Gastrointestinal

Physiology

Dirk Weihrauch
Duff Roblin W467 http://www.genesishealth.com/services/bariatric_surgery/digestive_diagram.aspx

weihrauc@cc.umanitoba.ca
What will be covered ?

1. Function of the Gastro-Intestinal

(GI)-tract

2. Organization

3. Regulation

4. Pathophysiology
Functions of the GI System

1. Propulsion/Motility

2. Secretion

3. Digestion

4. Absorption

5. Storage and Elimination

6. Immune Barrier
 Functions of the GI System
1. Propulsion/Motility
is responsible for the movement of food
through the digestive tract by:
– Ingestion - Taking food into the
mouth
– Deglutition – Swallowing the food
– Peristalsis – Rhythmic, wavelike
contractions that move food through
the GI tract
– Mass movements – a strong
wave of contraction over a long
segment
Functions of the GI System
2. Secretion
a) Exocrine secretions (towards the gut lumen)
Water
Hydrochloric acid (HCl)
Bicarbonate (HCO3-)
Enzymes
Bile (amphipathic molecules)
Mucus
b) Endocrine secretion (towards the interstitium/blood)
Hormones that regulate the digestive system
Functions of the GI System

3. Digestion
Breakdown of food molecules into their smaller
subunits, which can be absorbed

– Mechanical
• Mastication – chewing the food and
mixing with saliva
• Segmentation

– Chemical – pH and enzymes

Functions of the GI System

4. Absorption
Uptake of nutrients + water into the
blood or lymph by the epithelium

5. Storage and Elimination

Temporary storage and subsequent
elimination of non-digestible food
molecules
Functions of the GI System

6. Immune barrier
Tight junctions between columnar epithelium cells provide
a physical barrier to the penetration of pathological
organisms and their toxins

Top view with labeled

tight junction molecules
Network of
sealing bands
 Tight Junction
• The tight junction is a highly regulated multi-protein
complex
• Contractile cytoskeletal elements
• Perijunctional Acto-myosin Ring
(PAMR) Claudins
• Cytoplasmic complex Occludin
• Zonula occludens (ZO)-1, -2, -3
• etc. etc. etc.
• Integral membrane proteins
• The claudins (1 through 5 in the gut)
• Occludin
• Junctional Adhesion Molecule (JAM1)
• The function is to limit uncontrolled passage of
molecules from the gut lumen into the body fluids
Functions of the GI System
6. Immune barrier
- Peyer’s patches (immuno-
competent lymphatic tissue in the
Ileum)  IgA release
- IgA is transported into the lumen by
transcytosis and there coupled to a
Antigen
secretory component which protects
M-cell
from digestion
- M-cells mediate transport of
antigens from the gut to Peyer’s Peyer’s
patches patch

 Macrophages, Dendritic cells, B and

T Lymphocytes  activate immune
response
Functions of the GI System
6. Immune barrier
- Mucosa contains intraepithelial
Lymphocytes (T-killer cell-like)
- Kupffer cells (Marcophages) in
the Liver
- Bacterial flora of the intestine
(colon), ~ 400 different species
(likely more) outcompete
pathogens
 The GI Tract /Accessory Organs
• Mouth/Oral cavity PG
• Pharynx M Ph

• Esophagus (passage time: 10s) T SLG SMG

Accessory Organs
• Stomach (1-3h)
• Small intestine (ca. 7m, 7-9h) – Teeth/Tongue
Gut length: carniv. = short; herbiv.= very long
– Saliva glands
– Duodenum (25-30cm)
(parotid, sublingual,
– Jejunum (1-2m)
submandibular)
– Ileum (4-5m)
– Liver
• Caecum (blind pouch, incl. – Gall bladder
appendix) – Pancreas
• Large intestine, Colon,(2m, 1d)
Ascending, Transverse Latin
Descending, Sigmoid Lingua = Tongue
Mandible = Lower jaw
• Rectum (1-5d)
Duodecim = 12
• Anus R
Tissue Layers – Mucosa
• Mucous epithelium
– Overlying a basement membrane
– Esophagus- stratified squamous
– Stomach & bowels - simple columnar
• Lamina propria
– Loose connective tissue layer
– Contains small blood
vessels, lacteals
(lympathic capillary),
immune cells
• Muscularis mucosae
– Thin muscle layer
– Separates the mucosa
and submucosa
– An anatomical landmark
 Tissue Layers – Mucosa
Muscularis mucosae

– Thin muscle layer

– Separates the mucosa
and submucosa Section of colon (large intestine)
– An anatomical landmark

Function:
- keeps the mucosal
surface and underlying
glands in a constant
state of gentle agitation
-  to expel contents of
glandular crypts and
enhance contact
between epithelium and
the contents of the gut
lumen
www.ouhsc.edu/histology/Glass%20slides/56_05.jpg
Tissue Layers – Mucosa
Tissue Layers – Submucosa
• A thick layer of connective tissue
– Glands
– Nerves
– Blood vessels

• Contains the submucosal

plexus
– The first of two nerve
networks
Tissue Layers – Submucosa
Tissue Layers – Muscularis externa
• Two layers of smooth muscle
– Inner layer = circular
• Constriction/dilation
– Outer layer = longitudinal
• Shorten/lengthen
 Tissue Layers – Muscularis externa
www.spcollege.edu/.../ileum%205%20muscularis.jpg
Tissue Layers – Muscularis externa

– The stomach has a

third layer of muscles
for churning – oblique
(located between submucosa and
circular muscle layer)
Tissue Layers – Muscularis externa

• Between the muscle layers

is the myenteric plexus
– Second nerve network
Tissue Layers – Muscularis externa
• In the upper third of the
esophagus we find smooth
and skeletal muscles 
voluntary control  helps
swallowing

From Stuart Ira Fox 2009

Tissue Layers – Muscularis externa
Sphincter

- thickened circular muscle layer that controls

the directed flux of the food/chyme
- portions the amount of chyme to be moved
to the next section of the GI-tract
- prevent unwanted reflux
- regulate controlled emptying
 Tissue Layers – Muscularis externa
Esophageal Sphincter
Upper Esophageal Sphincter
- Is under conscious control
- During swallowing the UES opens so the bolus
can pass into the esophagus.
- A secondary role of the UES is to reduce
backflow from the esophagus into the pharynx

Lower Esophageal Sphincter

(Gastroesophageal Sphincter)
- Smooth muscle; not a true sphincter
- prevents usually (not always  heartburn) the
reflux of food and gastric juice into the From Silverthorn 2009
esophagus
- in infants (<1 year) it functions
randomly/uncontrolled  “spit up after a meal”
 Tissue Layers – Muscularis externa
Pyloric Sphincter

