Transcript FHB: GI physiology

GI physiology review
Function of the GI system
4 basic digestive processes
• MOTILITY
• SECRETION
• DIGESTION
• ABSORPTION
Upper esophageal
sphinct er
Delay of
3 seconds
Lower esophageal sphinct er
3
Sphincters
Upper esophageal
sphinct er
Lower esophageal sphinct er
3
Mucosa
Lymph node
4
Villus
Epithelium
Lamina propria
Serosa
Myenteric
plexus
Submucosal
plexus
Gland in
submucosa
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis externa
• 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)
Regulation of GI function
Autonomous
smooth muscle
function
Neural regulation
extrinsic NS (CNS)
intrinsic NS
pacemaker activity
electrical coupling
GI hormones
Paracrine
mediators
humoral regulation
5
Autonomous smooth muscle function
Lymph node
Intestinal smooth muscle cells:
effector organ of GI motility
3
Villus
Epithelium
Lamina propria
Serosa
Myenteric
plexus
Submucosal
plexus
Gland in
submucosa
Pacemaker activity:
Thin layer of interstitial cells (interstitial cells of Cajal) between
circular and longitudinal cell layer. Conduction through gap
junctions.
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis externa
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
Pacemaker activity:
Lymph node
Thin layer of interstitial cells
(interstitial cells of Cajal)
between circular and
longitudinal cell layer.
Conduction through gap
junctions.
3
Villus
Epithelium
Lamina propria
Serosa
Myenteric
plexus
Submucosal
plexus
Gland in
submucosa
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis externa
GI smooth muscle electrophysiology and contraction
6
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)
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.
extrinsic NS
somat ic
Neural
regulation
aut onomic
intrinsic NS
sympat het ic
parasympat het ic
ent eric NS
7
sympathetic
Neurotransmitters of the autonomic nervous system
1
parasympathetic
Cholinergic synapses
1
nicot inic
( blocked by curare)
2
muscarinic
( blocked by at ropine)
1
2
10
( modif ied f rom B & L)
Integration of sympathetic, parasympathetic and
enteric nervous system
Effect or syst em
of GI innervat ion:
12
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
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.
Enteric nervous system
11
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)
C
N
S
Integration of neuronal control of GI function
2
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mechanorecept ors
chemorecept ors
t hermorecept ors
nocicept ors
Af f erent
1
sensory neurons f rom ent eric NS
( local af f erent s)
2
af f erent sympat het ic nerve f ibers
af f erent parasympat het ic nerve f ibers
Ef f erent
13
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
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.
• 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).
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Important actions of GI hormones (compare with table 15)
Action
Acid secretion
Gastrin CCK Secretin GIP
S
I
Pancreatic HCO3- secretion
S
Pancreatic enzyme secretion
S
Bile HCO3-
S
Gallbladder contraction
S
Gastric emptying
I
Mucosal growth
Pancreatic growth
S = stimulates; I = inhibits
S
S
S
S
I
Additional GI hormones
Hormones are produced by enteroendocrine cells in the GI tract in stomach,
small and large intestine
Motilin
increases intestinal motility
Serotonin
increases intestinal motility
Substance P
increases intestinal motility
Vasoactive intestinal peptide
(VIP)
neurotransmitter for intestinal smooth
muscle
stimulates secretion of water and ions
Neurotensin
decreases intestinal motility
increases blood flow to ileum
16
Additional GI hormones (cont.)
Glucagon
Entero-glucagon
stimulate hepatic glycogenolysis
Glicentin
(glucagon-like substance)
stimulates hepatic glycogenolysis
Somatostatin
local inhibition of other endocrine cells
(e.g. G-cells)
Urogastrone
(Epidermal Growth Factor)
inhibits secretion of HCl
increases epithelial growth
Histamine
increases secretion of HCl
Gastrointestinal paracrine mediators
Paracrine agonists released by:
- paracrine cells
- GI immune system
Lymph
node
4
- antibodies
Villus
- inflammaory mediators
(prostaglandins, leukotrienes,
cytokines, histamine, others)
Epithelium
Lamina propria
Serosa
Myenteric
plexus
Submucosal
Gland in
plexus
submucosa
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
muscle
Muscularis
externa
3
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
Pancreatic Hormones
Pancreatic hormones:
insulin
glucagon
somatostatin
produced and secreted (endocrine pancreatic secretion) by the islets of
Langerhans
essential for the regulation of metabolism
Regulation of GI function
Autonomous
smooth muscle
function
Neural regulation
extrinsic NS (CNS)
intrinsic NS
pacemaker activity
electrical coupling
GI hormones
Paracrine
mediators
humoral regulation
> high degree of integration
> high degree of autonomy
5
Example: acid secretion by gastric parietal cell....
