Gastrointestinal System

Dr Philip Poronnik

Dept of Physiology

These notes accompany the material presented in the lectures and in the textbook

The gastrointestinal tract (GIT) provides the body with a constant supply of water, electrolytes and nutrients

This process requires

• movement of food through the tract

• secretion of digestive juices and digestion of the food

• absorption of the digestive products, water & electrolytes

• circulation of blood through the GIT organs to carry away absorbedsubstances

• control of this these systems by both neuronal and hormonalsystems

Each part of the GIT is adapted to its specific functions

• simple passage of food (oesophagus)

• storage and initial breakdown of food (stomach)

• digestion & absorption (small intestine)

• fecal storage (large intestine)

• secretion of enzymes and fluids to aid passage of food & digestion (salivary glands, pancreas, liver)

Five major processes occur in the gut

• motility - the way in which food is moved down the gut at different rates depending on what is happening to it

• secretion - juices from exocrine glands enter the tract at various points

• digestion - conversion of large organic molecules to smaller molecules

• absorption - the digested products and nutrients move across the wall of the small intestine to the blood

• elimination - indigestible materials & waste products are moved to the end of the tract and eliminated

Digestion and Absorption

• motor activity - chewing, kneading, grinding, mixing, propulsion

• secretory activity - lubrication and epithelial protection provision of digestive juices (transport of salts and water - synthesis of proteins)

• digestive activity - digestive enzymes - other factors, pH, bile salts

• absorption - transport of salts water and organic compounds

• integrative control - enteric nervous system, gut endocrine system

Secretory and digestive activity

• control of secretion and composition of secreted fluids

• properties of the digestive enzymes

• control of secretion of the enzymes

• factors that control activity of the enzymes

Food components are carbohydrates, fats, proteins

• digestion is hydrolysis performed by specialised enzymes.

• carbohydrates formed by condensation of H+ and OH- groups

hydrolysis restores the H+ and OH- groups

• triglycerides are 3 fatty acid molecules condensed with a glycerol molecule

hydrolysis by lipases separates these molecules

• proteins amino acids joined together with peptide bonds

hydrolysis by proteases/peptidases

Carbohydrates

• 300g ingested per day as

• complex polysaccharides

64% starch, 0.5% glycogen• disaccharides

26% sucrose, 6.5% lactose• monosaccharides

3% fructose

• complete hydrolysis would yield 80% glucose, 14% fructose, 5% galactose

Complex carbohydrates - polymeric glucose

1-4 and 1-6 bonds in starch (straight chain) and amylopectin (branched) attacked by salivary and pancreatic amylase

• maltose and triose and dextrins - broken down to glucose monomers by intestinal maltase and isomaltase

• sucrase (sucrose to glucose-fructose) and lactase (lactose to galactose-glucose)

• cellulose - glucose in 1-4 - not broken down

Proteins

• > 100g ingested daily as oligopeptides

• digested by proteolytic enzymes

• proteolytic enzymes secreted as zymogens (inactive proenzeymes)

• endopeptidases - cleave internal peptide bonds

• exopeptidases - carboxy or amino terminal cleavage

Fats

• 60-100g daily

• fatty acids

• triacylglycerols

• cholestrol (esterified)

• digestion by lipases

Morphology of GIT 1

mucosa consists of

• epithelial lining with invaginations

• lamina propria (connective tissue)

• muscularis mucosa - thin layer of smooth muscle

submucosa contains

• connective tissue,

• blood and lymph vessels that branch off

• submucosal plexus

Morphology of GIT 2

muscularis externa consists of

• inner layer of circular smooth muscle outer

• outer layer of longitudinal smooth muscle

• myenteric plexus

the serosa

• secretes watery fluid to lubricate organs

• is continuous with the mesentery which carries the blood vessels, lymphatics and nerves to and from the tract

GIT Integrative Control

• the GIT is a self-regulating system of organs

• once food has been swallowed there is no further voluntary activity involved until defecation

• this requires coordination of motor, secretory, digestive and absorptive functions

• involves highly sophisticated control mechanisms

• the enteric nervous system and gut endocrine system

Enteric nervous system

• a separate and autonomous division of the autonomic nervous system

• both extrinsic and intrinsic control

• intrinsic located entirely within the gut wall and mainly localised roles within gut segments

• extrinsic contol via both sympathetic and parasympathetic nervous system

• Extrinsic effects primarily mediated by modulation of enteric neural circuitry rather than direct action on effector cells

Myenteric plexus

• a linear plexus extending the entire length of the GIT

• concerned mainly with control of the motor activity

Stimulation leads to

• increased tone of gut wall

• increased intensity of rhythmical contractions

• slight increase in rate of the rhythm of contraction

• increased velocity of conduction of excitatory waves along the wall (peristalsis)