- Portions the amount

of chyme entering the
duodenum

From Stuart Ira Fox 2009

 Tissue Layers – Muscularis externa
Ileocecal Valve (Sphincter)

- Portions the amount

of chyme coming from
the Ileum and
entering the Cecum

From Stuart Ira Fox 2009

 Tissue Layers – Muscularis externa
Ileocecal Valve (Sphincter)

- Pressure on the cecal side

pushes the valve close and
contracts the sphincter
 preventing bacteria-laden content of large
intestine from contaminating nutrient rich-small
intestine

- Valve opens in response to

pressure on the ileal side
- Valve opens also in response to
Gastrin, which is secreted by the
stomach when new food arrived

From Sherwood
 Tissue Layers – Muscularis externa
Anal Sphincter

Internal Anal Sphincter

For defecation the smooth muscle of the internal sphincter relaxes and the
peristaltic contractions in the rectum push material towards the anus

External Anal Sphincter

At the same time the external anal sphincter relaxes if wanted. The external
sphincter is under voluntary control and defecation can be controlled by conscious!

From Silverthorn 2009

 Tissue Layers – Serosa
• Serosa is a continuation of the peritoneal membrane (peritoneum)
lining the abdominal cavity
– Connective tissue & simple squamous epithelium
– Forms sheets of Mesentery that hold the intestine in place
– Carries blood vessels and nerves
Tissue Layers
Neuronal Control of GI Function
• The GI tract is controlled locally by the enteric
nervous system (ENS)
– Runs from the esophagus to the anus
– Consists of two nerve networks
• The myenteric & submucosal plexus
• The nervous networks contain:
– Sensory neurons
• Chemoreceptors (food molecules, taste)
• Mechanoreceptors (tactile stim., distention)
– Motor neurons
• Muscle contraction/relaxation
• Gland secretion
– Interneurons
• Connect sensory & motor neurons
The Submucosal Plexus
• Located within the submucosal layer
• Controls mucosal functions
– Gland secretions
– Local blood flow

Submucosa

Submucosal
plexus
The Myenteric Plexus
• Located within the muscularis externa
– Between the circular and longitudinal muscle layers
• Responsible for GI movement

• Excitatory functions
– ↑ muscle tone Myenteric
plexus
– ↑ intensity of rhythmic contractions
– ↑ rate of rhythmic contractions
– ↑ velocity of peristaltic waves
• Inhibitory functions
– ↓ sphincter muscle tone
Intrinsic Control of GI Function
• Resting membrane potential of muscle cells (Vr ≈ -50 mV)
• Slow waves at rest are triggered by “Intestinal Cells of Cajal” (ICC)
 Pacemaker cells
– Electrical slow waves (+ action potentials) spread from ICC to
smooth muscle cells
– Changes of membrane potential Vm are spreading from muscle
cell to muscle cell via “Gap junctions”

At rest only undulating and minor

changes in the membrane potential
occur as long as the threshold (ca.
-40 mV) is not reached.
 No muscle contraction
 Intrinsic Control of GI Function
- In GI tract we find single unit smooth muscles electrically connected via
Gap junctions
-The postganglionic autonomic neuron divides into branches in the smooth
muscle fibers
- Each branch has a series of swollen regions called varicosities, which
contain vesicles filled with neurotransmitter that is released when an action
potential arrives

From Pearson
Intrinsic Control of GI Function
• Depolarization (excitation) occurs by:
– Stretch, parasympathetics, acetylcholine
• Spike potentials occur when the Vm reaches
threshold (~ -40 mV)
– Caused by a large influx of Ca++ from outside the cell and the
endoplasmic reticulum
– Frequency of spikes determines
strength of the muscle contraction
• More spikes /s (Hz) = stronger
contraction
• Frequency depends on
amount of depolarization
Intrinsic Control of GI Function
• Depolarization (excitation) occurs by:
– Stretch, parasympathetics, acetylcholine

Ca2+
Opens upon activation by - Neurotransmitters from motorneurons
neurotransmitters
PMCA open voltage-gated Ca++-channels
Very low Ca2+  Ca++ influx
- Depolarization opens Ca++-channels in
Endoplasmatic reticulum
Ca2+ - Via Calmodulin and
SERCA
Myosin Light Chain Kinase (MLCK)
muscle contraction initiated
- Neurotransmitters diffuse and can
activate several muscle cells at once

From Pearson
Intrinsic Control of GI Function

• Hyperpolarization (makes cell potential more

negative) occurs due to stimulation by
Norepinephrine = Noradrenaline
 No muscle contraction
Extrinsic Control of GI Function
• Although the GI tract can function
independently, coordinated function relies upon
extrinsic influences
1. The autonomic nervous system
• Parasympathetic nervous system
– “Pro-digestion”
• Sympathetic nervous system
– “Anti-digestion”
2. Hormonal regulation
3. Cognitive and emotional control
Parasympathetic Control
• Activity of parasympathetic NS increases most GI
functions
• The proximal gut is innervated by the Vagus nerve
– Innervates the esophagus, stomach, pancreas and upper
large intestine
• Deglutition, vomiting, gastric emptying, pancreatic
secretion
• The distal gut is innervated by the pelvic nerves
– Remainder of the large intestine
– Defecation
• There is little innervation of the small
intestine
– These activities require less control
 Sympathetic Control
• Activity generally decreases most GI functions
• Preganglionic neurons from T5 to L2 go to the
autonomic ganglia
– Postganglionic neurons then go to all portions of
the GI tract
• The release of norepinephrine (noradrenaline)
T1
has major inhibitory effects on plexi neurons
T2
T3
T4
T5
– Minor inhibitory effects on intestinal
T6
T7
T8
smooth muscle
T9
T10
T11
T12
L1
L2

Spinal
cord Ganglia
Hormonal Control
• More important in the control of secretion than
motility
– Cholecystokinin (CCK)
– Secretin
– Gastrin
• We will discuss this more when we talk about
secretion…
Cognitive Control
• Cognitive emotions are able to
modulate several gastric
functions
– Anger and stress

• Direct neurological pathways

from the senses, CNS and
motor neurons end up at the
stomach
– Increased acid production
– Increased motility
– Increased blood flow
– Can cause ULCER
Ulcer
Internal Communication
• Often, one portion of the gut needs to ‘talk’ to another
• Various stimuli send signals to the rest of the gut
– Irritants, distension (food), chemicals
– The target may be proximal or distal to the site of stimulation
• Afferent neurons send axons to prevertebral ganglia
– Interganglionic neurons carry impulses on a faster track
– Postganglionic neurons bring the signal back to the GI tract
• Involved in a variety of reflexes

