of trypsin digestion - Brush Border Enzymes: Aminooligopeptidase is the major proteolytic brush border enzyme Fat: -
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General: Triglycerides, lecithins/PL, sphingolipids, sterols, fat-soluble vitamins (A,D,E,K) Chewing and grinding peristalsis break fat droplets into smaller o pieces, helping to create an emulsion lingual lipase, gastric lipase o o (people with pancreatic insufficiency can partially digest) Pancreatic Secretions: Pancreatic lipase: an alkaline lipase, produces monoglyceride and o releases two FFAs from parent TG molecule. Products enter a micelle because they are insoluble. o o Other enzymes: phospholipase A, carboxyl ester lipase Brush Border Enzymes: Micelles coming close to the brush border release FA and monoglycerol which is taken up by the enterocytes. There is no enzyme action at this location
6. Describe mucosal barrier across which absorption takes place. A layer of poorly stirred fluid (the unstirred water layer) coats the surface of the instestinal villi). This layer reduces the absorption of the lipid digestion products because they are poorly soluble in water. This region is usually acidic. Large Intestine: 1. Identify substrates and products of colonic bacterial metabolism and predict the impact on the rate and composition of intestinal gas formation. The main bulking agent in stools are the non-starch
poly-saccharides. Resistant starches are subject to bacterial fermentation reactions in the colon. Bacterial formations produces SC-FA (acetate, propionate, and butyrate) and gas. Farts are due to bacteria fermentation reactions making gases like H2, CH4, CO2, and H2S. A higher fiber diet will force the GI to do more bacterial fermentation causing more gas.
2. Describe the production and absorption of short chain fatty acids in the colon. SC-FA are produced through bacterial fermentation of fibrous/unigestable fibers. Most of the SC-FA are absorbed.
3. Classify different types of diarrhea. Predict the impact of severe diarrhea on the whole body fluid and electrolyte homeostasis. Diarrhea: an increase in stool fluid to more than 200ml in 24 hours. Osmotic diarrhea: agent present in the intestinal lumen that cuases water to be retained within the lumen. Ex. Lactose intolerance: when lactase is damaged, lactose sits in the stomach pulling water into the stomach. Motor Diarrhea: rapid transit through the GI and there is insufficient time to complete fluid and electrolyte absorption. Ex. Intestinal bypass surgery, or IBS (hypersensitivity of enteric nerves) Secretory: when endogenous fluid is secreted. Ex. Occurs by enterotoxigenic bacteria (E.coli or cholera) increasing fluid secretion. Cholera causes diarrhea by stimulating Cl- secretion. When Cl- channels on the luminal membrane are opened, and Na+ and H2O follow Cl- into the lumen. Inflammatory: involves components of all diarrheas listed above (usually causes increased motility and secretion). Ex. Ulcerative colitis. An increase in fluid flow in the distal colon during diarrhea causes loss of K+ which often leads to hypokalemia. In the distal colon Na+ is transferred from the lumen through the cell, and K+ is secreted. In diarrhea, the fluid has high sodium concentration and low potassium concentration which increases the driving force of potassium out of the cell. Furthermore, since water is constantly being absorbed in the colon, the concentration of K+ increases in the stool. When fluid in the colon is increased: i) the fluid arriving has a low potassium concentration, therefore making Ek more negative ii) the increased rate of Na+ delivery from proximal sites results in more Na+ entry into distal colonocytes via ENaC. Combined, these things increase the electrochemical gradient for K+ secretion. Bicarbonate loss can occur in diarrhea too. You have an influx of fluid into the colon that has NaCl concentration. You are dehydrating your cells so Cl- is rapidly
taken up by cells through the Cl-/HCO3- pump. This causes a large depletion of bicarbonate and the hydrogen builds up inside the cells causing metabolic acidosis.
Enteric Motility: 1. Divide the GI tract into functional segments based on the location of sphincters. Review patters of motility that occur along the GI tract in the fed state. Sphincter Segments Separated Upper esophageal sphincter Mouth/pharynx Lower esophageal sphincter Esophagus/stomach Sphincter of Oddi Common bile duct/ duodenum Pyloric Sphincter Stomach/duodenum Ileocecal sphincter Ileum/cecum Anal Rectum/external environment The patterns of motility that occur along the GI tract are propulsion, mixing, and reservoirs. These are explained in earlier objectives 2. Describe the basic electrical rhythm (BER) of each region of the GI tract. Explain the role of Intestinal Cells of Cajal in the origin and propagation of the BER. Correlate the BER with motility patterns. In the smooth muscle cells of the G.I there are slow undulating changes in resting membrane potential known as BER. These are generator potentials, which themselves rarely cause muscle contraction. Only when threshold of 40mV is reached will contraction occur. Contractions are associated with spike potentials and only occur at the peak of a slow wave. Therefore the maximum possible frequency of contraction is set by the rate of slow wave generation. The smooth muscle cells have no pacemaker activity of their own, the origin of oscillations in their membrane potential is the Interstitial Cells of Cajal (ICC’s). These fibroblast-like cells are positioned between the longitudinal and circular smooth muscles and are closely associated with the myenteric plexus. The ICC’s have multiple processes which are electrically coupled to the smooth muscle cells. 3. Describe the sequence of events occurring during reflexive defecation, differentiating those movements under voluntary control and those under intrinsic control. When the rectum becomes sufficiently distended by fecal matter, the rectosphinteric reflex is initiated which causes internal sphincter to relax (intrinsic control). This event is associated with an urge to defecate. Through voluntary contraction of the external anal sphincter a person is able to override this reflex. The internal sphincter regains tone and rectal stretch receptors are able to accommodate the distention. Rectal wall relaxes and pressure returns to
normal. When more material enters the rectum following mass movements of the colon the process repeats. When the person finally gets to a toilet the complete defecation reflex occurs. Both the internal and external sphincters relax. The person voluntarily strains to raise intraabdominal pressure and relax the pelvic floor. This is in conjunction with propulsive involuntary contraction of the left colon and rectum.