• also some inhibitory functions (VIP) - inhibition of contraction of pyloric and ileocecal valves

Submucosal plexus

• mainly concerned with control within the inner walls of each gut segment

• local absorption, secretion, contraction

Major types of neurones in enteric nervous system

• cholinergic both extrinsic parasympathetic and intrinsic (cholinergic transmission is essential for maintenance of normalmotiliy pattern

• adrenergic almost entirely extrinsic and generally relax GIT by the inhibitory effect of NE on the neurons of the enteric system

• so strong stimulation of the sympathetic pathway can totally block movement of food through GIT

• NANC (non-adrenergic, non-cholinergic) all enteric ganglia mainly secrete VIP, Nitric oxide

Short and long reflexes

• short - occur entirely within enetric nervous system secretion, peristalsis, mixing contractions, local inhibition

• long -reflexes from the gut to prevertebral sympathetic ganglia and back to the GIT

• signals from the stomach to evacuate colon (gastrocolic relfex)

• signals from the colon & small intestine to inhibit stomach motility and secretion (enterogastric reflex)

• signals from the colon to inhibit emptying of ileal contents (colonileal reflex)

Long reflexes 2

• reflexes from gut to spinal cord or brain stem and back to GIT

• reflexes from stomach & duodenum to brain stem & back to control gastric motor and secretory function

• pain reflexes that cause general inhibition of GIT

• defecation reflexes to the spinal cord and back to produce the contractions required for defecation

Parasympathetic and sympathetic innervation

• 1) parasympathetic arises in 2 separate regions of the CNS supply to oesophagus, stomach, small intestine and ascending colon (as well as pancreas, liver, salivary glands) arises in the medulla and runs in vagus nerves

• 2) beyond ascending colon arises in the sacral spinal cord and runs in the pelvic nerves

• sympathetic arise in the spinal cord - form synapses in the superior cervical ganglion (prevertebral ganglia) with noradrenergic postganglionic cells projecting to the gut

Gut hormones

• Endocrine gland cells present along the GIT tract

• Carried through the blood to other cells

• Primarily released in response to specific local changes in composition of luminal fluid

• Act on pancreas to cause release of hormones from pancreatic endocrine cells

GIT receptors

• Chemoreceptors - sense changes in the chemical composition of luminal fluid

• Mechanoreceptors - sense changes in stretch or tension in the gut wall

• Osmoreceptors - sense changes in the osmotic composition of the luminal fluid

• These receptors can elicit both short and long reflexes to modulate rate of food movement along the digestive tract

Splanchic (GIT) circulation

• blood leaves heart via abdominal aorta

• leaves GIT via the portal vein

•

• portal circulation - metabolic products subjected to processing by the liver

• splanchic circulation receives ~25% of cardiac output 1400 ml/min

• this rate increases during meals to facilitate removal of digested products as well as providing extra oxygen

GIT musculature

• longitudinal and circular smooth muscle coats

• small spindle shaped cells forming bundles with cross connectionsto neighbouring bundles

• within each bundle cells are connected thus because of the electrical coupling it is the bundle rather than the individual muscle cell that forms the basic unit for propagation of action potentials

• GIT muscle usually shows rhythmic changes in membrane potential(slow waves) frequency of 3-15 cycles/min

Gut Muscle Tone

• muscle tone due to the presence of slow waves such that bundles are partly contracted generating muscle tone

• reaching threshold potential results in initiation of action spikes and complete muscle contraction

• if the resting membrane potential is bought to the threshold spasm occurs• if hyperpolarised slow waves disappear and tone diminishes leading to

paralysis

• each bundle has its own slow-wave frequency - but since adjacent bundles are connected the rhythm of a faster (pacemaker) bundle imposes itself on its slower neighbours

Gastrointestinal motility

• motility encompasses both contraction and relaxation

• contraction results in mixing of the digesta, propulsion or restriction of propulsion

• Relaxation is an essential component of the peristaltic reflex as well as being involved in the the accomodation reflex

Functional movements in the gut 1

• Propulsive movements

• peristalsis - a contractile ring appears and then moves forward

• usual stimulus is distension - others include irritation and parasympathetic stimulation

• peristaltic reflex - peristalsis occurs in the direction of the anus - at the same time that the contraction ring forms the gut relaxes several cms downstream - so-called receptive relaxation

Functional movements in the gut 2

• Mixing movements

• these are quite variable in different parts of the gut

• some involve peristaltic contractions against a sphincter resulting in churning

• in other cases local constrictive contractions occur every few cms lasting only a few seconds and then starting somewhere else resulting in chopping

Main functions of mastication

• to disrupt food mechanically to facilitate the action of digestive enzymes

• to mix food with saliva to initiate carbohydrate digestion by salivary -amylase

