2. GI physiology review

3. Function of the GI system
4 basic digestive processes
• MOTILITY
• SECRETION
• DIGESTION
• ABSORPTION

4. Delay of
3 seconds 3

5. Sphincters 3

6. 4 Mucosa • epithelium • lamina propria: • muscularis mucosae
• exocrine cells
• endocrine/paracrine cells
Submucosa
• connective tissue,
blood vessels, glands
• submucosal nerve plexus
(Meissner’s plexus)
Muscularis externa
• smooth muscle cell layer
inner circular layer
outer longitudinal layer
• myenteric nerve plexus
(Auerbach’s plexus)
Serosa (adventitia) 4
Epithelium
Lamina propria
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis externa
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa

7. Regulation of GI function
Autonomous
Neural regulation
smooth muscle
function
extrinsic NS (CNS)
pacemaker activity
intrinsic NS
electrical coupling
GI hormones
Paracrine
mediators
humoral regulation 5

8. Autonomous smooth muscle function3
Epithelium
Lamina propria
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis externa
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa
Intestinal smooth muscle cells:
effector organ of GI motility
Pacemaker activity:
Thin layer of interstitial cells (interstitial cells of Cajal) between circular and longitudinal cell layer. Conduction through gap junctions.

9. Excitation-contraction coupling intestinal smooth muscle
Contraction requires an increase of cytosolic calcium ([Ca2+]i)
Electro-mechanical coupling: Contractions are triggered by action potentials (APs) that travel from cell
to cell through gap junctions.
Pharmaco-mechanical coupling: Contraction occur in the absence of action potentials e.g. in response to neurotransmitter or hormones. 5

10. Pacemaker activity: 3
Epithelium
Lamina propria
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis externa
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa
Thin layer of interstitial cells (interstitial cells of Cajal) between circular and longitudinal cell layer. Conduction through gap junctions.

11. GI smooth muscle electrophysiology and contraction6
Resting membrane potential
-40 to -80 mV.
membrane potential oscillations
Na+/K+-ATPase.
Slow waves
Pacemaker activity
Ionic events during slow waves: Na-, Ca- and
K-currents
Modulation by enteric neurons
Action potentials
when slow-waves reach electrical threshold:
burst of APs
(10-20 ms, rising phase is carried by Na+ and Ca2+ ions)

12. Smooth muscle tone and contraction
• Contraction begins when depolarizing phase reaches mechanical threshold.
• Development of muscle tone and contraction correlate with the degree of depolarization
• can occur in the absence of APs.
• Baseline tension is ‘non-zero’ (constant basal tone).
• Tonic contractions: contractile tension that is maintained for prolonged periods of time.
• Phasic contraction: “twitch-like” contraction evoked by action potentials. Triggering of APs increases strength of contraction. Frequency and number of APs grade the degree and duration of contraction.

13. 7

14. Neurotransmitters of the autonomic nervous system
sympathetic 2
parasympathetic 10

15. Integration of sympathetic, parasympathetic and enteric nervous system12

16. Sympathetic efferent innervation
• Primarily via postganglionic adrenergic fibers with cell bodies in prevertebral and paravertebral plexuses (celiac plexus, superior and inferior mesenteric plexus, superior and inferior hypogastric plexus) terminate in submucosal and myenteric plexus.
• Typically inhibitory effect on synaptic transmission in the enteric plexuses.
• Effects of sympathetic activity
- vasoconstriction of gastrointestinal blood vessels
- inhibition of glandular function
- muscularis externa: inhibition of motor activity
- contraction of muscularis mucosae and certain sphincters

17. Parasympathetic efferent innervation
• Vagus nerve (upper gastrointestinal tract to transverse colon) and
parasympathetic fibers of pelvic nerves from the hypogastric plexus
Predominantly cholinergic fibers that terminate on ganglion cells of intramural plexuses.
• Stimulation of motor (smooth muscle cells) and secretory activity.