+
ent erochromaf f in-like
cells ( ECL cells)
cholinergic
nerve terminals
l s
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G-cells
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+
s
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+ gastric motility
enhances mixing of food
and disgestive juices
H+
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MOTILITY
muscular contractions that mix and move the
contents of the gastro-intestinal tract to the
appropriate sites of digestion and absorption
Patterns of GI motility
Type of contraction
• Tonic
contractions
• Propulsive
peristalsis
Organ/structure
upper and lower esophageal sphincters
pyloric valve
sphincter of Oddi
ileocecal valve
internal anal sphincter
esophagus
lower 2 thirds of stomach
small intestine
rectum
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
Patterns of GI motility (cont)
• Migrating
motor complex =
migrating myoelectric
complex
fasting/empty small intestine
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).
Swallowing
center
Neuronal control
of esophagus
Pharynx
1
UES
Innervation
afferent:
sensory feedback to
swallowing center
3
2
efferent:
• vagal somatic motor neurons
1
to striated muscle
2 • vagal visceral motoneurons
to smooth muscle, terminating
at neurons of myenteric plexus 3
18
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).
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
Control of esophageal
motility
Local and central
circuits
31
Esophageal pressure profile
P
U
s
l
32
Intraluminal esophageal pressure profile
Pressure in the body of esophagus is negative,
reflecting intrathoracic pressure
pressure wave
during swallowing
0 mm Hg = ambient pressure
Stomach
33
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
Reservoir
Fundus
Mixing + Transport
Stomach smooth
muscle electrical
activity
Sphincter
35
• 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).
• Gastric mixing
Chyme
= mixture of gastric
secretion and food
content
36
• Gastric emptying
• antral peristaltic contractions
• pylorus regulates emptying
• neural and humoral/hormonal fine regulation
gastric
duodenum/jejunum
factors outside GI system
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.
• Gastric factors
Volume of chyme: increased volume (distension) stimulates motility
Fluidity: increased fluidity allows more rapid emptying
• Duodenal/jejunal factors
37
CNS
Small intestine motility
Types of motility of the small intestine
• digestive motility pattern:
segmentation
peristalsis
• interdigestive motility pattern:
migrating myoelectric complex
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
Peristalsis
• Progressive contraction of successive sections (short distances) of
circular smooth muscle in orthograde direction.
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
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
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
75-90 minutes.
43
ligament of Treitz:
duodenum-jejunum border
Motility of the colon
• Haustration (corresponds to segmentation in small intestine)
• Segmental propulsion or systolic multihaustral propulsion
• Antipropulsion (reverse peristalsis)
• Mass movement
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
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
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
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
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
Intracellular mechanisms
• secretagogues
bind to surface membrane
receptors and stimulate
secretion
VIP
Secretin
ATP
Histamine
cAMP

ATP
• intracellular messengers:
• cAMP
• IP3 and Ca2+
• activation of kinases -->
altered ion channel
function -->
secretion
Secretion
products
Norepi

Ca 2+
ACh
Fluid
IP 3
Gastrin
CCK
Substance P
60
Salivary glands
• parotid
• submandibular (submaxillary)
• sublingual
• (minor glands in labial, palatine, buccal, lingual
and sublingual mucosa)
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
Composition of saliva
• electrolytes
• proteins
• mucin (glycoproteins --> viscosity)
• digestive enzymes (salivary amylase stored in zymogen granules,
released into acinar lumen by exocytosis)
• protective proteins (secretory IgA)
• water
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
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
• Composition and osmolarity dependent on secretion rate
63
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.
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
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
Gastric mucosa:
cardiac glandular region
oxyntic glandular region
pyloric glandular region......
35
.........with a variety of secretory cells
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
D cells
gastrin
somatostatin
Digestive functions
• digestive enzymes:
pepsinogen (endopeptidase)
gastric lipase
• HCl secretion (parietal cells): acidic environment for pH optimum (1.8-3.5)
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
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.
Ionic composition of gastric juice
Rate of secretion of gastric
acid:
Gastric juice
Plasma
• 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
66
63
Cellular mechanism of HCl production
CO2 + H2 0
carbonic anhy drase
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.