• stimulate afferent receptors that trigger the cephalic phase of digestion

• to form the food into a bolus in preparation for the onset of swallowing

Functions of saliva

• 1-1.5 l secreted per day

• to provide a fluid medium to dissolve food and to provide a lubricant to aid in chewing and swallowing

• to irrigate the mouth - to keep it moist and to prevent growth of infectious agents in the mouth - saliva contains lysozyme,

• peroxidase and IgA all of which have anti-bacterial/viral effects

• moist buccal cavity is essential for clear speech• secrete digestive enzymes and growth factors (NGF,EGF)• allow taste

Main salivary glands

• parotid - (from greek parotis - near the ear) - serous endpieces

• submandibular - mainly serous with some mixed mucosals

• sublingual - mainly mucous

• serous - water, electrolytes and amylase

• mucous - secretes mucins, electrolytes and water

3 basic salivary cell types

• acini (endpieces) - involved in secretion of primary fluid, electrolytes across a water permeable epithelium and mucous

• ducts - mainly involved in Na and Cl absorption and K and HCO3 secretion as well as secretion of various growth factors and enzymes - membrane is impermeable to water

• myoepithelial cells - prevent overdistension structures due to buildup of intraluminal pressures during secretion

Nervous control of salivary secretion

• endpieces and ducts are innervated by parasympathetic and sympathetic nerves

• the main agonists are ACh (parasympathetic) and noradrenaline (sympathetic)

• main stimulus of secretion is from the parasympathetic pathway acting via signals from the salivary nuclei

• excited by both taste and tactile areas of the tongue• also excited via stimuli arriving at the salivary nuclei from higher centres

of CNS - such as smell or thinking of food

• salivation also occurs in response to reflexes from stomach and upper intestines following gastric irritability - saliva serving to dilute the digesta

Two stage hypothesis of salivary formation

• first stage - primary juice with plasma like conc of Na, K, Cl and HCO3 secreted by the water permeable endpieces

• autonomic stimulation increases rate of juice secretion without altering its composition

• second stage - as juice passes along the water impermeable duct it is modified by absorption of Na and Cl and secretion of K and HCO3

• since rate of absorption of Na and Cl is greater than rate of K and HCO3 secretion - result is a final saliva rich in K and HCO3 - but dependent on the rate of flow

Main exportable proteins from salivary glands

• Mucins - glycoproteins which serve to mechnically protect the epithelium and stop it drying out

• lubricate food• protect the lining of the stomach and small intestine from acids

and digestive enzymes• trapping microorganisms

• Digestive enzymes - mainly -amylase which digests starch - main role is to promote oral hygeine by facilitating dislodgement of food particles impacted around the teeth

• (dietary starch digestion by pancreatic amylase in the duodenum)

Main functions of swallowing

• to transport the food bolus from the pharynx into the stomach

• to prevent esophagopharyngeal reflux and gastroesophagal reflux

• swallowing involves

complex interactions between voluntary and involuntary nervous and muscular systems

• closely coordinated with breathing and associated activities (i.e. talking)

Four phases of swallowing

• preparatory

• oral

• pharyngeal

• eosophagal

• preparatory is voluntary and involves bolus formation and lubrication during mastication

Four phases of swallowing 2

• Oral phase - bolus propelled into the pharynx by progressive contact of the tongue against the palate in a posterior direction

• Pharyngeal stage - a single contraction peak coinciding with the beginning of the peristaltic wave

• soft palate elevates and seals the nasopharynx to prevent postnasal regurgitation

• larynx ascends and epiglottis tilts downwards - facilitates closure of the laryngeal vestibule and removes laryngeal inlet from the oncoming bolus

• Upper oesophageal relaxation commences with the onset pharyngeal phase

Four phases of swallowing 3• Esophageal stage • as UES closes primary peristalsis occurs - a progressive circular

contraction that proceeds distally - induced by the swallow secondary peristalsis then proceeds in the oesophageal body which is invoked purely by intrinsic reflexes eg - by distension

• the lower oesophageal sphincter relaxes shortly after a swallow due to cessation of tonic neural excitation to the sphincter as well as inhibition by NANC inhibitory neurons

• this “receptive relaxation” of the LES ahead of the food bolus allows easy propulsion of the food into the stomach

• improper relaxation of the sphincter leads to achalasia• the tonic constriction of the LES helps to prevent significant reflux of the

contents of the stomach into the oesophagus

Stomach

• distal to the LES lies a valvelike mechanism underneath the diaphragm

• increased intrabdominal pressure caves the oesophagus inwards also serving to stop reflux

• stomach is divided into 3 main parts the fundus, body (corous) and the antrum

Stomach function 2

• store food before emptying it into small intestine

• begin digestive process

• stomach secretes 2-3 l of gastric juice/day

• homogenise the food to form chyme - a milky, murky semifuid or paste-like mixture resulting from food mixing with gastric secretions