18. Enteric nervous system11
semi-autonomous nervous system in the wall of the GI tract ("the little brain in the gut"):
major network of ganglia and interconnecting neurons (about 108 neurons!) 2 major plexuses
• myenteric plexus (Auerbach’s plexus)
• submucosal plexus (Meissner’s plexus)

19. Integration of neuronal control of GI function13

20. 14 Example of enteric reflex:
The neural circuit for peristaltic propulsion of GI (the”law of intestine”). 14
Stretching a segment of the GI tract is sensed by sensory enteric neurons.
This signal is transmitted via excitatory and inhibitory interneurons to excitatory (proximal)
and inhibitory (distal) motor neurons, causing ascending excitation and descending
inhibition of smooth muscle cells -->GI content is transported in aboral direction
VIP = vasoactive intestinal peptide

21. Intestinal reflexes
Short range reflexes: Food bolus causes aboral relaxation and proximal contraction --> food transport in orthograde direction (law of the intestine). Regulated by intrinsic nerves.

22. 58 • Gastro intestinal hormones
are released from distant endocrine cells and transported by blood streamto activate secretion (e.g. gastrin from G cells activate HCl secretion)
• Paracrine mediators
are released into the neighborhood of secretory cell and reaches target cells by diffusion (e.g. histamine = paracrine agonist for gastric HCl secretion). 58

23. Important actions of GI hormones (compare with table 15)
Action Gastrin CCK Secretin GIP
Acid secretion S I I
Pancreatic HCO3- secretion S S
Pancreatic enzyme secretion S
Bile HCO S
Gallbladder contraction S
Gastric emptying I
Mucosal growth S
Pancreatic growth S S
S = stimulates; I = inhibits

24. Additional GI hormones
Hormones are produced by enteroendocrine cells in the GI tract in stomach, small and large intestine
Motilin
Serotonin
Substance P
Vasoactive intestinal peptide
(VIP)
Neurotensin
increases intestinal motility
neurotransmitter for intestinal smooth muscle
stimulates secretion of water and ions
decreases intestinal motility
increases blood flow to ileum 16

25. Additional GI hormones (cont.)
Glucagon
Entero-glucagon
Glicentin
(glucagon-like substance)
Somatostatin
Urogastrone
(Epidermal Growth Factor)
Histamine
stimulate hepatic glycogenolysis
stimulates hepatic glycogenolysis
local inhibition of other endocrine cells
(e.g. G-cells)
inhibits secretion of HCl
increases epithelial growth
increases secretion of HCl

26. Gastrointestinal paracrine mediators
Paracrine agonists released by:
- paracrine cells
- GI immune system
- antibodies
- inflammaory mediators (prostaglandins, leukotrienes, cytokines, histamine, others)
Lymph node 4
Villus
Epithelium
Lamina propria
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa
Muscularis externa 3

27. GI immune system
- half of the mass of immune cells in the body are in the GI tract
- antibody secretion to specific food antigens
- immunologic defense against pathogenic microorganisms

28. Pancreatic Hormones Pancreatic hormones: insulin glucagon somatostatin
produced and secreted (endocrine pancreatic secretion) by the islets of Langerhans
essential for the regulation of metabolism

29. Regulation of GI function
Autonomous
Neural regulation
smooth muscle
function
extrinsic NS (CNS)
pacemaker activity
intrinsic NS
electrical coupling
GI hormones
Paracrine
mediators
humoral regulation
> high degree of integration
> high degree of autonomy 5

30. Example: acid secretion by gastric parietal cell....
cholinergic
nerve terminals
G-cells
+ gastric motility
enhances mixing of food
and disgestive juices H+ 71

31. MOTILITY muscular contractions that mix and move the
contents of the gastro-intestinal tract to the appropriate sites of digestion and absorption

32. Patterns of GI motility
Type of contraction Organ/structure
• Tonic
contractions upper and lower esophageal sphincters
pyloric valve
sphincter of Oddi
ileocecal valve
internal anal sphincter
• Propulsive
peristalsis esophagus
lower 2 thirds of stomach
small intestine
rectum

33. Patterns of GI motility (cont)
Type of contraction Organ/structure
• Reverse
peristalsis
(antipropulsion) proximal colon
• Mass
movements ascending, transverse and descending colon
• Nonpropulsive
segmentation small intestine
• Haustration ascending, transverse and descending colon

34. Patterns of GI motility (cont)
• Migrating
motor complex =
migrating myoelectric
complex fasting/empty small intestine

35. Esophagus
Tubular conduit (about 20 cm long) for food transport from mouth to stomach.
Structural and regulatory aspects:
• Upper third of the esophagus: circular and longitudinal muscle layers are striated;
innervation via cranial nerve.
• Middle third: coexistence of skeletal and smooth muscle.
Primary innervation from vagus nerve;
nerve input from neurons of myenteric plexus
• Lower third: smooth muscle, enteric nerve system (input from vagus nerve to
enteric nerve system).