( mo dified fro m B&L)
Regulation of acid secretion
+
cholinergic
nerve t er minals
ent erochr om af f inlike cells
( ECL cells)
+
G- cells
68
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
Pancreatic secretion
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
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
Pancreatic enzymes
Enzyme
specific hydrolytic activity
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
pH, osmolarity and electrolyte composition of
pancreatic secretion
71
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
Carbonic
anhydrase
recycle Cl- back into lumen
• Acid tide: net H+ release
into the blood stream during
pancreatic secretion.
72
Bile secretion
and
liver function
Structure of the liver
96
blood
flow
bile
flow
96
PS = portal space with
portal vein
hepatic artery
bile canaliculus
lyphatic vessel
CV= central vein
96
liver lobule
portal lobule
(defined by bile flow)
hepatic acinus
(defined by blood flow)
96
Hepatic acinus
HV = hepatic venule
96
Functions of the liver
• Energy metabolism and substrate interconversion
• Synthetic function
• Transport and storage function
• Protective and clearance function
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)
600-1200 ml/day
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.
enterohepatic circulation of bile
73
Mechanism of
uptake and
secretion of bile
acids by hepatocytes
ATP
74
Intestinal secretion: 1500 ml/day.
Composition:
• mucus
• electrolytes
• water
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
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)
Sites of
absorption
78
Absorption of
Small
upper
intestine
mid
lower
Sugars
Amino acids
Fatty acids
Bile salts
Water soluble vitamins
Vitamin B12
Na
K
Ca
Fe
Cl
sulfate
++
++
+++
+
+++
0
+++
+
+++
+++
+++
++
+++
+++
++
+
++
+
++
+
++
++
++
+
++
++
+
+++
0
+++
+++
+
+
+
+
0
1) secreted when
luminal [K] < 25 mM
Colon
0
0
0
0
0
0
+++
secreted 1)
?
?
+
?
79
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
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.
Standing gradient osmosis:
Int est inal lumen
Na+
1. Active
pumping
(Na/K ATPase) into lateral
intercellular space
2. passive entry of Cl- into
lateral intercellular space
3. establish osmotic gradient
in lateral space
H2 0
1
2
H2 0
Na+
Na+
Cl-
4. entry of water by osmosis
into lateral space
5. hydrostatic flow of water
H2 0
Tight
junct ion
ClPressure
Basement membrane
Capillary
81
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)
Int est inal lumen
H2 0
H2 0
Tight
junct ion
1
2
H2 0
Na+
Na+
ClClPressure
Basement membrane
Capillary
79
Digestion and absorption of
carbohydrates
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.
Digestive enzymes break down oligosaccharides
and polysaccharides into the 3 absorbable
monosaccharides
• glucose
• fructose
• galactose
Digestive enzymes for carbohydrate digestion
• luminal digestive enzymes
• brushborder enzymes
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
Brush border enzymes
digest disaccharides and oligosaccharides
Enzyme
Substrate
Site of
action
Products
• sucrase
sucrose
-1,2 glycosidic
linkage
glucose and fructose
• lactase
lactose
ß-1,4 glycos. linkage
glucose and galactose
• isomaltase
(= -dextrinase)
-limit dextrins
-1,6 glycos. linkage
glucose, maltose and
oligosaccharides
• maltase
maltose
-1,4 glycos. linkage
glucose
• glucoamylase
maltooligosaccharides -1,4 glycos. linkage
glucose
Digestion-absorption coupling
G2
G3
88
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
K+
Brush
border
GI tract
lumen
Na +
Galactose
Glucose
ATP
SGLT1
Galactose
Glucose
Na +
GLUT2
Fructose
2
GLUT5
mucosal
capillaries
Fructose
SGLT1 sodium-glucose transport protein1 for glucose and galactose
(secondary active transport)
GLUT5 transport protein rather specific for fructose (facilitated transport)
GLUT2 transport protein for glucose, fructose and galactose across
basolateral membrane (facilitated transport)
90
Digestion and absorption of
lipids
Lipids in the GI tract:
• exogenous (diet: triglycerides (90%), phospholipids,
sterols (e.g. cholesterol), sterol esters)
• endogenous (bile, desquamated intestinal epithelial
cells)
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).
91
Mechanism of lipid absorption
• The intestinal villi are coated by an unstirred water layer
which reduces the absorption of the poorly water soluble
lipids.
• 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
• 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).
• 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.
Lipid
digestion &
absorption
94
• 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
Digestion and absorption of
proteins
Proteolytic digestive enzymes
• gastric secretion (G)
• pancreatic secretion (P)
• brush border enzymes (BB)
• cytoplasmic (C)
• 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
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.
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).
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
protein
digestion &
absorption
95
Absorption of vitamins
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
• 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.