Stomach musculature

• proximal

• maintains a steady tone

• relaxes during swallowing (receptive relaxation)

• and when the food enters the stomach (accomodation)

• distal

• exhibits strong peristaltic waves driven by a pacemaker region. These waves which homogenise the food are essentially driven by intrinsic neurons

Stomach storage function• Storage function of the stomach is served by the smooth muscle of

the fundus and body• Initially following a swallow receptive relaxation occurs in the

stomach due to afferent neurones in the walls of the oesophagus

• Subsequently distension sensing afferents in the stomach wall reduces the tone of the muscle wall allowing it to bulge progressively outward (accomodation) to a limit of approx 1.5l without any significant increase in intragastric pressure

• There are also tonic contractions that maintain a continuous gastroduodenal pressure gradient (due to vagal efferents) that ensures that the solids progress into the distal stomach

Basic Electrical Rhythm

• Unlike muscle cells of the proximal stomach, cells of the distal stomach exhibit spontaneous action potentials.

• In the distal and antral regions of the stomach electrical activity ischaracterised by the presence of slow waves ~3/min - also called basic electrical rhythm set by the pacemaker cells

• these slow waves travel as a ring around the stomach towards the pylorus

Antral Peristalsis

• as the stomach fills with food - powerful antral peristaltic waves are initiated from the pacemaker region following the same pattern as the slow waves

• each time a peristaltic wave passes over the antrum it digs into the contents of the antrum - yet the opening of the pyloris is only small so that only a small amount can pass

• the pyloric muscle itself contracts such that most of the contents are squirted back through the peristaltic ring into the body of the stomach this is an important mixing process called retropulsion

Hunger contractions

• intense contractions which occur in the body of the stomach when it has been empty for a long time

• rhythmic contractions which can become extremely strong and fuse together resulting in a continual tetanic contraction lasting for as long as 2-3 min

• most frequent in young healthy persons with a high degree of gastrointestinal tonus

Stomach tubular glands

• oxyntic gland (greek oxys = sour) - on the body and fundus

• consists of 3 cell types

• Parietal cells - large acid secreting cells - also secrete intrinsic factor

• Chief cells - principle source of pepsinogen

• Mucous neck cell - secrete a mucous glycoprotein

• also surface mucous cells which secrete mucous and HCO3

Stomach tubular glands 2

• pyloric glands - in the antrum

• secrete mainly mucous to protect pyloris

• gastrin from G cells

• some pepsinogen

• NO parietal cells

Main components involved in digestion

• HCl • acid denaturation of digested food • activate pepsinogens• convert ferric salts into absorbable forms• kill ingested bacteria that would destroy vitamin B12

• Intrinsic factor - absorption of dietary vitamin B12 • absence of intrinsic factor leads to anaemia due to the failure of red blood

cells to develop

• Pepsinogen - principle enzyme (endoprotease) of the gastric juice pepsinogens are inactive forms which convert to an active form upon exposure to gastric juice

• when gastric juice is neutralised in the duodenum the pepsin is inactivated

Gastric-mucosal protection barrier

• the surface epithelia secrete a thick alkaline mucus that adheres to the surface and forms a protective barrier between the epithelium and the acid and pepsin in the gastric lumen

• mucus is heavily glycosylated to protect it from proteolysis by pepsin but it is nevertheless degraded so maintenance of this layer requires continued synthesis and secretion of mucus

• the mucus layer is also heavily buffered by NaHCO3 secreted by the surface epithelial cells thus there is a pH gradient across this “gel”

Three phases of gastric secretion

• the functional activity within the stomach is carefully coordinated with alimentation and digestive function throughout the entire GIT

• this is separated into 3 phases

• cephalic phase

• gastric phase

• intestinal phase

Cephalic phase• directly controlled by the brain• accounts for ~30% of the response to a meal• mediated through efferent fibres from the brain receptors associated with

smell taste sight and chewing• occurs within few minutes after appropriate afferent stimulus & can occur

in response to conditioned stimuli• vagal efferents stimulate ACh in the region of the secretory cells in the

main body of the stomach• -stimulate secretion of acid• -stimulate histamine release - histamine acts as a powerful paracrine

stimulant of HCl secretion by parietal cells• also in the antrum where vagal efferent impulses release gastrin

releasing peptide which in turn causes G cells in the antrumto release gastrin - which in turn stimulastes receptors on parietal and chief cells

Gastric phase 1

• regulated by events within the stomach

• accounts for ~60% of the response to a meal

• stimulus due to the presence of food & involves neural & humoral responses

• distension of the stomach activates intrinsic neurones but supports little secretory response unless potentiated by secretagogues

• distension activates the vago-vagal reflex - using vagus nerve to transmit afferent impulses to the medulla which return via the vagal efferents to stimulate secretion - similar to cephalic phase (ie secretion of acid & gastrin & pepsinogen)

