Structure of the GI tract

Epithelial cells: specialized in different parts of the GI tract for secretion of absorption.

Muscularis mucosa: contraction causes a change in the surface area for secretion or absorption.

Circular muscle: contraction causes a decrease in diameter of the lumen of the GI Tract.

Longitudinal muscle: contraction causes shortening of a segment of the GI Tract.

Submucosal plexus (meissner's plexus) and myenteric plexus: comprise the enteric nervous system of the GI tract; integrate and coordinate the motility, secretory, and endocrine functions of the GI tract

Parasympathetic and sympathetic

Efferent fibers: carry information from the brain stem and spinal cord to the GI tract.

Afferent fibers: carry sensory information from chemoreceptors and mechanoreceptors in the GI tract to the brain stem and spinal cord.

Parasympathetic

GI Tract

Usually excitatory on the functions of the GI tract.

Carried via the vagus and pelvic nerves.

Preganglionic parasympathetic fibers synapse in the myenteric and submucosal plexuses.

Cell bodies in the ganglia of the plexuses then send info to the smooth muscle, secretory cells, and endocrine cells of the GI tract.

Vagus Nerve

GI Tract

Innervates the esophagus, stomach, pancreas, and upper large intestine.

Reflexes in which both afferent and efferent pathways are contained in the vagus nerve are called vagovagal reflexes.

Sympathetic Nervous System

GI Tract

Usually inhibitory on the functions of the GI Tract.

Fibers originate in the spinal cord between T8 and L2.

Preganglionic sympathetic cholinergic fibers synapse in the prevertebral ganglia.

Postganglionic sympathetic adrenergic fibers leave the prevertebral ganglia and synapse in the myenteric and submucosal plexuses.

Cell bodies in the ganglia of the plexuses then send info to the smooth muscle, secretory cells, and endocrine cells of the GI Tract.

Intrinsic Innervation

GI Tract

Coordinates and relays info from the parasympathetic and sympathetic nervous systems to the GI tract.

Uses local reflexes to relay info within the GI tract.

Controls most functions of the GI tract, especially motility and secretion, even in the absence of extrinsic innervation.

Myenteric plexus (Auerbach's plexus): primarily controls the motility of the GI Smooth muscle.

Submucosal plexus (Meissner's plexus): primarily controls secretion and blood flow; receives sensory info from chemoreceptors and mechanoreceptors in the GI tract.

Pacemaking

GI Tract

Modulated by the enteric nervous system.

Occurs in at least 2 phases: rhythmic, propagating peristaltic contractions along the length of the tube, and local non-propagating contractions for mixing.

GI contractions are slow and highly variable in space and time (more frequent proximally, and stronger and more frequent during digestion).

The mode of GI contractions is exactly analogous to the heart, with timing being controlled by pacemaker cells & amplitude controlled by hormones, ANS and ENS.  NO AP.

Pacemaker cells are called the Interstitial Cells of Cajal (ICCs).

Pacemaker potentials are passed from ICCs to smooth muscle, and between smooth muscle via gap junctions.

Lie along the muscle layers and generate pacemaker potentials, or slow spontaneous oscillations in membrane potential.

Lack voltage sensitive Na and Ca channels and cannot generate typical APs, which is one reason the ICC pacemaker potential is so slow.

Cyclical waves in the membrane potential, not APs though they help generate APs.

Bring smooth muscle membrane potentials just to the mechanical threshold, where Ca channels open and contractions begin.

Have different timing in different secretions:

Stomach 3 ml/min

Duodenum 14 ml/min

Ileum 7-8 ml/min

This difference creates a gradient in the intestine which helps move food unidirectionally.

Released from endocrine cells in the GI mucosa into the portal circulation, enter the general circulation, andhave physiologic actions on target cells.

Four substances are official GI hormones: gastrin, cholecystokinin (CCK), secretin, and gastric inhibitory peptidfe (GIP).

17 Amino Acids

Small gastrin is the form secreted in response to a meal.

All the biologic activity of gastrin resides in the 4 C-terminal amino acids.

Big gastrin contains 34 amino acids, not a dimer of small gastrin.

Gastrin

Actions

Increases H+ secretion by the gastric parietal cel.s

Stimulates growth of gastric mucosa by stimulating the synthesis of RNA and new protein. 

Patients with gastrin-secreting tumors have hpertrophy and hyperplasia of the gastric mucosa.

Gastrin

Stimuli for Secretion

Secreted from G-cells of the gastric antrum in response to a meal.

Small peptides and amino acids in the lumen of the stomach; the most potent stimuli are phenylalanine and tryptophan.

Distention of the stomach.

Vagal stimulation, mediated by gastrin-releasing peptide (GRP).

Gastrin

Inhibition

H+ in the lumen of the stomach inhibits gastrin release.  This negative feedback control ensures that gastrin secretion is inhibited if the stomach contents are sufficiently acidified.

Zollinger-Ellison syndrome (gastrinoma): occurs when gastrin is secreted by non-Bcell tumors of the pancreas.

33 amino acids, homologous to gastrin

5 C-terminal amino acids are the same as gastrin.

Biologic activity of CCK resides in the C-terminal heptapeptide.

The heptapeptide contains the sequence that is homologous to gastrin and gastrin activity.

