GI physiology review
Function of the GI system
4 basic digestive processes
• MOTILITY
• SECRETION
• DIGESTION
• ABSORPTION
(modified from McPhee, Lingappa, Ganong & Lange, Pathophysiology of Disease, 1997, 2nd ed.
Upper esophagealsphincter
Lower esophageal sphincter
3
Delay of 3 seconds
(modified from McPhee, Lingappa, Ganong & Lange, Pathophysiology of Disease, 1997, 2nd ed.
Upper esophagealsphincter
Lower esophageal sphincter
Sphincters
3
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 layerouter longitudinal layer
• myenteric nerve plexus (Auerbach’s plexus)
Serosa (adventitia)
4
Epithelium
Lamina propria
Muscularis mucosaeSubmucosa
Circular muscleLongitudinal muscle
Muscularis externa
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa
Autonomoussmooth musclefunction
Neural regulationextrinsic NS (CNS)
intrinsic NS
GI hormones
Paracrinemediators
humoral regulation
pacemaker activityelectrical coupling
Regulation of GI function
5
Autonomous smooth muscle function
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.
3
Epithelium
Lamina propria
Muscularis mucosaeSubmucosa
Circular muscleLongitudinal muscle
Muscularis externa
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa
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
Thin layer of interstitial cells (interstitial cells of Cajal) between circular and longitudinal cell layer. Conduction through gap junctions.
3
Epithelium
Lamina propria
Muscularis mucosaeSubmucosa
Circular muscleLongitudinal muscle
Muscularis externa
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus
Gland in submucosa
Pacemaker activity:
GI smooth muscle electrophysiology and contraction
Resting membrane potential-40 to -80 mV. membrane potential oscillationsNa+/K+-ATPase.
Slow wavesPacemaker activityIonic events during slow waves: Na-, Ca- andK-currents Modulation by enteric neurons
Action potentialswhen slow-waves reach electrical threshold:burst of APs (10-20 ms, rising phase is carried by Na+ and Ca2+ ions)
6
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.
Neuralregulation
somatic
autonomic sympathetic parasympathetic
enteric NS
extrinsic NS
intrinsic NS
7
1
Cholinergic synapses
nicotinic (blocked by curare)
muscarinic (blocked by atropine)
122
1
(modified from B & L)
Neurotransmitters of the autonomic nervous system
2
10
sym
path
etic
para
sym
path
etic
Integration of sympathetic, parasympathetic and enteric nervous system
Effector system of GI innervation:
(modified from B&L)
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 plexusPredominantly cholinergic fibers that terminate on ganglion cells of intramural plexuses.
• Stimulation of motor (smooth muscle cells) and secretory activity.
Enteric nervous system
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)
11
Afferent Efferent
sensory neurons from enteric NS (local afferents)
afferent sympathetic nerve fibers afferent parasympathetic nerve fibers
2
1
en
te
ri
c
ne
rv
ou
s
sy
st
em
CN
S
mechanoreceptors chemoreceptors thermoreceptors
nociceptors
1
2
Integration of neuronal control of GI function
13
Example of enteric reflex: The neural circuit for peristaltic propulsion of GI (the”law of intestine”).
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
14
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 hormonesare 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
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 HCO3- S
Gallbladder contraction S
Gastric emptying I
Mucosal growth S
Pancreatic growth S S
S = stimulates; I = inhibits
Additional GI hormonesHormones 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
increases intestinal motility
increases intestinal motility
neurotransmitter for intestinal smooth musclestimulates secretion of water and ions
decreases intestinal motilityincreases blood flow to ileum
16
Additional GI hormones (cont.)
GlucagonEntero-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 HClincreases epithelial growth
increases secretion of HCl
Gastrointestinal paracrine mediatorsParacrine agonists released by:
- paracrine cells
- GI immune system
- antibodies
- inflammaory mediators (prostaglandins, leukotrienes, cytokines, histamine, others)
3
4
Epithelium
Lamina propria
Muscularis mucosaeSubmucosa
Circular muscleLongitudinal muscle
Villus
Lymph node
Serosa
Myenteric plexus
Submucosal plexus Gland in
submucosaMuscularis externa
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: insulinglucagonsomatostatin
produced and secreted (endocrine pancreatic secretion) by the islets of Langerhans
essential for the regulation of metabolism
Autonomoussmooth musclefunction
Neural regulationextrinsic NS (CNS)
intrinsic NS
GI hormones
Paracrinemediators
humoral regulation
pacemaker activityelectrical coupling
Regulation of GI function
> high degree of integration> high degree of autonomy 5
Example: acid secretion by gastric parietal cell....
enterochromaffin-like cells (ECL cells)
G-
ce
l lsc
ho
li n
er
gi c
ne
rv
e
te
rm
in
al s
++
(modified from B&L)
+ gastric motilityenhances mixing of food and disgestive juices
71
cholinergic nerve terminals
G-cells
H+
muscular contractions that mix and move the contents of the gastro-intestinal tract to the appropriate sites of digestion and absorption
MOTILITY
Patterns of GI motilityType of contraction Organ/structure
• Tonic contractions upper and lower esophageal sphincters
pyloric valvesphincter of Oddiileocecal valveinternal anal sphincter
• Propulsive peristalsis esophagus
lower 2 thirds of stomachsmall intestinerectum
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 myoelectriccomplex 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).