Gastric phase 2

• nature of the food in the antrum has a profound effect - the presence of polypeptides in the antrum stimulate G cells to secrete gastrin

• lowering of the pH of the surface of the antral mucosa greatly inhibits the gastric phase of secretion - this is due to the release of somoatostatin form endocrine cells in the gastric mucosa - somatostatin acts in a paracrine fashion to inhibit gastrin secretion

• this paracrine mechanism is a important aspect of negative feedback regulation of gastric HCl secretion

Intestinal phase

• accounts for less than 10% of the response to a meal• principle feedback mechanism is via hormones released by the

duodenal mucosa• some G cells spread from pylorus into duodenum - minor effect• secretin - has inhibitory effect on gastric acid secretion by causing

release of somatostatin - also reduces gastric motility• acid in the duodenum feedsback via intrinsic nerves• fats cause the release of CCK and GIP - CCK stimulates chief

cells to secrete pepsinogen and may enhance pyloric constriction• GIP (gastric inhibitory peptide) inhibits parietal sectretion and

output of gastrin via paracrine release of somtostatin

HCl secretion by parietal cells

• ACh - acetylcholine released by postganglionic neurons of the vagus

• Gastrin - endocrine stimulant released by G-cells

• Histamine - a paracrine stimulant released by enterochromaffin-like cells in close proximity to the basal aspect of parietal cells

• both ACh and gastrin act to increase cytosolic Ca • histamine acts via adenylate cyclase to stimulate acid secretion• (somatostin operates via the same system to inhibit!)• histamine in effect potentiates HCl secretion

Basis of HCl secretion

• H+ extruded by a H+/K+-ATPase which uses one ATP to pump out one H+ in exchange for one K+

• the apical surface of the parietal cell is invaginated by canals (called secretory canaliculi). The cells also contain a huge pool of tubulovesicles which contain large numbers of H+/K+ ATPase molecules

• upon stimulation the tubulovesicles fuse with the canalicular membrane resulting in a greatly enhanced surface area of elongated microvilli

• following removal of stimulation the H+/K+ATPases are recycled back into the tubulovesicle compartment

Stimulation of Chief Cells

• pepsinogen synthesised by chief cells is stored in granules near the apical pole of the cell

• following stimulation the granules fuse with the membrane and release their contents

• the main regulator is ACh which acts by elevating Ca

• CCk also acts through the same mechansim

• secretin acts via adenylate cyclase

• somatostatin can act to inhibit secretin induced stimulation

Ulcers

• due to the breakdown of the gastric mucosal barrier

• chemical agents (alcohol, aspirin)

• stress

• Helicobacter pylori

• treat with -

• antibiotics

• antihistamines - cimetidine

• H-K-ATPase antagonists (omeprazole)

Vomiting by numbers

• 1) diaphragm descends while the glottis remains closed leading to negative intrathoracic & oesophageal pressure (retching)

• 2) 0.5s later stomach and LES relax andthe abdominal wall muscles contract propelling the gastric contents through the LES

• 3) contraction of the oesophageal longitudinal muscle shortens the oesophagus and the thoracic cage expands further lowering pressure

• 4) gastric antrum contracts and the UES relaxes with expulsion of vomit(us)

Gastric emptying

• The pyloric sphincter remains partially open - enough to allow water and other fluids to leave the stomach

• intense antral peristaltic contractions forcing chyme through the tonically contracted pylorus - the peristaltic waves provide a pumping action - the so-called “pyloric pump”

• in addition the tone of the pyloric sphincter itself can be modulated by both humoral and neural signals

Gastric emptying 2

• Rate of gastric emptying is determined by signals from the stomach and the duodenum

• stomach signals are either nervous signals cause by distension or by gastrin

• gastrin has stimulatory effects on motor functions of the stomach as well as enhancing the pyloric pump

Enterogastric Reflexes• when food enters the duodenum multiple nervous reflexes are initiated from

the duodenal wall that pass back to the stomach to slow or stop stomach emptying if the volume of chyme has become too great these go via either enteric, extrinisic nerves or via the vagus and have 2 strong effects

• 1) inhibition of antral propulsive contractions• 2) increase slightly the tone of the pyloric sphincter

• factors that are continually monitored that can excite the enterogastric reflexes are:

• degree of distension of duodenum• irritation of the duodenum• degree of acidity of duodenum• osmolality of chyme• presence of breakdown products

Migrating Motor Complex• develops 4-5 hours after a meal and recurs every 90-120 min until food

is once more ingested• cycle consists of an inactive phase - followed by a brief phase

ofintense peristaltic activity which migrates along the intestine and may begin wither in the proximal stomach or duodenum