CCK

Actions

Stimulates the contraction of the gallbladder and simultaneously causes relaxation of the sphincter of Oddi for secretion of bile.

Stimulates pancreatic enzyme secretion.

Potentiates secretin-induced stimulation of pancreatic HCO3 secretion.

Stimulates growth of the exocrine pancreas.

Inhibits gastric emptying.  Meals containing fat stimulate the secretion of CCK, which slows gastric emptying to allow more time for intestinal digestion and absorption.

27 amino acids; Homologous to glucagon.

All of the amino acids are required for biologic activity.

Secretin

Actions

Coordinated to reduce the amount of H+ in the lumen of the small intestine.

Stimulates pancreatic HCO3 secretion and increases growth of the exocrine pancreas.  Pancreatic HCO3 neutralizes H+ in the intestinal lumen.

Stimulates HCO3 and H2O secretion by the liver, and increases bile production.

Inhibits H secretion by gastric parietal cells.

Secretin

Stimuli for release

Released by the S cells of the duodenum in response to:

H+ in the lumen of the duodenum.

Fatty acids in the lumen of the duodenum.

Gastric Inhibitory Peptide

GIP

42 amino acids, homologous to secretin and glucagon

Stimulates insulin release.  In the presence of an oral glucose load, GIP causes the release of insulin from the pancreas.  Oral glucose is more effective than IV glucose in causing insulin release and glucose utilization.

Inhibits H+ secretion by gastric parietal cells.

GIP

Stimuli for release

GIP is secreted by the duodenum and jejunum.

GIP is the only GI hormone that is released in response to fat, protein, and carbohydrate.

GIP secretion is stimulated by fatty acids, amino acids, and orally administered glucose.

Released from endocrine cells in the GI mucosa.

Diffuse over short distances to act on target cells located in the GI tract.

Somatostatin and Histamine

Secreted by cells throughout the GI tract in response to H+ in the lumen. 

Its secretion is inhibited by vagal stimulation.

Inhibits the release of all GI hormones.

Inhibits gastric H secretion.

Secreted by mast cells of the gastric mucosa.

Increases gastric H+ secretion directly and by potentiating the effects of gastrin and vagal stimulation.

Synthesized in neurons of the GI tract, moved by axonal transport down the axon, and released by action potentials in the nerves.

Vasoactive intestinal peptide (VIP), GRP (bombesin), and enkephalins.

28 amino acids, homolgous to secretin.

Released from neurons in the mucosa and smooth muscles of the GI tract.

Produces relaxation of GI smooth muscle, including the LES.

Stimulates pancreatic HCO3 secretion and inhibits gastric H secretion.  Resembling secretin.

Secreted by pancreatic islet cell tumors and is presumed to mediate pancreatic cholera.

Released from vagus nerves that innervate the G cells.

Stimulates the gastrin release from G cells.

met-enkephalin and leu-enkephalin

Secreted from nerves in the mucosa and smooth muscle of the GI tract.

Stimulate contraction of GI smooth muscle, particularly the lower esophageal, pyloric, and ileocecal sphincters.

Inhibit intestinal secreation of fluid and electrolytes.  Forming the basis for the usefulness of opiates in the treatment of diarrhea.

Food bolus causes enterochromaffin cells in epithelium to release serotonin, which activates primary sensory receptor cells locally.

Receptor cells excite a pool of submucosal and myenteric interneurons.

Proximal projections of interneurons excite neurons which innervate circular smooth muscle, which releases AcH and Substance P, causing constriction of the lumen behind the bolus.

Distal projections of the interneurons drive excitatory motor neurons innervating longitudinal smooth mucle and inhibitory motor neurons innervating circular smooth muscle, causing the tube to shorten and widen.

Bolus moves along and stimulates a new set of neurons, repeats until defecation.

Contractile tissue of the GI tract is almost exclusively unitary smooth muscle, with the exception of the pharynx, upper 1/3 of the esophagus, and external anal sphincter, all of which are striated muscle.

Depolarization of circular muscle leads to contraction of a ring of smooth  muscle and a decrease in diameter of that segment of the GI tract.

Depolarization of longitudinal muscle leads to a contraction in the longitudinal direction and a decrease in length of that segment of the GI tract.

GI Motility

Slow Waves

Oscillating membrane potentials inherent to the smooth muscle cells of some parts of the GI tract.

Occur spontaneously.

Originate in the interstitial cells of Cajal, which serves as the pacemaker for GI smooth muscle.

Not APs, although they determine the pattern of APs and therefore the pattern of contraction.

Cyclic activation and deactivation of the cell membrane Na/K pump.

Depolarization during each slow wave brings the membrane potential of smooth muscle cells closer to the threshold and increases the probability that APs will occur.

APs produced on top of the background of slow waves, then initiate contraction of the smooth muscle cells.

Lubricates food by mixing it with saliva.

Decreases the size of food particles to facilitate swallowing and to begin the digestive process.

Coordinated in the medulla.  Fibers in the vagus and glossopharyngeal nerves carry info between the GI tract and the medulla.

The nasopharynx closes and breathing is inhibited.

The laryngeal muscles contract to close the glottis and elevate the larynx.

Peristalsis begins in the pharynx to propel the food bolus toward the esophagus.  The Upper esophageal sphincter relaxes to permit the food bolus to enter the esophagus.