36. Neuronal control of esophagus
Swallowing
center
Neuronal control
of esophagus
Pharynx 1
UES
Innervation
afferent:
sensory feedback to swallowing center
efferent:
• vagal somatic motor neurons to striated muscle
• vagal visceral motoneurons to smooth muscle, terminating at neurons of myenteric plexus 2 3 1 2 3 18

37. 32 Esophageal sphincters
• Upper esophageal sphincter (UES): prevents entry of air
• Lower esophageal sphincter (LES): LES = zone of elevated resting pressure (~ 30 mm Hg)
prevents reflux of corrosive acidic stomach content.
LES tone is regulated by extrinsic and intrinsic nerves, hormones and neuromodulators.
Contraction: vagal cholinergic nerves (nicotinic, i.e. atropine insensitive) and
sympathetic nerves (-adrenergic).
Relaxation: primary peristalsis --> inhibitory vagal nerve input to circular muscle of
LES (neurotransmitters (VIP and NO) and reduced activity of vagal excitatory
fibers (cholinergic, nicotinic).

38. Swallowing
Swallowing can be initiated voluntarily, but then it is under reflex control.
Swallowing reflex = sequence of events that result in propulsion of food from the mouth to the stomach
1. Oral/voluntary phase
2. Pharyngeal phase
3. Esophageal phase

39. Control of esophageal
motility
Local and central
circuits 31

40. Esophageal pressure profile32

41. Intraluminal esophageal pressure profile
Pressure in the body of esophagus is negative,
reflecting intrathoracic pressure
pressure wave
during swallowing
0 mm Hg = ambient pressure

42. Stomach 33

43. Functions of stomach motility
• reservoir for large volumes of food
• fragmentation of food and mixing with gastric secretion --> digestion
• controlled emptying of gastric content into duodenum

44. Stomach smooth muscle electrical activity
Fundus
Stomach smooth muscle electrical activity 35
Reservoir
Mixing + Transport
Sphincter

45. • Gastric filling
Empty stomach (volume approx. 50 ml) can expand to > 1 liter; volume increase is n o t paralleled by similar increase of intragastric tension because of
• Plasticity: stomach smooth muscle cells can be stretched (within limits) without a change in tension (developed force).
• Receptive relaxation: Filling (gastric distension) causes reflective relaxation of the fundus and body of the stomach; reflex is mediated by vagus nerve (VIP and NO as neurotransmitters).

46. • Gastric mixing
Chyme
= mixture of gastric secretion and food content 36

47. • Gastric emptying • antral peristaltic contractions
• pylorus regulates emptying
• neural and humoral/hormonal fine regulation
gastric
duodenum/jejunum
factors outside GI system

48. Pyloric valve - regulates emptying of gastric content
- prevents regurgitation of
duodenal content 37
Pyloric relaxation: inhibitory vagal fibers (mediated by VIP and NO).
Pyloric constriction: excitatory cholinergic vagal fibers, sympathetic fibers and
hormones cholecystokinin, gastrin, gastric inhibitory peptide and secretin.

49. • Gastric factors
Volume of chyme: increased volume (distension) stimulates motility
Fluidity: increased fluidity allows more rapid emptying

50. • Duodenal/jejunal factors37
CNS

51. Small intestine motility

52. Types of motility of the small intestine
• digestive motility pattern:
segmentation
peristalsis
• interdigestive motility pattern:
migrating myoelectric complex

53. Segmentation • Most frequent type of motility
• Closely spaced contraction of the circular muscle layer, dividing the small intestine into small neighboring segments. In rhythmic segmentation the sites of circular contractions alternate --> mixing
• Frequency of segmentations decreases in aboral direction (11-12/min duodenum; 8-9/min ileum) --> slow forward transport of food content 53

54. Peristalsis
• Progressive contraction of successive sections (short distances) of circular smooth muscle in orthograde direction.