• a new complex starts whenever an earlier complex approaches the terminal ileum

• function of MMC is housekeeping - the means by which the residues (ie indigestible and large particulate matter) are removed from the stomach between meals

• also helps to control bacterial growth in the small bowel- a common consquence of bactrial overgrowth is steatorrhea which results from maldigestion of dietary fat

Exocrine Pancreas

• secretes about 2 l of fluid/day into duodenum via sphincter of Oddi (secretion increases ~10x postprandially)

• secretes digestive enzymes from the acini and an alkaline (HCO3 rich) juice from the ducts

• alkaline juice serves to neutralise acid from stomach and to provide the correct pH for enzyme activity

• interestingly - pancreas contains no myoepithelial cells thus when intraductal pressures rise acinar cells may rupture releasing digestive enzymes into the interstitium leading to chronic pancreatitis (ie in CF where ductal secretions are abnormally viscous)

Pancreatic enzymes

• digestive enzymes secreted as inactive precursors (zymogens) to prevent autodigestion

• important proteolytic enzymes are trypsin, chymotrypsin and carboxypeptidases

other enzymes are-• pancreatic lipase• pancreatic amylase

• trypsinogen is activated by enteropeptidase which is secreted by intestinal mucosa in response to chyme

• trypsin then activates the other proenzymes• trypsin inhibitor secreted to delay activation of trypsinogen

Pancreatic fluid secretion

• acini secrete a Cl- rich secretion similar to salivary glands

• ducts secrete HCO3 (when insufficient alkalkine fluid is produced for maximum enzyme activity is reduced leading to malabsorption and malnutrition)

• In CF there is chronic pancreatitis with reduced HCO3

• because lipases and bile salts are sensitive to pH - staetorrhea is a common problem in patients with CF (insufficient alkali) or patients with gastrinomas who secrete excess acid in the stomach

Pancreatic fluid secretion 2

• HCO3 secretion is a secondary active transport process

• CO2 diffuses in from the blood and is combined with water by the enzme carbonic anhydrase (CA) to form HCO3 and H+ - the H+ is exchanged for Na+ by the Na-H exchanger using the Na+ gradient maintained by the Na+/K+ ATPase. ie Na-H exchanger and ATPase keep on creating a gradient for H+ to drive CA.

• HCO3 leaves the cell via an apical Cl/HCO3 exchanger with Cl recycling via a Cl channel

Stimuli of Pancreatic Secretion

• ACh - parasympathic vagus nerves as well as myenteric cholinergics

• Gastrin - liberated during gastric phase of stomach secretion

• CCK (cholecystokinin) - secreted by duodenal and upper jejunal mucosa when food enters small intestine

• these 3 all stimulate production of digestive enzymes by the acini and act via IP3 to release intracellular Ca

• Secretin - same duodenal and upper jejunal mucosa but secretin acts via cAMP on the ductal cells to increase HCO3 secretion

Phases of pancreatic secretion

• cephalic phase ~15% mainly causes secretion of enzymes into the acini - vagus mediated

• gastric phase ~15% gastric distension by means of vago-vagal reflex evokes enzyme secretion

• gastrin release by antral lumen causing more enzyme release

• intestinal phase ~70% -pancreatic HCO3 secretion strongly stimulated when duodenal pH is acid - S cells secrete secretin into the blood and this stimluates pancreatic duct cells

• chyme also causes I cells to release CCK which causes pancreatic enzymes to be secreted (mainly due to peptones and fatty acids)

Liver and Bile

• One main function of liver is to secrete bile (600-1200ml/day)

• Bile has an important role in fat digestion and absorption• bile salts (which are cholesterol metabolites sythesised in

hepatocytes) emulsify large fat particles into minute particles that can be attacked by lipases

• also aid in the transport and absorption of the digested fat products to and into the intestinal mucosa

• bile serves as a means for excretion of several waste products from the blood, especially bilirubin and the excess cholesterol synthesised by the liver

Bile secretion• Bile is secreted in 2 stages by the liver

• 1) Bile is secreted initially by the hepatocytes and contains large amounts of bile acids, cholesterol, lecithin etc and is secreted into the bile canaliculi the lie between the hepatic cells in the hepatic plates

• 2) The bile empties into the terminal bile ducts, the hepatic duct and finally common bile duct - here the bile either empties directly into the duodenum or is diverted through the cystic duct into the gallbladder -

• on its way through the duct a secondary secretion is added - a watery solution of Na and HCO3

Enterohepatic circulation

• Up to 94% of bile salts are reabsorbed by active transport in the distal ilieum

• they enter the portal blood and pass to the liver where they are reabsorbed by the venous sinusoids

• ~20g of bile salts are required to digest & absorb 100g dietary fat

• however the total amount of bile salts is ~5 g and only

0.5g /day is synthesised by the liver • the rest is due to recirculation (on average each bile salt

molecule recirculates 18 times before being lost in the faeces)

Bile salts• Bile salts are synthesised by hepatocytes from cholesterol (most

common are cholic, chenodeoxycholic and deoxycholic acids)• they are then conjugated to either glycine or taurine giving rise to

glycocholates and taurocholates this step makes a highly polar molecule - the lipophilic steroid backbone and the hydrophilic amino acid - these conjugates can then function as detergents.

