GI physiology review

Function of the GI system

4 basic digestive processes

• MOTILITY

• SECRETION

• DIGESTION

• ABSORPTION
 Up p e r e s o p h a g e a l
s p h in c t e r

Delay of
3 seconds

Lo we r e s o p ha g e a l s p h in c t e r

3
 Sphincters
Up p e r e s o p h a g e a l
s p h in c t e r

Lo we r e s o p ha g e a l s p h in c t e r

3
 Mucosa
• epithelium
• lamina propria:
• muscularis mucosae
Lymph node • exocrine cells
4 • endocrine/paracrine cells

Villus Submucosa
Epithelium • connective tissue,
Lamina propria
blood vessels, glands
Muscularis mucosae
Submucosa • submucosal nerve plexus
Circular muscle
Longitudinal (Meissner’s plexus)
Serosa muscle

Myenteric
plexus Muscularis externa
Submucosal
plexus
Gland in
• smooth muscle cell layer
Muscularis externa
submucosa
inner circular layer
outer longitudinal layer
• myenteric nerve plexus
(Auerbach’s plexus)

Serosa (adventitia)
 Regulation of GI function

Autonomous Neural regulation

smooth muscle extrinsic NS (CNS)
function
pacemaker activity intrinsic NS
electrical coupling

GI hormones
Paracrine
mediators
humoral regulation

5
Autonomous smooth muscle function
Lymph node
3
Intestinal smooth muscle cells: Villus

effector organ of GI motility Epithelium

Lamina propria
Muscularis mucosae
Submucosa
Circular muscle
Longitudinal
Serosa muscle

Myenteric
plexus
Submucosal
plexus
Gland in Muscularis externa
submucosa

Pacemaker activity:
Thin layer of interstitial cells (interstitial cells of Cajal) between
circular and longitudinal cell layer. Conduction through gap
junctions.
 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
3
Thin layer of interstitial cells
(interstitial cells of Cajal)
Villus
between circular and
Epithelium
longitudinal cell layer. Lamina propria
Conduction through gap Muscularis mucosae
Submucosa
junctions. Circular muscle
Longitudinal
Serosa muscle

Myenteric
plexus
Submucosal
plexus
Gland in Muscularis externa
submucosa
GI smooth muscle electrophysiology and contraction
6

Resting membrane potential Action potentials

-40 to -80 mV. when slow-waves reach electrical threshold:
membrane potential oscillations burst of APs
Na+/K+-ATPase. (10-20 ms, rising phase is carried by Na + and Ca2+ ions)

Slow waves
Pacemaker activity
Ionic events during slow waves: Na-, Ca- and
K-currents
Modulation by enteric neurons
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
s o m a t ic

Neural
regulation
a ut o no m ic s ym p a t he t ic
p a ra s ym p a t he t ic

intrinsic NS e nt e ric NS

7
sympathetic Neurotransmitters of the autonomic nervous system

Choline rg ic s yna ps e s

1 nic ot inic
( b lo c ke d b y c ura re )
parasympathetic

1
2
2 2 m us c a rinic
( b lo c ke d b y a t ropine )

10
( m o difie d fro m B & L)
Integration of sympathetic, parasympathetic and
enteric nervous system

Effe c t o r s ys t e m
o f GI inne rva t io n:

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 10 8 neurons!) 2 major plexuses

• myenteric plexus (Auerbach’s plexus)

• submucosal plexus (Meissner’s plexus)
Integration of neuronal control of GI function

S
N
C
2

m
e
t
s
y
s
s
u
o
v
r
m e c h a n o re c e p t o rs

e
c h e m o re c e p t o rs

n
t h e rm o re c e p t o rs

c
i
no c ic e p t o rs

r
e
t
n
e
Affe re nt Effe re nt

s e ns o ry ne uro ns fro m e n t e ric NS

1
( lo ca l a ffe re n t s )

a ffe re n t s ym p a t he t ic ne rve fib e rs

2
a ffe re n t p a ra s ym p a t h e t ic n e rve fib e rs 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).
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 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 neurotransmitter for intestinal smooth

(VIP) muscle
stimulates secretion of water and ions

Neurotensin decreases intestinal motility

increases blood flow to ileum
16
Additional GI hormones (cont.)
Glucagon stimulate hepatic glycogenolysis
Entero-glucagon

Glicentin stimulates hepatic glycogenolysis

(glucagon-like substance)

Somatostatin local inhibition of other endocrine cells

(e.g. G-cells)

Urogastrone inhibits secretion of HCl

(Epidermal Growth Factor) 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 Epithelium