The esophagus propels the swallowed food into the stomach.

Sphincters at either end of the esophagus prevent air from entering the upper esophagus and gastric acid from entering the lower esophagus.

Because the esophagus is located in the thorax, intraesophageal pressure equals thoracic pressures, which is lower than atmospheric pressure.

As part of the swallowing reflex, the upper esophageal sphincter relaxes to permit swallowed food to enter the esophagus.

The upper esophageal sphincter then contracts so that food will not reflux into the pharynx.

Primary peristaltic contraction creates an area of high pressure behind the food bolus, then moves down the esophagus and propels the food bolus along.  Gravity accelerates the movement.

Secondary peristaltic contraction clears the esophagus of any remaining food.

As the food bolus approaches the lower end of the esophagus, the lower esophageal sphincter relaxes, this is vagally meidated and the NT is VIP.

The orad region of the stomach relaxes (receptive relaxation) to allow the food bolus to enter the stomach.

3 layers of smooth muscle: longitudinal, circular, and oblique.

3 anatomic divisions: fundus, body, antrum.

Orad region includes the fundus and the proximal body.  Contains oxyntic glands and is responsible for receiving the ingested meal.

Caudad region includes the antrum and distal body.  Responsible for the contractions that mix food and propel it into the duodenum.

Vagovagal reflex initiated by distention of the stomach and is abolished by vagotomy.

Orad region relaxes to accomodate the ingested meal.

CCK participates by increasing the distensibility of the orad stomach.

Caudad region contracts to mix the food with gastric secretions and beings the process of digestion.  The size of food particles is reduced.

Slow waves occur at a frequence of 3-5 ml/min.  They depolarize the smooth muscle cells.

If threshold is reached during the slow waves, APs are fired, followed by contraction.  Thus the frequency of slow waves sets the max frequency of contraction.

A wave of contraction closes the distal antrum.  As the caudad stomach contracts, food is propelled back into the stomach to be mixed (retropulsion).

Gastric contractions are increased by vagal stimulation and decreased by sympathetic stimulation.

Even during fasting, contractions occur at 90-minute intervals and clear the stomach of residual food (migrating myoelectric complex).

Caudad region contracts to propel food into the duodenum.

Rate of gastric emptying is fastest when the stomach contents are isotonic.  Gastric emptying slowed by hyper or hypotonic contents.

fat inhibits gastric emptying by stimulating the release of CCK.

H+ in the duodenum inhibits gastric emptying via direct neural reflexes.  H+ receptros in the duodenum relay info to the gastric smooth muscle via interneurons in the GI plexuses.

Functions in the digestion and absorption of nutrients.  Mixes nutrients with digestive enzymes, exposes the digested nutrients to the absorptive mucosa, and then propels any non-absorbed material to the large intestine.

Slow waves set the basic electrical rhythm, which occurs at a frequency of 12 waves/min.  APs occur on top of the slow waves and lead to contractions.

Parasympathetic stimulations increases intestinal smooth muscle contraction, sympathetic stimulation decreases it.

Mix the intestinal contents.

Section of small intestine contracts, sending the intestinal contents (chyme) in both orad and caudad directions.  That section of small intestine then relaxes, and the contents move back into the segment.

This back and forth movement causes mixing without any net forward movement of chyme.

Highly coordinated and propel the chyme through the small intestine toward the large intestine.  Peristalsis occurs after digestion and absorption have taken place.

Contraction behind the bolus and relaxation in front of the bolus cause the chyme to be propelled caudally.

Peristaltic reflex coordinated by the enteric nervous system.

Mediated by the extrinsic ANS and possibly by gastrin.

Presence of food in the stomach triggers increased peristalsis in the ileum and relaxation of the ileocecal sphincter.  The intestinal contents are delivered to the large intestine.

Fecal material moves from the cecum to the colon to the rectum and then to the anal canal.

Haustra - sac like segments - appear after contractions of the large intestine.

Large intestinal motility

Cecum and Proximal colon

When the proximal colon is distended with fecal material, the ileocecal sphincter contracts to prevent reflux into the ileum.

Segmentation contractions in the proximal colon mix the contents and are responsible for the appearance of haustra.

mass movements occur 1-3 times/day and cause the colonic contents to move distally for long distance.

Large intestinal motility

Distal Colon

Because most colonic water absorption occurs in the proximal colon, fecal material in the distal colon becomes semisolid and moves slowly.  Mass movements propel it into the rectum.

Large intestinal motility

Rectum, anal canal, defecation

As the rectum fills with fecal material, it contracts and the internal anal sphincter relaxes.

Once the rectum is filled to 25%, there is an urge to defecate, however, this is prevented because the external anal sphincter is tonically contracted.

When it is convenient to defecate, the external anal sphincter is relaxed voluntarily.  The smooth muscle of the rectum contracts, forcing the feces out.

Intra-abdominal pressure is increased by expiring against a closed glottis.

Large intestinal motility

gastrocolic reflex

The presence of food in the stomach increases the motility of the colon and increases the frequency of mass movements.

The gastrocolic reflex has a rapid parasympathetic component that is initiated when the stomach is stretched by food.

Slower, hormonal component is mediated by CCK and gastrin.