Interganglionic neurons
Control of the Digestive System
• Control of motility is done primarily through a
number of reflexes within the ENS
– Local control without much CNS involvement

• Gastrointestinal reflexes include:

– Gastrogastric
– Enteroenteric
– Peristaltic reflex The first half of the term is the source
– Gastroileal/Gastrocolonic
The second half is the target
– Ileogastric
– Colonoileal
– Defecation
The Gastrogastric Reflex
• The presence of food causes distention of the
stomach wall
– Baroreceptors and chemoreceptors send info to the
brain via the vagus (1)
– Activation of the parasympathetic NS
– Signals return via the vagus (2)
(vagovagal reflex)
• Stimulates stomach (3)
movements and secretion
(more later)
Gastric Movements
• The stomach has an extra layer of smooth
muscle, the oblique muscle layer
– Contraction creates a wringing movement
Gastric Movements

• Rugae allow the stomach to stretch immensely

 Empty: size of a fist, Full: 1.5 to 4 liter volume

http://becomehealthynow.com/images/organs/digestive/stomach2_lrg.jpg
 Gastric Movements
Movements:
(after activation via the vagus)

• Mixing or churning
waves
– The pyloric sphincter
remains closed while
waves of contraction
force the chyme
against it
– Production of a liquid
chyme Pyloric
sphincter
 Gastric Movements
• Peristaltic waves
– Turned on by gastrogastric reflex
– A second, stronger wave follows a mixing
wave creating high pressure
• The pyloric sphincter opens slightly
– A small amount of liquid chyme is pushed
through pyloric sphincter
• Solid chyme moves back as in a mixing
wave
• The amount released is
carefully controlled
Small Intestinal Movements
• Peristalsis
– Weak but repetitive peristaltic waves to move luminal
contents
• Usually travel 1 cm or less
– The frequency of peristaltic waves is efficient to move
luminal contents
The Peristaltic Reflex
• Transit time along the small intestine is normally
3–9 hours
• Peristalsis is controlled primarily by the myenteric
plexus
– What signals/muscle actions are required?
• Downstream segment must relax
• Upstream segment must contract
The Peristaltic Reflex
Motorneuron Contraction
Distension sensor Interneuron  Shortening of downstream segment
Activated by passing
+ + Longitudinal
bolus + muscle

Plexus
myentericus

_ _ _ _
Circular
muscle
+ Relaxation
_ _ _ + +  Dilatation

Relaxation Contraction
 Constriction of Movement
upstream segment
Small Intestinal Movements
• Segmentation – a chopping action that mixes ingested
material in the lumen  Exposure to digestive enzymes
– Minimal contribution to propulsion

From Lauralee Sherwood

Small Intestinal Movements

• Migrating Motor Complexes (MMCs) – similar to

peristalsis
– Waves are stronger and may travel the entire gut length
– A cleansing movement (e.g. pathogens, bacteria, rest of
undigested material)
– Housekeeping function
The Enteroenteric Reflex
• Distal distension of the small intestine sends a
signal to the proximal intestine
– Afferent neurons send axons to prevertebral ganglia
– Interganglionic neurons carry impulses proximally
– Postganglionic neurons bring the signal back to the
GI tract
– Inhibition of peristalsis

(–) Ouch!
 Small Intestinal Movements
• What happens when motility is disturbed?
• Accelerated motility → diarrhea
– Increased strength and frequency of the Migrating
Motor Complexes
– A protective mechanism of the host to “flush out” a
luminal pathogen
• Decreased motility → Constipation
– Constipation → distention (megacolon)
→ perforation → death 
• Can be caused by the destruction of the
ENS that regulates motility
The Ileogastric Reflex
• Distension of the distal ileum
sends a signal to the
stomach
– No room for more contents
(–)
– Gastric emptying is slowed

– Similar to the enteroenteric

reflex
Control of the Ileocecal Sphincter
• Regulates the flow of material from the ileum to
the caecum and colon
• The ileocecal sphincter is usually partially open
– Slow, but constant flow of material into the caecum
• Food in the stomach signals to start emptying
the ileum (gastroileal reflex)
– Inhibitory neurons reduce sphincter tone
• Distension of the colon signals there is no where
to go (colonoileal reflex)
– Cecal distension increases sphincter tone
The Gastrocolic Reflex
• Also called the defecation reflex
• May be initiated by gastric or duodenal distension (duodenocolic
reflex)
• Parasympathetic reflexes cause strong contractions of the rectum
1. Stimulates internal anal sphincter to relax
2. External anal sphincter is under voluntary control
– Voluntary movements assist defecation
• Mass movements are common
– >20 cm of the colon contract at once in unison
– Very common 15 minutes after breakfast = postprandial response
Gastrointestinal
Secretion
Fluid Secretion by the GI Tract
• Throughout the GI tract fluids
are secreted into the lumen
– Various functions include:
• Liquefying
• Lubricating
• Digestion
~ 8.5 L are secreted daily!
• Generally only released in
response to luminal contents
– Amount and consistency
depends on the types of food
Total: 8500
present ml/day
Water Absorption
• Obviously water is vital to survival
• Water enters the GI tract from diet
& secretions
– Remember ~8.5 L/day

• Major uptake is actually in the

small intestine
– 92% (9 L) via osmosis
• Only 6–7% (ca. 1 L) uptake in the
large intestine
– Important for feces formation
• Poor uptake = wet stool (diarrhea)
• Diarrhea can lead to severe
dehydration & death
• Too much uptake (slow movement of 8500 ml
feces) can lead to constipation
Fluid Secretion by the GI Tract

Oral Cavity
Saliva
~1.5 L of saliva is produced daily
– Three major pairs of glands
• Plus many small glands too

Functions include:
1. Moistening & Lubrication
• Contains mucin, a proteoglycan
• Acts as a lubricant
2. Antibacterial properties
• Contains lysozyme & IgA
3. Digestion
• Parotid & submandibular gland produce Salivary Amylase
– Breaks bonds between glucose molecules in amylose
• Salivary Lipase
– Digestion of fat (minor role)
Control of Salivation
• Salivation can be controlled locally or centrally
• Tactile stimulation
– Contact of the oral epithelium induces salivation
• Parasympathetic stimulation
– Increased stimulation increases salivation
– Pro-digestion
– Inhibited by the sympathetic NS
• Dry mouth when you have to do a presentation
• Cognitive stimulation
– Increases by thought, sight, smell, conditioning
(Ivan Pavlov, Medicine Nobel Prize 1904)
Ivan Pavlov, Russian Scientist
Pavlov’s dogs….
Presentation of food was
combined with a non-related
signal (bell ringing)
Dogs started to produce
saliva even without food being
presented when hearing the
bell
 Conditioning
Fluid Secretion by the GI Tract