55. Contractile activity of the muscularis mucosae
Irregular contractions of sections of the muscularis mucosae (3/min) --> change in topography of the internal surface of the gut --> enhancement of the contact between mucosa and content and facilitation of absorption. Increased emptying of central lacteals and increased intestinal lymph flow. 4

56. Emptying of the ileum
Ileocecal sphincter: normally closed. Short-range peristalsis in terminal ileum and distension relaxes IC sphincter --> small amount of chyme is squirted into the cecum.
Distension of cecum contracts IC sphincter.
Gastro-ileal reflex enhances ileal emptying after eating.
The hormone gastrin relaxes ileocecal sphincter. 54

57. The migrating myoelectric complex (MMC) = migrating motor complex
• occurs in fasted organism
• bursts (lasting 5-10 minutes) of intense electrical and contractile activity that propagate from stomach (origin) to the terminal ileum. Repeats every minutes. 43
ligament of Treitz:
duodenum-jejunum border

58. Motility of the colon
• Haustration (corresponds to segmentation in small intestine)
• Segmental propulsion or systolic multihaustral propulsion
• Antipropulsion (reverse peristalsis)
• Mass movement

59. Defecation Complex behavior involving voluntary actions and reflexes.
Defecation reflex: sacral spinal cord and efferent cholinergic parasympathetic fibers in pelvic nerves. Distension of rectum and relaxation of internal sphincter.
Voluntary actions: relaxation of external sphincter (striated muscle, innervated by somatic fibers via pudendal nerves) and increase of intraabdominal pressure 57

60. SECRETION exocrine glands secrete digestive juices, consisting of
water
electrolytes
specific organic constituents important for
digestive process (enzymes, bile salts, mucus)
endocrine glands: hormones for regulation of the GI system

61. Functions of GI secretion are • digestive • protective
For example.....
• provide enzymatic machinery for degradation of nutrients
• provide factors to facilitate absorption (e.g. bile salts, intrinsic factor)
• lubricate food bolus
• provide the proper ionic and osmotic milieus (e.g. pH) for enzymatic hydrolysis and absorption
• aid in repair, replacement and barrier functions of the intestinal epithelium (e.g. epidermal growth factor)
• contribute to body fluid homeostasis
• immunological functions through secretory immunoglobulins (antibodies) and antibacterial compounds

62. Secretagogue = substance that stimulates a secretory cell to secrete
• neurocrine secretagogue: neurotransmitters released from neurons that innervate the secretory cell (e.g. ACh from vagus nerve)
• endocrine secretagogue: hormones released from distant cells and transported by blood streamto activate secretion (e.g. gastrin from G cells activate HCl secretion)
• paracrine secretagogue:
released into the neighborhood of secretory cell and reaches target cells by diffusion (e.g. histamine = paracrine agonist for gastric HCl secretion). 58

63. Mechanism of exocrine gland secretion
Exocrine gland cells
extract from the plasma raw materials necessary for the synthesis of secretion products. Secretion products are emptied into the ducts of the secretory gland and delivered to the GI tract.
Secretion-blood flow coupling
secretion is coupled with increased blood flow to the exocrine gland (functional hyperemia) to optimize availability of raw materials. 59

64. Intracellular mechanisms
• secretagogues
bind to surface membrane receptors and stimulate secretion
• intracellular messengers:
• cAMP
• IP3 and Ca2+
• activation of kinases -->
altered ion channel
function -->
secretion
60

65. Salivary glands
• parotid
• submandibular (submaxillary)
• sublingual
• (minor glands in labial, palatine, buccal, lingual and sublingual mucosa)

66. Structure of salivary glands
acinus = secretory endpiece with
• serous acinar cells with zymogen granules (salivary amylase, salivary proteins)
• mucous acinar cells secrete glycoprotein mucins
ducts = drainage system modifications of acinar secretions
• intercalated ducts
• striated (intralobular) ducts
• excretory (interlobular) ducts. 61