Neuronal controlof esophagus
Pharynx
UES
Swallowingcenter
18
Innervationafferent: 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
3
1
2
1
2
3
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).
32
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
l
s
U
P
Esophageal pressure profile
32
Intraluminal esophageal pressure profile
0 mm Hg = ambient pressure
Pressure in the body of esophagus is negative, reflecting intrathoracic pressure
pressure wave during swallowing
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
Fundus
Stomach smooth muscle electrical activity
35
Reservoir
Sphincter
Mixing + Transport
• 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
gastricduodenum/jejunumfactors outside GI system
Pyloric valve
- regulates emptying of gastric content
- prevents regurgitation of duodenal content
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.
37
• 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.
ligament of Treitz:duodenum-jejunum border
43
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
exocrine glands secrete digestive juices, consisting of waterelectrolytes specific organic constituents important for
digestive process (enzymes, bile salts, mucus)
endocrine glands: hormones for regulation of the GI system
SECRETION
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 couplingsecretion 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
• intracellular messengers: • cAMP• IP3 and Ca2+
• activation of kinases -->altered ion channel function -->secretion
VIP
Secretin
Histamine
Norepi
ACh
Gastrin
Substance P
CCK
IP3
Ca2+
cAMP
ATP
ATP
Secretionproducts
Fluid
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 glandsgoblet cellsBrunners glandneck cells of gastric glandspancreatic 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 regionoxyntic glandular regionpyloric glandular region......
.........with a variety of secretory cells
35
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
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:
• 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
PlasmaGastric juice
CO2 + H
20
carbonic anhydrase
(modified from B&L)
Cellular mechanism of HCl production
• 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.
67
omeprazole
-
enterochromaffin- like cells
(ECL cells) ++
(modified f rom B&L)
cholinergic nerve terminals G-cells
Regulation of acid secretion
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 againstself-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
• 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
Enzyme activation
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
recycle Cl- back into lumen
• Acid tide: net H+ release
into the blood stream during
pancreatic secretion.72
Carbonic anhydrase
Bile secretionand
liver function
Structure of the liver
96
bloodflow
bileflow
96
PS = portal space withportal veinhepatic arterybile canaliculuslyphatic vessel
CV= central vein
96
liver lobule
portal lobule(defined by bile flow)
hepatic acinus(defined by blood flow)
96
HV = hepatic venule
Hepatic acinus
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
74
Mechanism of uptake and secretion of bile acids by hepatocytes
ATP
Intestinal secretion: 1500 ml/day.
Composition:
• mucus
• electrolytes
• water
degradation of structurally complex foodstuffs by digestive enzymes
3 categories of energy-rich foodstuffs: carbohydrates, proteins and lipids
DIGESTION
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
ABSORPTION
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 Smallupper
intestinemid lower
Colon
SugarsAmino acidsFatty acidsBile saltsWater soluble vitaminsVitamin B12
NaKCaFeClsulfate
1) secreted whenluminal [K] < 25 mM
+++++++++++0+++++++++++++++
++++++++++++++++++++++
++++++++0++++++++++0
000000+++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.
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
H20 Na+
Cl-
Pressure
Intestinal lumen
Cl-Na+
Tightjunction
H20H20
Capillary
Basement membrane
1 2
Standing gradient osmosis:
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)
H20 Na+
Cl-
Pressure
Intestinal lumen
Cl-Na+
Tightjunction
H20H20
Capillary
Basement membrane
1 2
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
Enzyme Substrate Site ofaction
Products
• sucrase
• lactase
• isomaltase (= -dextrinase)
• maltase
• glucoamylase
sucrose
lactose
-limit dextrins
maltose
maltooligosaccharides
-1,2 glycosidic linkage
ß-1,4 glycos. linkage
-1,6 glycos. linkage
-1,4 glycos. linkage
-1,4 glycos. linkage
glucose and fructose
glucose and galactose
glucose, maltose andoligosaccharides
glucose
glucose
Brush border enzymes
digest disaccharides and oligosaccharides
Digestion-absorption coupling
88
G2
G3
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: GLUT5absorption by facilitated (carrier mediated), Na-independent mechanism
90
ATPNa+
Galactose Glucose
Fructose
Brush border
K+
2GLUT5
mucosal capillaries
GI tract lumen
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)
Galactose Glucose
Na+
Fructose
GLUT2
SGLT1
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).
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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.
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• 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.
Lipiddigestion & absorption
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• 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.
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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
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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.