Large intestinal motility

Disorders

Emotional factors strongly influence large intestinal motility via the extrinsic ANS.  IBS may occur during periods of stress and may result in constipation or diarrhea.

Megacolon (Hirschsprung's disease), the absence of the colonic enteric nervous system, results in constriction of the involved segment, marked dilation, and accumulation of intestinal contents proximal to the constrication, and severe constipation.

Wave of reverse peristalsis begins in the small intestine, moving GI contents in the orad direction.

Gastric contents are eventually pushed into the esophagus.  If the Upper esophageal sphincter remains closed, retching occurs, if the pressure becomes to high and it opens, vomiting occurs.

Vomiting center in the medulla is stimulated by tickling the back of the throat, gastric distension, and vestibular stimulation.

Chemoreceptor trigger zone in the 4th ventricle is activated by emetics, radiation, and vestibular stimulation.

Motor Aspects of GI function

Mouth

Chewing, making saliva, swallowing

Time 1 sec

Motor aspects of GI function

Esophagus

Upper sphincter relaxes

Peristalsis

Lower sphincter relaxes and food allowed into stomach.

Transit time 10 sec.

Motor aspects of GI function

Stomach

Receptive relaxation - fundus relaxes to allow distension, food entry occurs in concert with lower esophageal sphincter relaxation.  Prevents discomfort and forced entry of food into small intestine faster than we could process.

Peristaltic waves (3/min) in body of stomach churn food to chyme over 2-4 hours.

Antrum and pylorus (caudad region) also churn, but with powerful contractions whcih release 1 ml/contraction (3/min).

People with gastric bypass must eat small amounts of food more often or risk vomiting.

Motor aspects of GI function

Small intestine

Food enters, peristaltic and segmental contractions begin.

Segmental contractions are important for food movement and mixing of food with enzymes, as well as enhancing access of digested nutrients to absorptive surfaces of intestine.

Ileocecal junction (like a sphincter) periodically relaxes to allow controlled entry into the colon.

Transit time: 6 hours

Motor aspects of GI function

Large intestine

Periodic convulsive peristaltic contractions involving 15-30 cm of colon at a time.

Water and electrolytes resorbed and the contents become progessively more solid.

Fecal material moves to the rectum when the descending and sigmoid colon become filled, this causes the urge to defecation.

Transit time 12-36 hours.

In the body or oxnytic region of the stomach.

Surface/neck cells which reside at the top half of the gland (closest to the lumen) and secrete mucus.

Parietal cells (oxyntic cells) in the middle part of gland, secrete HCl, intrinsic factor (IF).

Chief Cells are at the base of the gland and secrete pepsinogen.

The antrum of the stomach.

Similar to oxyntic glands, but with out parietal cells, and with gastrin-secreting glands.

Together are collectively called gastric glands.

Exocrine secretions: divided into parietly and non-parietal components; all are released into the lumen of the gland by apical transport or exocytosis.  High rates of secretion increase lumen osmotic pressure, recruit water, and thereby drive fluid down the duct to the stomach.

HCl - antibacterial, solubilizes food, activates pepsinogen, conversion to pepsin, denatures proteins making food more suceptible to mechanical digestive processes, and hydrolyzes carbs.

Intrinsic Factor (IF) - glycoprotein cofactor, resistant to acids and proteases, which complexes with vit B-12 and is essential for B12 absorption - the only indispensible component of gastric juice - absence = B12 deficiency = anemia.

Mucus-Mucin is glycoprotein of high MW secreted by goblet cells that absorbs water and electrolytes to make a sticky gel, which both protects the mucosa from acid and lubes the way for food.

Pepsinogen - precursor to pepsin, an endoptidase, which produced by chief cells.  Converts pepsin autocatalytically in acid pH but is inactive at neutral pH, which is protective for the gland.  Pepsin is the first protease to come into contact with dietary protein, but in its absence pancreatic enzymes are sufficient to fully digest protein.

Electrolytes - Na, K, Ca, HCO3, Cl are all secreted constantly at low rates.  Determine the composition of gastric juice.

Somatostatin - inhibitor of acid secretion which is found in endocrine D cells lining the stomach.

Gastrin - an activator of acid secretion made by endocrine G cells in pyloric glands.

Histamine - an activator of acid secretion which is produced by enteric neurons, mast cells, and endocrine cells.

Ingestion of a Meal

Interdigestive Phase

GI is quiet. 

Low pH inhibits gastrin release and promotes continual release of somatostatin, which itself inhibits both gastrin and acid release.

Ingestion of a Meal

Cephalic Phase

When you see, smell, and taste food but you aren't actually eating it.

Vagal efferents activated, release ACh and cause enteric NS to do the same.

Acid and Pepsinogen secretion is weakly stimulated, from parietal and chief cells, and somatostatin is slightly inhibited.

Vagus, ENS stimulate gastrin release via ACh and GRP, but plasma gastrin is low because low stomach pH continues to promot somatostatin release, which minimizes gastrin.

Ingestion of a Meal

Gastric Phase

Highest levels of plasma gastrin and stomach acid release.

Proteins stimulate G cell chemoreceptors, which directly triggers gastrin release.