67. Composition of saliva • electrolytes • proteins • water
• mucin (glycoproteins --> viscosity)
• digestive enzymes (salivary amylase stored in zymogen granules, released into acinar lumen by exocytosis)
• protective proteins (secretory IgA)
• water

68. Protective function
• bicarbonate (neutralization of acid produced by bacteria and gastric reflux)
• antibacterial (lysozyme)
• lactoferrin (binds Fe, decreases bacterial growth)
• secretory immunoglobulin (IgA)
• epidermal growth factor
• mouth hygiene
• facilitates speaking
Digestive function
• -amylase (= ptyalin)
• lingual lipase
• lubrification food for swallowing
• dissolving substances for taste mechanism

69. 2-stage model of salivary secretion
• Primary secretion product (acinus) is nearly isotonic with plasma.
• Secondary modification in ducts extract Na+, Cl-, and add K+ , HCO3-, resulting in a hypoosmotic (hypotonic) secretion. 62

70. • Composition and osmolarity dependent on secretion rate63

71. Mucus
• Collective term for secretions that contain glycoprotein mucins which are characteristically viscous and sticky.
• Protects mucosal surfaces from abrasion by food contents, lubricates the food bolus in the upper GI tract and alkaline pH counters regional acidity (e.g. stomach).
• Mucus is produced by various cells in the GI tract:
mucous cells in salivary glands
goblet cells
Brunners gland
neck cells of gastric glands
pancreatic acinar cells.

72. Regulation of salivary secretion
• The primary physiological control of salivary gland function is by the parasympathetic nervous system!
• the sympathetic nervous system and hormones contribute to regulation

73. Regulation of salivary secretion
Autonomic nervous system:
• Parasympathetic (ACh, VIP):
• high and sustained output
• synthesis and secretion of amylase and mucins
• transport activity of ductular epithelium
• vasodilation and increased blood flow
• positive feed back on blood supply through kallikrein kininogen system
• stimulation of glandular metabolism and growth
• Sympathetic:
• transient increase of secretion
• vasoconstriction leads to decrease of salivation
VIP= vasoactive intestinal peptide

74. cardiac glandular region oxyntic glandular region
Gastric mucosa:
cardiac glandular region
oxyntic glandular region
pyloric glandular region......
with a variety of secretory cells 35

75. Secretory cells Secretion product • surface mucous cells,
mucous neck cells mucus, HCO3- • oxyntic (= parietal) cells HCl, intrinsic factor • chief (= peptic) cells pepsinogen, gastric lipase • neuroendocrine cells G cells gastrin D cells somatostatin

76. Digestive functions Protective functions • digestive enzymes:
pepsinogen (endopeptidase)
gastric lipase
• HCl secretion (parietal cells): acidic environment for pH optimum ( ) of digestive enzyme pepsin (activated from pepsinogen) and lingual lipase (pH optimum 4). HCl softens food
• Intrinsic factor: binds Vit B12 and protects from gastric and intestinal digestion
Protective functions
• gastric acidity: antibacterial
• mucus and HCO3-: protective layer against damage of gastric mucosa by low pH

77. Pepsinogen secretion • Pepsin = protease (endopeptidase)
• Low gastric pH converts proenzyme pepsinogen into active pepsin; pepsin itself proteolytically cleaves pepsinogen (positive feedback)
• Optimum for proteolytic activity is around pH 3.
• ACh, gastrin, secretin, cholecystokinin and acid stimulate pepsinogen secretion.
• Pepsinogen is stored in zymogen granules and released by exocytosis.

78. Ionic composition of gastric juice
Rate of secretion of gastric acid:
• basal rate = 1-5 mEq/hr
• maximal stimulation = 6-40 mEq/hr
• higher in patients with duodenal ulcers
• low flow rate: hypotonic
• high flow rate: nearly isotonic, mainly HCl
Gastric juice
Plasma 66 63

79. Cellular mechanism of HCl production-
omeprazole 67
• Carbonic anhydrase drives HCO3- production
• H+/K+ pump (ATP-dependent) drives H+ out and Cl- follows (via electrogenic anion channel)
• HCO3-/Cl- exchange maintains Cl- supply
• Alkaline tide: net HCO3- release into the blood stream during gastric acid secretion.