Lamina propria

(prostaglandins, leukotrienes, Muscularis mucosae

Submucosa
cytokines, histamine, others) Circular muscle
Longitudinal
Serosa muscle
Myenteric
plexus
Submucosal
plexus Gland in
Muscularis
submucosa
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 Neural regulation

smooth muscle extrinsic NS (CNS)
function
pacemaker activity intrinsic NS
electrical coupling

GI hormones
Paracrine
mediators
humoral regulation

> high degree of integration

> high degree of autonomy 5
Example: acid secretion by gastric parietal cell....
e nt e ro c hro m affin-like
+ ce lls ( ECL ce lls ) +

cholinergic
nerve terminals r
g
i c

i
n
a
l s

G-cells
e G
i n m -
c
l r
o e e
h t l l
c s
e
v
r
e
n

+ gastric motility
enhances mixing of food
and disgestive juices
H+ 71
 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 Organ/structure

• Tonic
contractions upper and lower esophageal
sphincters
pyloric valve
sphincter of Oddi
ileocecal valve
internal anal sphincter

• Propulsive
peristalsis esophagus
lower 2 thirds of stomach
small intestine
rectum
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 2
3
efferent:
1 • vagal somatic motor neurons
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

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 = 58
paracrine agonist for gastric HCl
secretion).
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 VIP

bind to surface membrane Secretin

ATP
receptors and stimulate Histamine
secretion cAMP


ATP
Norepi Secretion

• intracellular messengers: 
products

• cAMP ACh
Ca 2+ Fluid

• IP3 and Ca2+ IP 3

Gastrin

CCK
• activation of kinases -->
altered ion channel Substance P

function --> 60
secretion
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)
61
ducts
• excretory (interlobular)
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 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: 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
c a rb o n ic a n hy d ra s e

omeprazole

67

• Carbonic anhydrase drives HCO3- production

• H+/K+ pump (ATP-dependent) drives H+ out and Cl- follows
( mo difie d fro m B&L)

(via electrogenic anion channel)

• HCO3-/Cl- exchange maintains Cl- supply
• Alkaline tide: net HCO3- release into the blood stream during
gastric acid secretion.
 Regulation of acid secretion
e n t e ro c hr om a ff in -
like c e lls
+ ( ECL c e lls ) +

c h oline rg ic
ne rve t e r m ina ls G- c e lls

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
Carbonic
• electrogenic Cl channels
- 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 intestine Colon
upper mid lower
Sugars ++ +++ ++ 0
Amino acids ++ +++ ++ 0
Fatty acids +++ ++ + 0
Bile salts + + +++ 0
Water soluble vitamins +++ ++ 0 0
Vitamin B12 0 + +++ 0
Na +++ ++ +++ +++
K + + + secreted 1)
Ca +++ ++ + ?
Fe +++ ++ + ?
Cl +++ ++ + +
sulfate ++ + 0 ?

1) secreted when
luminal [K] < 25 mM
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:
In t e s t ina l lum e n
1. Active Na pumping
+
H2 0 H2 0
(Na/K ATPase) into lateral Tigh t
ju n c t ion
intercellular space
2. passive entry of Cl- into
lateral intercellular space
1 2
3. establish osmotic gradient
in lateral space H2 0 Na +
Na +
Cl-
4. entry of water by osmosis
Cl-
into lateral space
5. hydrostatic flow of water Pre s s ure

Ba s e m e n t m e m b ra ne
Ca pilla ry

81
Tight junctions:
transcellular vs. paracellular
transport

In t e s t ina l lum e n

Tight junctions connect epithelial H2 0 Tigh t

H2 0

cells of the GI tract. Tight junctions

ju n c t ion

are leaky (the most in the

duodenum) for water and ions. 1 2

Transmucosal transport of water and Na +

H2 0 Na +

ions can occur through tight Cl-

Cl-
junctions and lateral intercellular
Pre s s ure

space (paracellular transport = 2)

or through epithelial cells Ba s e m e n t m e m b ra ne
Ca pilla ry

(transcellular transport = 1)
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 Products

action
• sucrase sucrose -1,2 glycosidic glucose and fructose
linkage
• lactase lactose ß-1,4 glycos. linkage glucose and galactose
• isomaltase -limit dextrins -1,6 glycos. linkage glucose, maltose and
(= -dextrinase) 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 ATP
Glucose
SGLT1
Galactose
Na+ Glucose
GLUT2 mucosal
capillaries

Fructose 2
GLUT5 Fructose

SGLT1 sodium-glucose transport

protein1
for glucose and galactose
(secondary active transport)
GLUT5transport protein rather specific for fructose (facilitated transport)
GLUT2transport 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.