Mechano/Chemoreceptors in the stomach wall are activated by food entry into the stomach and also cause gastrin and pepsinogen secretion.Vagus and ENS are still very active, and ACh from them keeps stimulating gastrin, HCl release and inhibiting somatostatin.

Stomach pH is raised by food buffering, which also keeps somatostatin release low, allowing max release of gastrin.

Max gastrin causes massive histamine release, which works with ACh and gastrin to stimulate parietal cells.

Ingestion of a Meal

Early Intestinal Phase

Occurs as chyme is propelled into the small intestine and sensed by receptors on intestinal endocrine cells.

Protein components induce gastrin release into circulation from proximal duodenal G cells, this gastrin further enhances histamine, HCl production.

Amino acids, peptides, fats cause CCK release into the circulation, that helps the pyloric sphincter increase tone, slowing chyme entry to duodenum, a feedback loop to protect the intesting so it won't exceed its buffering capacity.

Ingestion of a Meal

Inhibitory gastric/Late intestinal phase

Events terminating acid secretion occuring nearly simultaneously in intesting, stomach.

As food empties, gastric pH goes down, when pH<2, gastrin release is inhibited, somatostatin enhanced, both of which inhibit acid secretion.

Vagus, ENS stop releasing ACh, GRP, which enhances:

Food in intestine has low pH, high carbs, fatty acids, and amino acids.  Acid causes S cells in duodenum to release secretin into circulation, which weakly inhibits gastric acid secretion.

Food components and high osmolarity in intestine cause release of enterogastrones which are strong inhibitors of gastric acid secretion.

CCK release continues, keeps slowing the rate of chyme release from the stomach, and is a contributor to somatostatin stimulation.

Secretin and CCK are released systemically, and therefore have effects outside the tube, i.e., enhanced secretion of pancreatic enzymes, biles salts, and that CCK may be the satiety factor that tells the brain you are full.

Ingestion of a Meal

Mech of HCl formation

Carbonic Anhydrase makes carbonic acid from H2O and Co2 which dissociate into HCO3 and H+.

Cl must get into the cell by one of 2 ways:|
Na/Cl cotransport system driven by the regular Na gradient.

Cl/HCO3 antiporter driven by leftover HCO3 from step 1, this is brilliant because it also prevents the cell from alkalizing.  HCO3 is released into the blood, causing a rise in blood pH called the alkaline tide.

Forms when acid/pepsin overcomes the ability of the mucosa ot repair and protect itself.

Common only in stomach and duodenum.

Usually initiated by H. Pylori or chronic use of NSAIDS, often aggraved but not initiated by other factors such as stress and alcohol.

Live within the mcuus lining to protect themselves.

Secrete urease, which converts abundant urea into ammonia and bicarb, both strong bases which create an acid-free microenvironment.

Urease is basis for clinical test for H. Pylori, pt is given radioactive urea, and exhaled breath is monitored, if urea is broken down, pt exhales radioactive CO2, if not, the urea is excreted intact and no radiation is exhaled.

Duodenal and pancreatic tumors that elevate gastic acid to ulcer-producing levels by making excessive gastrin.

Symptoms: very high gastric acid, diarrhea, and overgrowth of gastric mucosa, caused by gastrin acting as a growth factor.

Steatorrhea - fatty diarrhea, caused because of excessive acid inactivates pancreatic enzymes, especially pancreatic lipase, which are made to work at slightly alkaline pH.

Diagnosis is touch to make from gastrin levels, because they vary a lot in the population, but secretin,w hen injected will suppress normal gastrin secretion but not that of tumors.

Acid is not usually the cause of an ulcer, but is always a factor in treatment. no acid = no ulcer.

Antacids can work some, but more effective to attack one of the sources.

ACh blocked by selective vagotomy or by pirenzipine, a selective muscarinic M1 blocker.

Gastrin can be blocked by an analogue which inhibits the gastrin-CCK-B receptor, but this also inhibits pancreatic secretion by x-rxn w/CCK-A receptor.

Histamine can be selectively inhibited in the stomach by blocking H2 receptors, (only located in the stomach).

Complete elimination of stomach acid, and can be caused using proton pump inhibitors, omeprazole.

Potential problems because this creates excessive gastrin release.

Unknown effect because gastrin is a growth factor, and a potent mitogen for all GI mucosa.

Chronic heartburn, caused by excessive reflux of stomach acid into esophagus, in quantities sufficient to overcome the usual buffering mechanism, can result in Barrett's Esophagus.

Replacement of the usual squamous epithelium of the lower esophagus with aberrant columnar epithelium, like that in the stomach. 

40x greater risk of esophageal cancer.

Tx: lifestyle changes, sleep upright, alter diet, stop smoking, lose weight, acid controllers, drugs to increase sphincter tone.

Crypts and villi in the intestine covered with a continuous sheet of epithelial cells, which are born in the crypts from permanent stem cells down there, and migrate up to the tips of the villi, where they die.  When epithelial cells die, they are sloughed off and digested like food to recycle their contents.

As intestinal epithelium migrates, it differentiates gradually in crypts epithelium secretes, in villi specialized to absorb.

Types of epithelial cells

Paneth cells - defend crypt stem cells from infection by viruses and bacteria.

M cells - also part of intestinal defense, but these are the sampling cells in the Peyer's patches and other gut associate lymphoid tissue (GALT).