80. Regulation of acid secretion68

81. Gastric mucosal barrier
• (1) unstirred, bicarbonate rich mucus layer maintains pH 7 at cell surface and protects gastric mucosa from gastric juice (pH 2)
• (2) tight junctions between gastric mucosal cells prevent penetration of HCl between cells
• (3) luminal membrane of gastric mucosal cells is impermeable for protons
Protection against
self-digestion 70

82. Pancreatic secretion

83. Secretory functions of the pancreas:
• endocrine pancreatic secretion (islets of Langerhans): hormones (insulin, glucagon, somatostatin) essential for regulation of metabolism
• exocrine pancreatic secretion: • aqueous component
• enzyme component 98

84. Digestive function
• production and secretion of digestive enzymes
• neutralization of acidic chyme (pancreatic enzymes pH optimum near neutral pH)
Protective function
• neutralization of acidic chyme --> protection from acid damage of intestinal mucosa

85. Pancreatic enzymes
Enzyme specific hydrolytic activity

86. Enzyme activation
• Proteolytic enzymes are secreted in inactive zymogen form. Enteropeptidase (= enterokinase) secreted by duodenal mucosa activates trypsinogen (--> trypsin). Trypsin activates itself and the other proteolytic enzymes.
• Trypsin inhibitor: protein in pancreatic secretion that prevents premature activation of proteolytic enzymes in pancreatic ducts
• -amylase is secreted in active form

87. pH, osmolarity and electrolyte composition of pancreatic secretion71

88. Cellular mechanism of pancreatic secretion:
• carbonic anhydrase reaction
produces H2CO3
• Na/H exchange and
H/K-ATPase eliminate H+
• Cl-/HCO3- exchange secretes
bicarbonate into duct lumen
• electrogenic Cl- channels
recycle Cl- back into lumen
• Acid tide: net H+ release
into the blood stream during
pancreatic secretion.
Carbonic
anhydrase 72

89. Bile secretion and liver function

90. Structure of the liver 96

91. blood
flow
bile
flow 96

92. 96 PS = portal space with portal vein hepatic artery bile canaliculus
lyphatic vessel
CV= central vein 96

93. 96 liver lobule portal lobule (defined by bile flow) hepatic acinus
(defined by blood flow) 96

94. Hepatic acinus
HV = hepatic venule 96

95. Functions of the liver
• Energy metabolism and substrate interconversion
• Synthetic function
• Transport and storage function
• Protective and clearance function

96. Bile secretion = digestive/absorptive function of the liver
Components of bile
• bile salts (conjugates of bile acids)
• bile pigments (e.g. bilirubin)
• cholesterol
• phospholipids (lecithins)
• proteins
• electrolytes (similar to plasma, isotonic with plasma)
ml/day

97. Function of bile
• bile salts (conjugates of bile acids with taurine or glycine) important for absorption of lipids in small intestine. Bile acids emulsify lipids and form mixed micelles necessary for lipid absorption.
• bile acids are derived from cholesterol and therefore are responsible for excretion of cholesterol.
• excretion of bilirubin (product of hemoglobin degradation).
• bile acids are actively absorbed and recirculated through enterohepatic circulation.

98. enterohepatic circulation of bile73

99. Mechanism of uptake and secretion of bile acids by hepatocytes
ATP 74

100. Intestinal secretion: 1500 ml/day.
Composition:
• mucus
• electrolytes
• water

101. DIGESTION
degradation of structurally complex foodstuffs by digestive enzymes
3 categories of energy-rich foodstuffs:
carbohydrates, proteins and lipids
ABSORPTION
absorbable units as a result of the digestive process are
transported along with water, vitamins and electrolytes
from the lumen of the GI tract into the blood and lymph

102. Digestion chemical degradation of nutrient macromolecules by
digestive enzymes
• Luminal disgestion: enzymes secreted into the lumen of GI tract from salivary glands, stomach and pancreas
• Membrane or contact digestion : hydrolytic enzymes synthesized by enterocytes and inserted into the brush border membranes. Integral part of the microvillar membrane in close vicinity of specific carrier proteins (= digestion-absorption coupling)
• cytoplasmic disgestion: digestive enzymes in the cytoplasm (peptidases)

103. Sites of
absorption 78

105. 79

106. • loss through GI tract: 100 ml (only 5% of intake) through feces
Average daily....
• intake: ~ 2 liters
• loss through GI tract: 100 ml (only 5% of intake) through feces
• GI secretion: 7 liters
• water absorption by GI tract: 9 liters 80

107. Mechanism of water absorption: standing osmotic gradient hypothesis
Absorption of water is passive and is determined by differences in osmolarity of luminal content and blood, therefore net transport of water can occur in both direction.