Stomach
 Gastric Secretion
• Mucosa is a simple columnar epithelium
with deep invaginations – gastric pits
– Gastric pits are the openings to
gastric glands
• Multiple epithelial cell types
– Surface mucous cells
– Mucous neck cells (Goblet cells)
Gastric
– Parietal cells (HCl secretion, Pit
Intrinsic factor  Vit. B-12 absorpt.)
– Chief cells (Pepsinogen, Gastric
lipase)
– Endocrine cells
• Enterochromaffin-like cells Gastric
Gland
(ECL) (Histamine)
• G cells (Gastrin)
• D cells (Somatostatin)
Gastric Acid Secretion
• Gastric juice containing acid (HCl) is secreted by
parietal cells in the gastric pits
– ~2500 ml/day
• Main functions of gastric acid include:
1. Bacteriocidal role
2. Digestion of protein
• Acid hydrolysis plays a modest role
• Denaturation (unfolding of tertiary structure)
3. Digestion of bone
Gastric Acid Secretion
Too much secretion….
– Disrupting protective alkaline mucosal barrier layer
 Peptic ulcer disease (digest of mucosa, submucosa, etc. by acid
and Pepsin)
Heliobacter pylori
- Promotes Pectic Ulcers
- Occurs in 30% of population
- mobile  finds cover from
low pH in alkaline mucosal
barrier
- Contains urease 
produces NH3 and CO2 
pH buffer
- secreting toxins that causes
persistent inflammation
- disrupting tight junctions
Gastric Acid Secretion
Too much secretion….
– GastroEsophageal Reflux Disease (GERD)
Gastric Acid Secretion
• The H+/K+ -ATPase (Parietal Cells) is
responsible for the secretion of acid into the
stomach lumen
• Multiple secretagogues increase gastric
secretion
– Acetylcholine
– Gastrin (G cells)
– Histamine (Enterochromaffin-like cells)
• While anti-secretagogues decrease secretion
– Prostaglandin E2 (PGE2)
– Norepinephrine
 Gastric Acid Secretion

Stomach
Parietal Lumen
Cell

Mitochondria

Cavity
 Gastric Acid Secretion

Parietal
Cell K+ K+
H+
Carbonic ATP
CO2 + H2O Anhydrase
H+ + HCO3-
ADP + Pi
HCO3-
Cl- Cl- Cl-

Alkaline
tide
Prevention of Acid Secretion
• There are two major therapeutic targets to
decrease gastric acid secretion
1. Histamine (H2) blockers – Tagamet, Zantac, Pepcid
• H2-receptor for histamine mediates its secretagogue effects
via Adenylate cyclase (AC) and Protein Kinase
• Blocking this specific receptor decreases acid secretion
• Reversible receptor competition
2. Proton pump inhibitors – Prilosec, Prevacid
• Blocking the H+/K+ exchange pump directly is the most
effective approach
• Irreversible bind to the proton pump
Prevention of Acid Secretion

ATP
Histamine AC
K+
Protein Kinases
H+
H+
cAMP
 Other Gastric Secretions
• Protein digestion starts in the stomach
– Acid denaturation and hydolysis of peptide
bonds
Gastric
• Chief cells secrete pepsinogen Pit

– A proenzyme or zymogen

• Parietal cells also produce a

substance that is essential for Gastric
Gland
vitamin B12 uptake
– Intrinsic factor binds to vit B12 and
escorts it to the ileum for absorption
Other Gastric Secretions
• Surface goblet cells produce a very
viscous, alkaline mucus
– Protection against acid and abrasion
Gastric
• Pyloric gastric glands contain many Pit

goblet cells that produce a thin

mucus
– Lubricates food material
Gastric
Gland
• Many minor digestive enzymes
including:
– Gastric lipase
– Gastric amylase
– Gelatinase
Alkaline Tide
• Parietal cells secrete H+ across their apical membrane
– Potentially harmful to the epithelium and underlying
tissues
• Recall there is concurrent release of HCO3- across the
basolateral membrane
– This increases the pH of blood and urine by buffering
free protons

H2CO3 H+
CO2 + H2O CA H+ + HCO3-
HCO3-

H+
Control of Stomach Secretions
Cephalic phase:
• Initiated by the brain in response to thought, smell, taste
• Medulla oblongata signals the Enteric NS via the vagus
nerve
– Enteric neurons directly stimulate parietal cells
• Acid production
– Also stimulates G and ECL -
cells to produce
gastrin & histamine
• Gastrin
– Stimulates HCl & pepsinogen
secretion
• Histamine
– Stimulates acid secretion
Control of Stomach Secretions
Gastric phase:
• Triggered by the presence of food in the stomach
– Stretch (baroreceptors) & amino acids (chemoreceptors)
• Recall the Gastrogastric reflex

• Stimulates the secretion of:

– Mucus
– HCl
– Pepsinogen
– Intrinsic factor
– Gastrin
• Negative feedback when
the pH < 2
 Regulation of Gastric Secretion
1. AA (+ Vagus nerve) stimulate
Gastrin secretion (G-cells)
2. Gastrin (+ Vagus nerve)
stimulates secretion of
Histamine (ECL cells)
3. Histamine stimulates HCL
secretion by Parietal cells
4. Low pH inhibits release of
Gastrin (likely mediated by
Somatostatin (D-cells)
Control of Stomach Secretions
Intestinal phase:
• The enterogastric reflex
– Triggered by acidic chyme entering the duodenum
– Triggered by lipids in the duodenum & jejunum
• The hormone secretin is
released to inhibit parietal
& chief cell secretion
• Other hormones include:
– Gastric inhibitory peptide:
strong inhibition of gastric
secretions
– Cholecystokinin: lesser
inhibition of gastric
secretions
• Motility is also slowed
Fluid Secretion by the GI Tract

Small Intestine
Pancreas
• Mix of endocrine & exocrine tissues
• Endocrine pancreas controls blood sugar levels
– Pancreatic islets (Islets of Langerhans) produce:
• Insulin (β-cells)  uptake of sugar
• Glucagon (α-cells)  mobilization of Glucose
• Exocrine pancreas is extremely important in
digestion
– Secretions exit through the pancreatic duct
Pancreas
Pancreas
Exocrine Pancreas Secretions
• Products collectively called pancreatic juice
(~1500 ml/day)
• Aqueous component
– Increases the luminal pH from ~3 to ~7
– K+, Na+, bicarbonate ion, water
– Bicarbonate produced by the enzyme
carbonic anhydrase (CA)
CA
H2O + CO2 H2CO3
H2CO3 H+ + HCO3–
Exocrine Pancreas Secretions