Endocrine cells - release hormones, mainly on the basolateral side of the epithelium, which control food-related responses in pancrease, liver, stomach, and brain, as well as having local paracrine effects.

Columnar cells - secretions play a role in hydration and lubrication of the intestine, as well as expressing a number or specific apical and basolateral proteins in a polarized fashion.

Goblet cells - primarily protection, hydration, and lubrication of the gut.

Polarization of intestinal epithelium is critical, and allows the cells to:

Detect nutrients or hormones at either end.

Participate in digestion of luminal contents.

Vectorially translocate digestion products from lumen to body.

Vectorially transport electrolytes into or out of the lumen.

Acini-basic unit of the exocrine pancreas, is a small sac-like structure lined with secretory cells that produce pancreatic enzymes.  The lumen can serve as a holding tank for the enzymes, which will eventually travel into the digestion down a duct. 

The electrolyte component of pancreatic juice is secreted by centroacinar and duct cells.

Digestion of protein, fat, carbs are mainly via the components of pancreatic juice, i.e. pancreatic amylase, lipase, and proteases.

Pancreas also the sole producer of RNAse and DNAse, and is essential for digestion.

Pancreatic bicarbonate, produced when pancreas is secreting at high flow rates, is required, along with bile, to completely neutralize gastric juice (HCl) entering duodenum.  Normal duodenal pH is slightly alkaline.

Contains H2O, HCO3, and digestive enzymes.

Complete digestion of food requires action of both pancreatic and brush border enzymes.  Most pancreatic enzymes are produced as zymogens.  Trypsin triggers the activation of other pancreatic enzymes.

Pancreatic trypsin inhibitor attaches to trypsin.  Inhibits its activity in the pancreas.

Control of Pancreatic Secretion

Interdigestive/Cephalic Phase

Interdigestive Phase - entire GI quiet, minial pancreas activity.

Cephalic Phase - Vagal efferents activated, release ACh, which stimulates pancreatic enzyme secretion.  ACh also causes gallbaldder to contract and sphincter of Oddi to relax, allowing bile/pancreatic juice into duodenum.

Pancreatic Juice

Gastric Phase

Gastric Phase - Vagus continues to release NT.  Gastrin released into blood acts weakly on CCK receptors which further enhance pancreatic enzyme secretion and contraction of gallbladder.

Pancreatic Juice

Early Intestinal Phase

Early intestinal phase - Chyme activates duodenal endocrine chemoreceptors, amina acids/peptides cause gastrin release from G cells, and along with fat digestion products stimulate CCK release from I cells.  CCK acts strongly on CCK receptors in pancrease to enhance acinar cell enzyme secretion, and in the gall bladder produces strong contractions, as well as further releasing the sphincter of Oddi.  Remember that CCK also slows the rate of entry of chyme into duodenum by increasing tone of pyloric sphincter.

Pancreatic Juice

Late Intestinal Phase

Relatively low duodenal pH causes S cells to release secretin, which strongly stimulates electrolyte secretion by pancreatic and bile duct cells, which are important in neutralizing the acid.

Fats, carbs, amino acids, and hyperosmolarity all act to release enterogastrones (secretin, enteroglucagon, GIP; all hormones inhibiting acid release).

CCK continues to be released.

Vagal activity is very much reduced, but residual activity reinforces activities of circulating hormones.

Ultimately, all food is digested/absorbed, and the inter digestive phase returns.

Control of Pancreatic Secretion

Acinar Cells

Basal sides receive vagal innervation, bringing ACh throughout most of digestion, and also has blood vessels bring in gastrin and CCK all of which act to stimulate secretions, although CCK is much stronger and gastrin probably acts by cross-reaction with the CCK receptor.

ACh, CCK, gastrin all act by mobilizing intracellular CA and are all potentiated by secretin, probably via cAMP.

Control of Pancreatic Secretion

Pancreatic Duct Cells

Circulating secretin stimulates and somatostatin inhibits these cells, whose main job is to secrete HCO3 for acid neutralization and large amounts of H20 to wash HCO3 enzymes along the duct.

CCK, ACh, gastrin have no effect.

Control of Pancreatic Secretion

Secretory Mech.

3 steps on Apical

Use carbonic anydrase to convert CO2, H20 to HCO3 and H+.

Normal Na gradient used to antiport H+ out, Na into cell across basolateral membrane (prevents catastrophic intracellular pH drop).
HCO3 is exchanged for Cl across the apical membrane. 

Some Cl comes as NaCl from acinar cells, but most is secreted by the duct cells themselves.

Acute - characterized by upper abdominal pain radiating into back, usually affects middle-aged to elderly.

Usually caused by obstruction of the pancreatic or common bile duct, from stones, sticky mucus in CF patients, or by damage from long-term alcohol use or viral infections.

Chronic almost always caused by long term alcohol abuse.

If there is a blockage, pro-enzymes build up, they are made to be harmless until activated, but at high concentration over extended time they (Zymogens) will auto-activate and start eating the pancreas.

Problems from loss of both endocrine and exocrine pancrease, so in addition to wet, fatty sool from a loss of pancreatic enzymes, pt can get diabetic symptoms.

Diagnosis can be made, after a while, by measuring blood levels of pancreatic enzymes.