108. Standing gradient osmosis:
1. Active Na+ pumping (Na/K ATPase) into lateral intercellular space
2. passive entry of Cl- into lateral intercellular space
3. establish osmotic gradient in lateral space
4. entry of water by osmosis into lateral space
5. hydrostatic flow of water 81

109. transcellular vs. paracellular transport
Tight junctions:
transcellular vs. paracellular transport
Tight junctions connect epithelial cells of the GI tract. Tight junctions are leaky (the most in the duodenum) for water and ions. Transmucosal transport of water and ions can occur through tight junctions and lateral intercellular space (paracellular transport = 2) or through epithelial cells (transcellular transport = 1) 79

110. Digestion and absorption of carbohydrates

111. Diet contains
• digestible carbohydrates
• monosaccharides: glucose, fructose, sorbitol, (galactose in form of milk lactose = galactose+glucose)
• disaccharides: sucrose, lactose, maltose
• oligosaccharides/polysaccharides: starch (made of amylose and amylopectin), dextrins, glycogen
• non-digestible carbohydrates
dietary fibers, mainly cellulose (ß-1,4 linked glucose polymer; humans lack enzyme to hydrolyse ß-1,4 bonds). Fibers are extremely important for regular bowel movements.

112. Digestive enzymes break down oligosaccharides and polysaccharides into the 3 absorbable monosaccharides
• glucose
• fructose
• galactose

113. Digestive enzymes for carbohydrate digestion
• luminal digestive enzymes
• brushborder enzymes

114. Luminal digestive enzymes for carbohydrate digestion:
salivary and pancreatic amylase: cleaves the -1,4 glycosidic bond of amylose and amylopectin (starch and glycogen) to produce maltose, maltotriose and -limit dextrins.
Note:  -amylase cannot hydrolyze  -1,6 and terminal  -1,4 glycosidic bonds. 87

115. Brush border enzymes
digest disaccharides and oligosaccharides

116. Digestion-absorption coupling88

117. Absorption mechanism of monosaccharides
Digestion by brush border enzymes occurs in close vicinity
to monosaccharide transporters.
• Glucose and galactose: SGLT1
absorption via a secondary active (uphill), Na-dependent transport
• Fructose: GLUT5
absorption by facilitated (carrier mediated), Na-independent mechanism 90

118. Digestion and absorption of lipids

119. Lipids in the GI tract:
• exogenous (diet: triglycerides (90%), phospholipids, sterols (e.g. cholesterol), sterol esters)
• endogenous (bile, desquamated intestinal epithelial cells)

120. Digestion of lipids
Most of the lipids are digested in the small intestine, but also in stomach.
Enzymes for lipid digestion
• lingual lipase (from salivary secretion; break down of mainly medium-chain triglycerides as abundant in milk; optimal pH = 4 --> lipid digestion in the stomach)
• gastric lipase (secreted by chief cells)
• pancreatic lipase = glycerol ester hydrolase (triglycerides)
• pancreatic phospholipase A2 (phospholipids)
• pancreatic cholesterol esterase (cholesterol ester).

121. 91

122. Mechanism of lipid absorption
• The intestinal villi are coated by an unstirred water layer which reduces the absorption of the poorly water soluble lipids.

123. • Emulsification: In the small intestine lipids are emulsified by bile acids (i.e. formation of small droplets of lipids coated with bile acids). Bile salts (bile salts = conjugation of bile acids with taurine or glycine) are polar and water soluble, and function as detergents. Emulsion droplets allow access of the water-soluble lipolytic enzymes by increasing surface area. 92

124. • Micelle formation and lipid absorption:
- At a certain concentration (critical micellar concentration) bile salts aggregate into micelles that incorporate lipid digestion products. Lipids become water soluble by micellar solubilization.
- Lipids diffuse across the unstirred water layer as micelles and are mostly absorbed passively (diffusion) by enterocytes (mainly in the jejunum).
- Absorption is enhanced by Na+-dependent long-chain fatty acid transport protein (MVM-FABP=microvillous membrane fatty acid-binding protein) and cholesterol transport protein in the brush border membrane (secondary active and facilitated transport).