ATP

Pancreatic Duct Cells

Exocrine Pancreas Secretions
• Enzyme component
– Major contribution to digestion
– Proteolytic enzymes released as zymogens and
require activation in the lumen
• Why?
– Polysaccharide digestion – Pancreatic amylase
– Lipid digestion – Pancreatic lipases
– Protein digestion – Trypsin, Chymotrypsin

– More later …
Control of Pancreatic Secretion
• Vagus nerve controls secretion of pancreatic enzymes
– Parasympathetic: release of acetylcholine increases secretion
• Mainly the enzymatic component
– Sympathetic: decreases secretion
• Cholecystokinin (CCK) stimulates enzyme secretion by
the pancreas
• Mainly the enzymatic component
– Stimulated by fatty acids & other fats in duodenum
– Also causes increased gall bladder contraction and
decreased stomach emptying
• Secretin induces a watery secretion high in bicarbonate
• Mainly the aqueous component
– Stimulated by acidic chyme in duodenum
– Decreases gastric emptying as well
 Control of Pancreatic Secretion
CCK
Secretin

Zymogens
acidic H2O, HCO3-
chyme Food

Pancreas
Peptides,
Fatty acids

Duodenum
Pancreatic Secretion

Pancreatic Zymogenes: Will become…

• Trypsinogen
• Chymotripsinogen Endopeptidases

• Precursor of Elastase
• Precursor of
Carboxypeptidase A Exopeptidases

Carboxypepdidase B
Action of Trypsin

CCK
stimulates
secretion
Chymotrypsinogen &
other zymogens
Trypsinogen

Entero-
peptidase hydrolyze
Chymotrypsin &
other enzymes
Trypsin
Pancreatic Secretion

Pancreatic Zymogenes:
• Procolipase Activated by
Trypsin
• Prophospholipase
Liver
• The liver is the site of bile production
– Production is continual - yielding ~500 ml/day
– Most is stored and concentrated (5 – 15) in the
gallbladder
• Water and electrolytes are reabsorbed in the gallbladder
• Stores about 30–60 ml
• Functions of bile include:
– Neutralization & dilution of
stomach acids
– Bile salts emulsify fats,
essential for digestion
• Important components:
– Bile salts – lipid emulsification
– Bicarb. – pH neutralization
Control of Gallbladder Emptying
• The major stimulant for gallbladder emptying is
cholecystokinin (CCK)
– Literally means: bile-bladder-movement
– Recall that fatty foods in the duodenum trigger the release of
CCK
• Weakly stimulated by
the vagus nerve and
acetylcholine release
– Parasympathetic
activation of the gut
• Secretin increases bile
production by the liver
– HCO3- rich
Control of Gallbladder Emptying
• Cholecystokinin relaxes the “Sphincter of Oddi”

Sphincter of Oddi
(hepatopancreatic ampulla)
Silva A C et al. Radiographics 2004;24:677-687
 Bile Acids

• Bile acids are made by hepatocytes of the liver by the oxidation of

cholesterol

•  Synthesis of cholesterol is very energy consuming process

• The body produces about 800 mg of cholesterol per day and about half
of that is used for bile acid synthesis.

• In total about 20-30 grams of bile acids are secreted into the intestine
daily

• Before final secretion into the hepatic canaliculi, bile acids are
conjugated with taurine or the amino acid glycine, or with a sulfate or
a glucuronide

• The term bile acid refers to the unconjugated form. Bile salt refers to
the conjugated form
 Bile Acids
Carboxyl group
Hydroxyl group

Cholic acid Taurocholic acid

Desoxycholic acid
Cholesterol Glycocholic acid
hydrophobic
Essential
component of cell Conjucated bile salts
membranes • more hydrophilic
• passive reabsorption is
reduced
Chenodesoxycholic acid
Bile Acids are recycled to the liver via the
“Enterohepatic Circulation” chiefly by
active re-absorption in the ileum

Liver
95% BA Reabsorbed

conversion to 2o BA by bacteria
10 BA
Ileum Colon
20 BA
 Bile Acid Transporters/Receptors

Bile Acid, e.g. TDC Lumen Blood

BA

Apical Sodium
dependent Bile Acid
Transporter (ASBT) BA
ASBT LBP LBP
Na+ BA BA Mrp3
Ost α/β (organic
solute transporter)
BA T-Asbt
LBP
Mrp 3

BA Ostα/β
Truncated ASBT BA
BA

Farnesyl Orphan BA
Receptor
(transcription factor)

Lipid Binding BA
Protein/ Bile Acid
Binding Protein
 ASBT
(Apical Sodium Dependent Bile Acid Transporter)

 In adults ASBT is the most important

transporter involved in intestinal bile ASBT

acid clearance.

 ASBT is located on the apical membrane

of the distal ileum.

 ASBT promotes a secondary active bile acid

absorption from the lumen into the cells in an electrogenic
mode with a sodium to bile stoichiometry of 2:1.
 LBP/BABP
(Lipid Binding Protein/Bile Acid Binding Protein)

 LBP is a 14-kDa cytoplasmatic LBP

protein expressed in ileum.

 Most important protein for

transcellular movements of
bile acids across intestinal epithelial cells.

 For bile acid uptake LBP forms a complex with ASBT

 LBP expression is regulated by the nuclear bile

acid receptor FXR.
 FXR/BAR
(Farnesoid Orphan Receptor, Bile Acid Receptor)

 FXR is a 60 kDa nuclear bile

acid receptor expressed
dominantly in ileum and liver.

 When bound to bile acids

FXR up-regulates the transcription
of LBP, BSEP (Bile Salt Excretory Pump, Liver) and
Mrp2.
 T-ASBT
(Truncated Apical Sodium Dependent Bile Acid
Transporter)

T-ASBT

 T-ASBT is a splice variant of ASBT

(missing exon 2).

 Shown to transport bile acids when expressed in

oocytes.

 Expressed in cholangiocytes, ileum and kidney.

 Localized at the basolateral membrane of cholangiocytes.

 Ost-α/β
(Organic Solute Transporter)

Ostα

 Shown to be a bile acid transporter with

strong expression in the ileum
 Bile Acid Transporters/Receptors
Lumen Blood

BA Bile Acid, e.g. TDC

BA
Apical Sodium ASBT LBP
LBP
dependent Bile Acid Na+ BA BA Mrp3
Transporter (ASBT)
BA T-Asbt
Ost α/β (organic LBP
solute transporter)

BA Ostα/β
Mrp 3 BA
BA
Truncated ASBT

Farnesyl Orphan BA
Receptor
BA
Lipid Binding
Protein/ Bile Acid
Binding Protein
 In Adults Bile Acids entering the
distal colon causing diarrhea

 Usually ca. 5% of the total bile acids are entering the distal colon

 In certain pathophysiological states, such as irritable bowel syndrome,

Crohn’s disease, and surgical ileal resection, active bile acid
absorption in the ileum is compromised.

