Transcript presentation source

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 absorbed
substances
• control of this these systems by both neuronal and hormonal
systems
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 OHgroups
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 vagovagal 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 (6001200ml/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