Largest internal organ.

Hepatocytes form hepatic plates that are 1-2 cells thick.

Arranged into functional units called lobules.

Plates separated by sinusoids, more permeable than other capillaries.

Contain phagocytic Kupffer cells.

Secretes bile in bile canaliculi, which are drained by bile ducts.

Compounds that recirculate between liver and intestine.

Many compounds can be absorbed through small intestine and enter hepatic portal blood.

Variety of exogenous compounds are secreted by the liver into the bile ducts.

Can excrete these compounds into the intestine with the bile.

Products of digestion that are absorbed are delivered to the liver.

Capillaries drain into the hepatic portal vein, which carries blood to the liver.

3/4 blood is deoxygenated.

Hepatic vein drains liver.

Liver and pancreas share a common bile duct through which the liver delivers bile and electrolytes to intestinal lumen.

Liver is perfused by bother areterial and portal venous blood, which contains outflow from intestines.

1st recipient of blood leaving intestines, liver has large capacity to absorb and store nutrients, so they don't flood circulatory system at every meal.

The liver is important defense against toxins.

bile is produced in the liver and secreted via canaliculi into the duct, the to intestine.

Bile is stored in the gall bladder and released from there into bile duct.

First function is to help solubilize essential elements of the diet which are hydrophobic and to disperse them in an enzyme suceptible form.

Bile Salts

Na-glycocholate

Na-taurocholate

Enterophepatic cycline of bile salts - cycle through the digestion, entering at duodenum via common bile duct, passing through the small intestine, and resorbed at terminal ileum.  They then return to the liver via portal circulation.  A small amount is lost each cycle to colon, but the system is 95% efficient and the complete pool of bile salts is said to cycle 2x for each meal.

Highly ionized at body pH, therefore, require transporters to cross hydrophobic cytoplasmic membrane.

3 transporter families: ATP-drive, Na gradient, and permitting facilitated diffusion.

Bile salts can also be synthesized by hepatocytes from cholesterol to offset loss and keep pool constant.

Functions of bile salts rely on their amphipathic nature.

Emulsifying fats to aid digestion.

Make micelles to make fat digestion products soluble in aqueous solution.

Facilitate release of enterokinase from intestinal mucosa.

Considered to be excretory products from hemoglobin breakdown with no digestive function.

Since bilirubin circulates bound to albumin, it cannot be eliminated by filtration at the glomerulus in a healthy kidney and must be excreted in bile.

Liver damage-related jaundice is caused by visible bilirubin buildup in blood.

Main function is to help neutralized HCl released into duodenum.

Method of excretion (include Na, Cl, HCO3) is identical to that of pancreatic duct cells.

Bile acids are derivatives of cholesterol.  Major pathway of cholesterol breakdown in the body.

Principal bile acids are cholic acid and chenodeoxycholic acid, which combine with glycine or taurine to form bile salts.

95% of bile acids are absorbed by the ileum.

Liver can remove hormones, drugs, and other biologically active molecules from the blood by:

Excretion into the bile.

Phagocytosis by Kupffer cells.

Chemical alteration of the molecules.

Inactivation of steroid homrones and drugs by:

Conjugation of steroid hormones and xenobiotics make them anionic, can be transported into bile by multispecific organic anion transport carriers.

Steroid and xenobiotic receptors stimulate production of cytochrome P450 enzymes.

Too little water or bile salt or too much insoluble material, which precipitates a stone.

Cholesterol stones are more common (75%), women are 2-3x more likely to get them.

Gallstone symptoms depend on site of obstruction - if stone is in bile duct/biliary tree, mostly liver is affected; in common duct, both liver and pancreas affected.

Tx: cholecystectomy, eliminates pool of stored bile and of stone formation; Lithotropsy, use ultrasound to bust up stones; bile salts administered orally will recycle from intestine to help dissolve the stone.

Undigested when they get to the duodenum, but are dispersed as minute droplets 200-500 nm across.  Bile salts emulsify these and prevent them from coalescing into bigger drops.

Fattty acids and triglycerides are incorporated into micelles of biles salts. When they reach the microvilli of enterocytes, fatty acids, and triglycerides diffuse out of the micelle and into the cell.  Bile salts remain in lumen.

Digestion/Absorption of Fats

Inside the enterocyte

Fatty acids< 14 C atoms exit directly across the basolateral membrane and enter portal circulation as free fatty acids (FFA).

Fatty acids> 14 C atoms, cholesterol, lysophospholipids are all taken up by smooth ER.  FFA's are esterified with glycerol or monoglyceride to make triglycerides, and with lysophosphatides to make phospholipids.

When smooth and rough ER fuse to make Golgi, triglycerides are aggregated into lipid droplets, coated with a layer of cholesterol, phospholipid, and apolipoprotein to make chylomicrons, which are used to transport lipids in blood (HDL, LDL, VLDL).

Digestion of CHO: a little in the mouth, none in stomach, all the real work of breaking complex carbs is done by pancreatic enzymes.

Enzymatic digestion of carbs gives hexoses (6-C sugars).

Enzymes which catalyze hexose production are located in close proximity to transporters on epithelial brush border.

Glucose and galactose are absorbed by secondary active transport by the same transporter (SGLT1).  They can be absorbed against a steep gradient.  SGLT1 gene expressed only villus cells, mostly in jejunum.