 Under these conditions, more bile acids enter the colon, where
dihydroxy bile acids, such as chenodeoxycholic acid and
deoxycholic acid stimulate net electrolyte and fluid secretion

 Diarrhea in adults but, not in weanlings

BA Transporter and BA Transport in the GI

blog.lib.umn.edu/.../SmallIntestine.jpg www.dkimages.com/.../previews/1051/276771.JPG

Ussing Chamber

Basal bath Apical bath

Air Air

Gut tissue
BA Transporter and BA Transport in the GI

Ileum Distal colon

Bile acid uptake Little bile acid secretion

Weihrauch et al., Am J Physiol Gastrointest Liver Physiol 290:439-450, 2006.
 Gallstones

Cholesterol Bile Stones

knol.google.com/.../PyLeBQ/pigment%20stone.jpg

Pigment Stones
www.pilotfriend.com/.../medical/images2/22.jpg
Bilirubin Bile Stones
Small Intestine Histology
• Villi are finger like projections line the small
intestinal mucosa
– Contain blood vessels and lacteals
– Site of absorption
• Crypts (of Lieberkühn) are pits between the
villi
– Both are completely covered by a simple
columnar epithelium
– Site of secretion Crypts
– Regeneration Villi
of villi epithelial cells
Small Intestinal Secretion
• Often overlooked, secretion is a very important
function of the small intestine
– About 1500 ml/day
• Small intestinal secretions include both:
– A watery secretion from the crypts
– A mucoid secretion from the goblet cells on the villi
Small Intestinal Secretion
• Secretion and absorption are performed by
different populations of epithelial cells
– Immature epithelial cells secrete
– Mature epithelial cells absorb
 Small Intestinal Secretion
• Secretions from the crypts amount to ~1500 ml/day

– Watery fluid containing electrolytes

– A large number of chloride channels
pump Cl– into the lumen
• Sodium ions follow to neutralize
charge
• Water follows by osmosis

• Why do we want to secrete this

water?
– Flushing action
Small Intestinal fluid secretion
Gut lumen
Na+ Cl- H2O

CFTR

K+
K+ 2Cl- Na+

ATP

Na+
 Cystic fibrosis (Mucoviscidosis)
Inborn defect of the cyctic fibrosis transmembrane conductance regulator
(CFTR)  - reduced water secretion, greasy stool, effects fat absorption
- CFTR important in many tissues: Lung, Pancreas, Intestine
- Many die young (20-30) mostly due to lung infections

Na+ Cl- H2O

CFTR

K+ 2Cl- Na+ K+

ATP

Na
+
Small Intestinal Secretion
• Paneth cells secrete antimicrobial
molecules such as cryptdins or
defensins

• A large amount of mucus for

lubrication is produced by epithelial
goblet cells

Goblet Cells
Control of Small Intestinal Secretion
• Secretion is mainly controlled by the local
distention of the bowel
– Therefore secretion usually only occurs when food is
present

• Secretion can be increased by secretagogues

– Often in response to infection
– Cholera toxin, prostaglandins, etc. increase [cAMP] or
[Ca++]
Fluid Secretion by the GI Tract

Large Intestine
Large Intestine
• The colonic mucosa contains many crypts of Lieberkühn
but no villi
– The epithelium is dominated by goblet cells which produce loads
of mucus
– The mucus is used in part for lubrication
– Approximately 1000 ml/day of fluid

• The major role is the conversion of chyme into feces

– Mucus provides an adhesive medium to hold fecal matter
together
Control of Large Intestinal Secretion
• Similar to the small intestine, colonic secretion is
stimulated primarily by tactile stimulation & local
irritation
– Parasympathetic nervous system also increases
production
• From the pelvic nerve
– Some emotions stresses can lead to excessive
secretion and a mucoid diarrhea
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
Gastrin Enzyme secretion Pancreas
Neuronal G-cells
Stimulus Stomach Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids Via Gastrin Emptying

H+ HCO3- secretion
Histamine Enzyme secretion Pancreas
Enterochromaffin-
Neuronal like cells
Stimulus Stomach Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
Somatostatin Enzyme secretion Pancreas
D-Cells
Neuronal
Stomach
Stimulus Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
Secretin Enzyme secretion Pancreas
Neuronal S-cells
Duodenum-crypts
Stimulus Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
Motilin Enzyme secretion Pancreas
Neuronal M-cells
Stimulus Small Intestine
Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
GIP Enzyme secretion Pancreas
(gastric inhibitory
Neuronal polypeptide)
Stimulus K-cells Release of insulin Pancreas
Duodenum/
Jejunum Bile production Bile duct
Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
GLP-1 Enzyme secretion Pancreas
(Glucagon-like
Neuronal peptide-1)
Stimulus Intestinal L-cells Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
 Summary GI Hormones
Trigger Hormone Action Site of Action
Acid secretion
Distension
Motility (digestive) Stomach
Peptides, Motility (interdigestive)
Amino Acids
Emptying

H+ HCO3- secretion
CCK Enzyme secretion Pancreas
(Cholecystokinin)
Neuronal S. Intestine/Duod
Stimulus Release of insulin Pancreas

Bile production Bile duct

Glucose
Gallbladder emptying Gallbladder
Fatty Acids Motility (interdigestive) Intestine
Enhancement
Satiety Brain
Inhibition
Digestion, Absorption, & Transport
• Digestion is the breakdown of large molecules
into smaller units
– Mechanical – mastication, churning, chopping
(Segmentation)
– Chemical – pH, enzymatic

• Absorption and Transport are the movements of

molecules from digestive tract into circulation
– Occurs mostly in the small intestine
– Some small molecules (e.g. ethanol & aspirin) can
diffuse across the epithelium of the stomach

– Not all nutrients are digested, some can be absorbed

as is
Enzymatic Digestion
• Enzymatic digestion starts in the mouth and continues
through to the small intestine
• Digestive enzymes are produced and released by glands
in the proximal GI tract
– Salivary glands
– Gastric pits Saliva
– Exocrine pancreas
– Bile salts involved in lipid digestion
• The small intestine also has Gastric
enzymes attached to the Juice
epithelial brush border (e.g. Bile Pancreatic
enteropeptidases) Juice

Membrane bound enzymes

Small Intestine Ultrastructure
• Small intestine is lined with finger-like projections
– the villi
• Each is covered with epithelial cells that have
small microvilli forming the brush border
• The overall increase in surface area is ~500 fold
– About the size of a doubles tennis court!
10× 50×