• cholesterol can be secreted into the bile at much higher concentrations than it solubility in water would allow

• since they are present at concentrations above the critical micellar conc they spontaneously aggregate with fats to form micelles

• the different bile salts have different pKas - to cope with the different pHs encountered in the duodenum

Gallbladder

• Bile is normally stored in the gallbladder until it is need in the duodenum

• The volume of the gallbladder is only 20-60 ml however it can store up to 12 hours worth of bile secretion (~450 ml)

• This is made possible because the gallbladder mucosa absorb Na & Cl and osmotically removing the water concentrating the other constituents - normally 5 fold but can be as high as 20-fold

Emptying of gallbladder

• food entering the duodenum causes galbladder to empty

• three processes involved

• - CCK induced rhythmic contractions of the gallbaldder

• - CCK induced relaxation of the sphincter of Oddi

• relaxation phase of peristaltic waves moving down the duodenum also relax sphincter of Oddi

• presence of fat is important in getting gallbladder to empty

• secretin stimulates secretion of HCO3 rich juice from bile ducts

Control of bile salt secretion by bile salts

• in bile-salt dependent flow - (~40% of total flow) - bile salts are extracted from the portal blood by a Na-bile salt cotransporter and bound to a cytosolic protein which brings them to the apical membrane where they are secreted by a Na-independent carrier - thus it is a saturable process

• bile-salt independent flow -(40%) - unknown mechanism depending on the secretion of organic cations - this step is important for the excretion of steroids

• alkali secretion by bile duct epithelium - ~20%

• as the concentration of bile salts in the plasma rises so does the rate of bile salt secretion - the secretion rate being highest during digestion when the levels of bile salts are highest

Haemoglobin breakdown

• Haem is broken down to bilirubin by macrophages

• bilirubin (yellow) is then absorbed by hepatocytes and conjugated with glucoronic acid to form bilirubin glucorinide which is excreted into the bile canaliculi

• once in the intestine it is converted by bacteria to urobilinogen which is highly water soluble - some is reabsorbed into the blood which is then re-excreted into the gut by the liver

• about 5% gets to the kidneys and is oxidesed to urobilin and gives urine its yellow colour

• in faeces it is oxidised to stercobilin

Jaundice

• Jaundice (yellowish tint to the body) is due to large quantities of bilirubin in extracellular fluids

• 1) haemolyitc jaundice - red blood cells are haemolysed rapidly and hepatocytes cannot secrete faster than it is formed leading to high plasma concentrations of bilirubin (thalasseamia)

• 2) obstructive jaundice - the bile ducts are blocked by a gallstone or a cancer or due to damage in hepatitis

Gallstones

• when cholesterol precipitates in the gallbladder

• amount of cholesterol in bile is in part determined by the amount of dietary cholesterol - so people on a high fat diet are prone to gallstones

• inflammation of the gall bladder epithelium can lead to a chronic low grade infection that alters the transport properties of the epithelium

• treated by removal of gallbladder (cholecystectomy) or prolonged treatment with chenodeoxycholic acid which is a natural bile acid

Small intestinal motility• postprandially the small intestine has several vital functions• - to mix food with digestive secretions• - to circulate chyme so that mucosal contact is maximal• - to propel contents in a net distal direction• - to clear residua left over from the digestive process• - to transport continuing secretions from the upper gut during fasting• regional motor specialisation of the small bowel• -jejunum (40% of small bowel) acts primarily as a mixing and conduit

segment• -ilieum (distal 60%) retains chyme until digestion and absorption are

complete• -terminal ileum and ileocolonic junction control emptying of contents

into the colon & minimise coloileal reflux

Small Intestine

• major site of digestion and absorption of nutrients

• divided into 3 segments

• duodenum (20 cm)

• jejunum (2.5 m)

• illeum (3.6m)

Small intestinal motility 2

• muscularis externa of the small intestine consists of 2 layers• thick inner layer of circular muscle and thin outer longitudinal

layer

• there is a basal slow wave and when spikes are superimposed rhythmic muscular contractions occur with the same frequency as the slow waves

• the slow waves have a higher frequency at the proximal end (11/min) and only 8/min distally - this means that the net movement of intestinal contents is in the direction of the large intestine

Gastro-ileal reflex

• the motor response of the terminal ilieum to feeding • chyme may remain in the terminal ilieum for several hours until

another meal is eaten -• when signals from the upper GIT intensify peristalsis in the

ilieum expels the remaining chyme.

