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.