Villi Microvilli
 Dietary Carbohydrates
• Carbohydrates make up 50% of the average
human diet (e.g. Bread, Potatoes, Pasta, Rice)
• Complex carbohydrates
– Polysaccharides (polymers of glucose)
• Starch (amylose or amylopectin) – plant storage molecule
• Glycogen – animal storage molecule (made by liver and muscle)
• Cellulose – indigestible plant structural material

Branched Glycogen
Linear and helical Amylose (20-25%), Cellulose (cell wall compound)
α1-4 bond, branch α1-6 bond
Branched Amylopectin (75-80%)
 Dietary Carbohydrates
• Simple carbohydrates
– Disaccharides (reducing sugars)
– Ingested disaccharides include:
• Sucrose (glucose-fructose) Sucrose
• Lactose, Milk sugar (glucose-galactose)
• Maltose (glucose-glucose)
– A breakdown product of starch

Lactose

Maltose
Dietary Carbohydrates
Monosaccharides
The only sugars that can be absorbed by the
intestine
Therefore a lot of digestion is required
The most common monosaccharides
(C6H12O6) are:
Fructose Glucose Galactose
Carbohydrate Digestion
• Oral cavity – Salivary amylase
– Hydrolyzes starch (amylose) into maltose (dimer),
maltotriose (trimer) and -dextrins
• Only 5% of starch digestion occurs in the mouth
• A further 30% is denatured by the gastric pH

Starch Maltose Maltotriose

+

-Dextrins
• Stomach – Gastric amylase
– Very minor contribution
Carbohydrate Digestion
• Duodenum – Pancreatic amylase
– Pacreatic juice contains a very powerful amylase
– Able to completely hydrolyze the starch within 30 min
• Luminal digestion
• The end result is a high concentration of maltose, maltotriose
and α-dextrins
• Duodenum – Sucrase-isomaltase and Lactase
– These enzymes are physically bound to the brush
border
• Isomaltase breaks down maltose into 2 glucose
• Sucrase breaks down sucrose into glucose + fructose
• Lactase breaks down lactose into glucose + galactose
– The final products are glucose, galactose and
fructose
• All monosaccharides
Carbohydrate Absorption
• Monosaccharides are the only
carbohydrates that can be absorbed
by the epithelium
• Have to cross two membranes before
they can enter the blood
• At the apical membrane:
– Glucose & galactose are taken up by a
cotransporter
• Sodium/glucose linked transporter 1 (SGLT1)
• Na+ and glucose/galactose are brought into
the cell together
– Fructose by facilitated diffusion
• Glucose transporter 5 (GLUT5)
 Carbohydrate Absorption
• At the basolateral membrane:
– Glucose, galactose and fructose
are all able to diffuse across the
basolateral membrane through
the same channel
• Glucose transporter 2 (GLUT2)
– The action of the Na+/K+-
ATPase energizes the SGLT1
mediated Na+ cotransport of
Glucose and Galactose
– Galactose and fructose are
converted to Glucose
– Stored as glycogen in muscles
& liver
– Excess sugars are converted to
lipids
Carbohydrate Absorption
• Why the different mechanisms?
– Normal blood [glucose] is 4–7 mM while cytoplasm [glucose] is
about 10 mM
– The gut ranges from 1 mM (between meals) to 40 mM (when food
is present)
• If transport was mediated by diffusion it would work during
a meal
5 mM 10 mM 40 mM

• But between meals, cells would be losing glucose

5 mM 10 mM 1 mM

• Blood fructose is near zero, diffusion still works between

meals
 A word on LACTOSE (Glucose-Galactose)
• Usually Lactase is found in juveniles
• Brushborder enzyme in small intestine
• After weaning (switch from mothers milk to adult diet)
expression of lactase gene is down-regulated
• Exceptions: Humans with European background

Lactose Intolerance:
• Asian and African people (90% of adults) have very little
lactase
 Abdominal bloating and cramps, flatulence, diarrhea, nausea, rumbling
stomach, and/or vomiting after Lactose consumption
Protein Digestion
Oral Cavity
– Mechanical digestion only
Mastication tears and grinds meats into smaller pieces
Protein Digestion
Stomach
– Acid hydrolysis
– Low pH denatures and acid hydrolysis chops peptides
– Chief cells secrete pepsinogen, a proenzyme
• Acid activates Pepsinogen, converting it into Pepsin
– Pepsin enzymatically breaks peptide bonds
• Active only in low pH environments (pH 2 – 3)
• Digests 10–20% of ingested proteins while they are in the
stomach
 Products of pepsin digestion are shorter polypeptides
 Protein Digestion
Duodenum – Pancreatic proteolytic enzymes
– All require activation in the lumen
Enterokinase
Trypsinogen Trypsin
Trypsin
Chymotrypsinogen Chymotrypsin
Trypsin
Proexopeptidases Exopeptidases

• Enterokinase (on brush border) activates Trypsinogen

• Trypsin activates the other proenzymes
– Trypsin and Chymotrypsin
• Cleave proteins into smaller polypeptides
NH3 COOH

NH3 COOH
NH3 COOH
NH3 COOH
Protein Digestion
• Duodenum – Pancreatic proteolytic enzymes
– Exopeptidases
• Cleave individual amino acids off the ends of polypeptides

– Unlike carbohydrate digestion, these enzymes are

non-specific
– End result is mainly dipeptides, tripeptides and
oligopeptides, and a few amino acids

NH3 COOH

NH3 COOH NH3 COOH NH3 COOH

Protein Digestion
• Duodenum – Brush border peptidases
• Embedded in the apical membrane are
peptidases
– Aminopolypeptidase and dipeptidases
• Cleave remaining oligopeptides into tripeptides, dipeptides
and amino acids

• Epithelium – Cytoplasmic peptidases

– Breakdown remaining di- and tripeptides into amino
acids
 Protein Absorption
• Amino acids, dipeptides, and tripeptides can all be
taken up by cotransporters on the apical membrane
– Several transporters for groups of amino acids
• Coupled with either Na+ (single AA) or
H+ (Di,Tripeptides)
– Dipeptides & tripeptides are further digested into
amino acids inside epithelial cells
– Transcytosis of small peptides

• Amino acids are transported out into blood by

basolateral transporters
– Rarely do dipeptides cross the basolateral membrane
Protein Absorption

K+

ATP

Na+

Portal vein
Lipids
• The vast majority of dietary lipids are
triglycerides
– Three fatty acid chains attached to a glycerol
backbone
• Saturated fats
– Single bonds only, no room for any more hydrogen
– Solid fats
• Unsaturated fats
– Monounsaturated or polyunsaturated
– Liquid oils
• Cholesterol
– An animal sterol
Lipid Digestion
• Oral cavity – Salivary Lipase
– Short lived activity contributing very little to lipid
digestion
– Important in newborns (helps pancreatic lipase)
– Cleaning action (+ prevents bacteria build-up)
– Lipase cleaves triglycerides into monoglycerides and
free fatty acids