125. • In the enterocytes lipids are bound by cytosolic lipid transport proteins and transported to the smooth endoplasmic reticulum. There triglycerides are reassembled from fatty acids and monoglycerides
• Triglycerides together with lecithin, cholesterol and cholesterol ester, are packaged into lipoproteins to form water-soluble chylomicrons (lipid aggregates).
• Transport of lipids to the lymphatic vessels by exocytosis. Additionally, mainly medium-chain and short-chain fatty acids directly reach the blood stream and are transported bound to serum albumin.

126. Lipid
digestion &
absorption 94

127. • Absorption of bile acids
• Absorption of bile acids. Bile acids are absorbed in the terminal ileum by Na+-dependent secondary active transport (mainly conjugated bile acids) and by diffusion (mainly unconjugated bile acids). Bile acids are recirculated to the liver via portal circulation and extracted from portal blood for reuse. 93

128. Digestion and absorption of proteins

129. Proteolytic digestive enzymes
• gastric secretion (G)
• pancreatic secretion (P)
• brush border enzymes (BB)
• cytoplasmic (C)

130. • Endopeptidase: hydrolyzes internal peptide bonds:
• trypsin (P)
• chymotrypsin (P)
• elastase (P)
• pepsin (G)
• Exopeptidase: hydrolyzes external peptide bonds:
• carboxypeptidase A (P)
• carboxypeptidase B (P)
• aminopeptidase (P, BB, C)
P = pancreas, BB = brush border, C = cytoplasm

131. Protein digestion >> Gastric proteolysis:
pepsin is activated by low pH from proenzyme pepsinogen and acts as endopeptidase.
>> Small intestine: major site of protein digestion.
• Luminal protein digestion: Pancreatic proteases are secreted as inactive proenzymes. Chyme in the duodenum stimulates the release of enterokinase (= enteropeptidase) which converts trypsinogen into trypsin (active form). Trypsin itself converts the other proenzymes to active enzymes. Luminal protein digestions produces single amino acids and small peptides (dipeptides, tripeptides and tetrapeptides)
• Brush border peptidases are integral membrane proteins produce single amino acids and smaller peptides from tetrapeptides and larger peptides.
• Intracellular cytoplasmic peptidases break down dipeptides and tripeptides into single amino acids.

132. Protein absorption: Products of protein digestion are absorbed as
• amino acids: 7 amino acid transporters in brush border membrane (B&L, table 39-2):
- 5 Na-dependent (absorption occurs via secondary active process by carrier that are energetically coupled to the Na+ concentration gradient across the brush border membrane of intestinal epithelial cells)
- 2 Na-independent (facilitated transport).
• peptides: di- and tripeptides by peptide transporters.
(• proteins: in the newborn of some animal species absorption of immunoglobulins provides an important form of passive immunity).

133. Amino acid transport across the basolateral membrane
• 5 classes of amino acid transporter at the basolateral membrane (B&L, table 39-3)
- 2 Na-dependent
- 3 Na-independent
• Amino acids are transported in the portal blood

134. protein
digestion &
absorption 95

135. Absorption of vitamins

136. Vitamins:
organic substances needed in small quantities for normal metabolic function, growth and maintenance of the body.
• Fat-soluble vitamins:
Vitamins A, D, E and K
• Water-soluble vitamins:
Vitamins B1, B2, B6, B12, niacin, biotin and folic acid

137. • Water-soluble vitamins (cont.):
Absorption of Vitamin B12
• Vitamin B12 (cobalamin) is bound to a cobalamin binding protein (intrinsic factor) secreted by the parietal cells of the stomach.
• The Vitamin B12-intrinsic factor complex is absorbed in the terminal ileum.
• Transport in the blood of Vitamin B12 by binding to the protein transcobalamin.
• Vitamin B12 is stored in the liver.