1. Gastrointestinal System
Dr Philip Poronnik
Dept of Physiology
These notes accompany the material presented in the lectures and in the textbook

2. 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

3. 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)

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Fats 60-100g daily fatty acids triacylglycerols
cholestrol (esterified)
digestion by lipases

12. 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

13. 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

14. 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

15. 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

16. 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

17. Submucosal plexus
mainly concerned with control within the inner walls of each gut segment
local absorption, secretion, contraction

18. 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

19. 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)

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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 a-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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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 a-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)

37. 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)

38. Four phases of swallowing
preparatory
oral
pharyngeal
eosophagal
preparatory is voluntary and involves bolus formation and lubrication during mastication

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. Stomach tubular glands 2
pyloric glands - in the antrum
secrete mainly mucous to protect pyloris
gastrin from G cells
some pepsinogen
NO parietal cells

50. 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

51. 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”

52. 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

53. 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

54. 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)

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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)

61. 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)

62. 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

63. 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

64. 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

65. Migrating Motor Complex
develops 4-5 hours after a meal and recurs every 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

66. 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)

67. 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

68. 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

69. 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

70. 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

71. 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)

72. Liver and Bile
One main function of liver is to secrete bile ( ml/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

73. 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

74. 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)

75. 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

76. Gallbladder
Bile is normally stored in the gallbladder until it is need in the duodenum
The volume of the gallbladder is only 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

77. 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

78. 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

79. 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

80. 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

81. 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

82. 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

83. Small Intestine major site of digestion and absorption of nutrients
divided into 3 segments
duodenum (20 cm)
jejunum (2.5 m)
illeum (3.6m)

84. 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

85. 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

86. 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

87. 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

88. 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

89. 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

90. 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

91. 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

92. 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

93. 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

94. 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

95. 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)

96. 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

97. 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

98. 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

99. 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

100. 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

101. 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