• as in the stomach - the presence of nutrients in the ilieum exert a negative effect on jejunal motility and transit - the “ilieal brake”

• particularly in the case of fat and partially digested carbohydrate• this prolongs the stay of chyme in the ilieum facilitating

absorption

Control of small intestine motility

• poorly understood but both both extrinsic and intrinsic nerves as well as humoral factors are involved

• initiation and maintenance of postprandial motor patterns requires an intact vagus

• gastrin and CCK both enhance motility - gastrin relaxes sphincter

• secretin inhibits motility

• NANC neurones may be important in relaxing sphincter

Fluid movement in intestine

• intestinal membrane highly permeable to water

• water therefore flows according to osmotic gradient

• absorption movement of water and nutrients from gut to lymph and blood

• most nutrients absorbed by upper half of intestine

Fluid movement in intestine 2

• brush border of small inestine greatly increases surface area for absorption

• main process is absorption of Na (and Cl)

• Na can go via Na channels or Na-nutrient cotransporters

• Na is then pumped into the blood by Na-K ATPase which maintains a net gut>blood Na gradient

Cholera

• crypt cells secrete Cl via cAMP Cl channels

• CT modifies Gs so that it is always active

• Gs then stimulates adenylate cyclase to produce cAMP

• Cl is then secreted into the intestine

• Na and osmotically obliged water then follow

Cholera 2

• results in a huge flow of water into the intestines

• secretory diarrhoea

• initially fluid good to wash away bacteria

• loss of 5-10l/day

• treated by administration of NaCl

Carbohydrate digestion

• pancreatic juices cannot further hydrolyse oligosaccharides

• brush border oligosaccharidases• brush border lactase, sucrase-isomaltase and maltaserelease

monosaccharides (glucose, galactose and fructose)

• glucose and galactose taken up by SGLT1• fructose by GLUT5

• all three transported via GLUT2 out into the portal vein and to the liver

Lactose intolerance

• lactose intolerance due to a defect in lactase enzyme

• insufficient amounts of lactose are provided to the transporter leading to poor absorption and subsequent build up of osmotically active lactose

• this in turn leads to a watery diarrhoea

Protein absorption

• aminopeptidases in brush borders

• peptides are broken down to individual amino acids (as well as di & tripeptides) by oligopeptidases

• reabsorption but gut cells similar to that of sugars

• both Na-dependent and independent uptake pathways

Fat absorption

• lipids- mainly triacylglycerols

• 1 - large oil droplets (shearing forces in gut)• 2 - emulsified oil drops with bile salts

• pancreatic lipase at oil-water interface

• 3 - formation of micelles

• micellescome to the absorptive surface of gut monoglycerides and free fatty acids are then absorbed

Fat absorption 2

• inside cells resynthesis of triacylglycerols, cholesterol

• and phospholipids to chylomicrons

• secreted into lacteal and to systemic circulation

• to adipose tissue where the chylomicron is stripped of its triacylglycerols and chylomicron remnant goes to liver - dietary cholesterol to liver

• free fatty acids are also synthesised to prostaglandins

• (can act as local gut hormones)

Coeliac disease

• strong inflammatory reaction in intestinal mucosa

• due to immune reaction to gluten products

• results in atrophy of villi and disturbance of absorption

• subsequent severe diahorrea

• treat by elimination of gluten from diet

Motor functions of the colon

• mixing the contents to promote absorption of water and electrolytes

• maintaining an appropriate intraluminal bacterial mass• transporting contents in a net distal direction• storing fecal material until defecation• rapid emptying of colonic contents during defecation

• ceacum, ascending colon and rectum act as reservoirs for the storage of feces

• the rest (transverse, descending and sigmoid colon) acts to propel the feces from the first to the second reservoir

Colon musculature

• bundles of the outer longitudinal muscle are grouped into 3 thick bands- taeniae of the colon

• inner circular muscle coat

• taniae are shorter than underlying circular muscle coat giving rise to haustra

Colon function

• large intestine absorbs water and Na - lacks villi

• secrete HCO3 to balance acid produced by bacteria

• also mucous to lubricate faeces

• bacteria in colon to digest cellulose & carbohydrates

• bacteria ~30% dry mass of stool

• also methane and H2 from dietary fibre - gas

Motility in colon

• low frequency segmentation in proximal colon

• to expose contents to mucosa

• mass movements - a contraction wave passing over the proximal colon driving contents into distal colon

• 3-4 times/day

• usually followed by defecation

• mass movement triggered by food in stomach - long reflex gastrocolic reflex

Defecation

• mass movement brings feces into rectum

• defecation reflex - started by distension

• long & short reflexes

• anal sphincter is under voluntary control

• muscular movements coordinate to expel contents