Fructose is passively absorbed.

GLUT2 transports all sugars out the basolateral side into ECM, where they enter blood, liver, other tissues in that order.

Lactose malabsorption Syndrome

Loss of lactase activity.

Excess lactose creates high osmotic pressure in the lumen, causing diarrhea, cramps, and abdominal distension.

Can cause life-threatening diarrhea in infants.

Simultaneous loss of sucrase and maltase activities.

Almost always coordinately expressed, probably either share genetic control or are formed as a heterodimer.

Similar symptoms as lactos intolerance.

Probably a deficiency of SGLT1.

Ingestion of carbs produces serious problems with inestinal fluid balance.

Mgmt: carb free diet.

Mainly digested by pancreatic enzymes, into peptides large and small, and free amino acids.

Large (>3 amino acids) peptides, intact proteins - not really absorbed to any great extent, but significant because they can generate significant immune responses.

Small peptides (<3 amino acids) effectively absorbed by transporters which are not well-defined.  Hydrolyzed to free amino acids in intestinal cells.

Amino acids - also multiple transporters which, while characterized based on energy source and substrate, are not well characterized.

Amino acids move to ECF and blood via facilitated diffusion.

3 Basolateral transporters are used, which are different from apical transporters, are similar or identical to transporters found in other cells.

Renal, intestinal malabsorption of basic amino acids and cysteine.

Caused by defect of brush border transport system.

Renal, intestinal malabsorption of neutral amino acids.

Defect of brush border transport system B.

Cationic amino acid absorption is affected in nearlhy every tissue of the body.
Defect of a basolateral transporter in GI, other body cells.

Severity because the transporters have different targets (apical vs. basolateral).

Apical defects can be compensated because systems B, BO+, and b0+ can partly compensate for each other.

Apical defects can also be compensated because every type of amino acid can be absorbed to some degree via apical peptide transporter.

Basolateral defect shows severe malnutrition, inability to absorb ornithine, which causes hyperammoniemia.

Necessary for proper mucus formation.

Suspends and transports food, enzymes, provides aqueous environment for enzyme action.

9ml of water presented to small intestines every day.

1/3 water is ingested, 2/3 secreted into lumen by digestive organs.

Intestines avoid accumulation of H2O, especially up to and beyond available volume.

Also it avoids dehydration by absorbing ingested water, reabsorbing secreted water.

Usually most water is reabsorbed by the time food gets to the large intestine, if absorption is inhibited, or secretion stimulated the water buildup will cause diarrhea.

Water follows osmotic gradients in GI Tract

Food provides osmotic force: as food is digested, water is drawn into the lumen of the intestine; as nutrients are absorbed, they provide an osmotic force for reabsorption.

Electrolytes provide osmotic force: parietal cells secrete HCl, pancreatic acinar cells secrete NaCl, and pancreatic enzymes, hepatic duct cells secrete HCO3 and crypt cells secrete NaCl, HCO3.

Paths by which electrolytes can be taken up from the lumen to the body: Na cotransport with sugars; neutral NaCl uptake works by using 2 transporters to take Na and Cl into cells in exchange for H, HCO3.  Acid, HCO3 combine in lumen to make H2O, Co2, which reduces luminal osmolarity.  In the colon, specialized system uses Na channel which is not dependent on the membrane.

Resting Cl conductance is low, so cytoplasmic concentration is maintained, but crypt cells express the special cystic fibrosis transmembrane conductance regular (CFTR) chloride channel in the apical membrane, which can be opened by cyclic nucleotides produced in response to neuronal, hormonal input.  This is not an electroneutral transporter, causes lumenal side to become negative relative to cytoplasmic side.

Intestinal Secretion

hormonal control

cAMP metabolism is regulated by G-protein coupled receptors in the basolateral membrane of intestinal epithelium.

Defecation

Waste material passes to the rectum.

Occurs when rectal pressure rises and external anal sphincter relaxes.

Longitudinal rectal muscles contract to increase rectal pressure.  Relaxation of internal anal sphincter.

Excretion is aided by contractions of abdominal and pelvic skeletal muscles.  Push feces from the rectum.

Caused by excess osmotically active material in the lumen.

Unabsorbable osmolytes in lumen.

Poor intake of excess Mg++ in laxatives; diarrhea persists until Mg is gone; artifical sweeteners - also not abosrbed well; Olestra - fat substitute is tasty, but not metabolized, poorly transported.

Genetics: sugar enzyme disorders, amino acid transport defects.

Disease: Zollinger-Ellison syndrome; Pancreatitis/stones; general mucosal disease, IBS, and celiac spure (gluten allergy).

Most common bacterial diseases produce toxins which over activate natural components of secretory pathway -> facilitate bacterial spread.

heat-labile toxins: cholera toxin - transported to basolateral membrane by transcytosis Rice Water Diarrhea.

Heat-stable toxins: heat stable enterotoxin (STa) produced by E. Coli strains.

CFTR present in apical surface of almost all epithelia (airway)

CF arises from under activity of the channel - can't get Cl therefore enough H2O, into mucus secretion, makes them sticky.

Outside lungs, CF gives pancreatic mucus blockages, bowel obstructions, etc.