Monoglycerides

Triglycerides

Free fatty acids

Lipid Digestion
• Stomach – Gastric Lipase
– Lipids are insoluble, churning breaks up fats into
small droplets
– GL, again only a minor contribution to digestion
• Combined ~10%
– Action only on the surface of the lipid droplets
 Lipid Digestion

• Duodenum – Bile Salts & Pancreatic Lipase

– Lipids are insoluble in water and must be emulsified with
mixing & bile salts

• Forms tiny droplets or micelles of lipids surrounded

by bile salts

• Further increases surface area for enzymatic

degradation  50 times greater surface/volume ratio
 Lipid Digestion
- Lipase cleaves triglycerides into monoglycerides and free fatty acids
- Problem: Bile salts block access to of lipase
- Pancreatic Colipase displaces some BS and mediates access

Pancreatic
Bile salts lipase
COO-

Pancreatic
Hydrophobic OH
Colipase
side
Lipase
OH digestion

OH Hydophilic side
20-50 nm

Bile salt Micelle Fatty acids

Disk-shaped Monoglycerides
 Lipid Absorption
• Micelles fuse with the epithelial Cholesterol

cell membrane
– Monoglycerides and fatty acids
diffuse in to the cell
– Cholesterol is transported by
transporter
– Contents appear in the smooth ER
where triglycerides are
reassembled
 Lipid Absorption
Apolipoproteins are synthesized in Cholesterol

the rough ER and mix with the

triglycerides in the Golgi to form
Chylomicrons

– Triglycerides, cholesterol and

proteins
– Soluble complexes used to move
lipids  Phospholipids,
Apolipoproteins: Amphipathic!

Chylomicron
Lipid Absorption
• Chylomicrons are then shipped to
and across the basolateral
membrane
• Chylomicrons enter the lacteals
– The lymph chylomicrons eventually
enter blood through the thoracic ducts

• At the adipose tissues:

– Triglycerides broken down
again and enter the cell
– Reassembled into triglycerides
inside adipose cell
– Empty chylomicrons are
recycled in liver
Water Absorption
• Obviously water is vital to survival
• Water enters the GI tract from diet
& secretions
– Remember ~8.5 L/day

• Major uptake is actually in the

small intestine
– 92% (9 L) via osmosis
• Only 6–7% (ca. 1 L) uptake in the
large intestine
– Important for feces formation
• Poor uptake = wet stool (diarrhea)
• Diarrhea can lead to severe
dehydration & death
• Too much uptake (slow movement of 8500 ml
feces) can lead to constipation
Most troubles with our GI system
is home-made!!!!

TOILETS OF THE
WORLD
Cholera
• Caused by the bacterium Vibrio cholerae
• Transmitted by ingestion contaminated food/water
• Causes an extreme diarrhea leading to dehydration and
death!
• Causes severe gastroenteritis in children
– Often fed powdered milk in contaminated water
– Production of a toxin leads to the pathology
Cholera
• World-wide distribution
• Multiple endemics and spreads rapidly
Cholera Toxin
• The bacterium releases a 2 subunit toxin,
cholera toxin
– Each subunit had a specific role in pathogenesis
1. The B subunit binds to ligands on the
enterocyte membrane with high affinity
2. The bound A subunit is released towards the
membrane
Subunit A
Binding presented
Cholera
A
A
toxin

Cell
plasma membrane

Latent
G-proteins
Adenylate Cyclase
Cholera Toxin
3. The A subunit enters the cell membrane
4. Splits into 2 smaller subunits A1 and A2
5. These subunits work together to:
a. Shut off GTPase
b. Turn on adenylate cyclase
6. cAMP is a potent Cl– secretagogue
Entry of Dissociation of
subunit A A1 and A2

A2

A1

ATP cAMP
AC
Effects of Cholera Toxin
• So cholera toxin increases Chloride secretion, so what?
• The enterocyte loses Cl– to the lumen
– To maintain electrochemical gradient, Na+ follows
– To maintain tonic balance, water follows both Cl– and
Na+
Small Intestinal fluid secretion
Gut lumen
Na+ Cl- H2O

CFTR

K+
K+ 2Cl- Na+

ATP

Na+
cAMP enhances fluid secretion by
activating the Na/K-ATPase
Gut lumen
Na+ Cl-
CFTR

cAMP

K+
K+ 2Cl- Na+

ATP

Na+
H2O
Effects of Cholera Toxin
• Excess loss of chloride translates into a massive loss of
water into the gut lumen
• When secretion surpasses re-absorption

→ Hypersecretory diarrhea
– Frequent diarrhea (15-20 min apart)
– Up to 1 liter per hour!
Treatment of Cholera
• Since re-absorption of water is
not affected
– Oral Rehydration Therapy (ORT)

– Making sure that intake > output!

– This is only effective as

absorption remains unaltered
Cholera and Cystic Fibrosis
• CF is caused by a nonfunctional chloride
channel (CFTR, Cystic fibrosis transmembrane
conductance regulator )
– Very little Cl– secretion in the lungs (and other organs)
– Means very little water secretion
– Leading to a thick dense mucus

• Just as sickle-cell anemia has persisted in

malaria endemic areas, CF offers some
protection against the cholera toxin
Diarrhea
• Diarrhea is not a simple disease with a simple
explanation
• Multiple possible causes which may not be
mutually exclusive
– Maldigestion & malabsorption

– Hypersecretion

– Hypermotility
Giardia spp. (flagellated protozoan parasite)
• Ranked #8 on the top 10 human parasites world-wide!
– World-wide prevalence ~8%
• Up to 100% in some areas
• The most common intestinal parasite
• Most common waterborne disease in North America
• G. lamblia (= G. intestinales)
infects humans and other
mammals
• Transmitted by the fecal-oral
route or contaminated food/water
– Zoonosis (transfer form other
mammals is possible– Disease
common name “Beaver fever”

Giardia lamblia
Giardiasis Profile
• Asymptomatic
– Most common where the infection passes without any
noticeable affects
• Symptomatic-Acute
– A self-limiting diarrhea with abdominal cramps, fever,
nausea, and weight loss
• Symptomatic-Chronic
– All of the above plus malabsorption, food allergies
develop
Giardia Disrupts the Cytoskeleton
• Giardia causes reorganization
of cytoskeletal actin and tight
junctional Zonula Occludens-1
– What does this mean?
– Tight junctional barrier dysfunction
may be predisposing to intestinal
inflammation

Actin ZO-1
Giardia Causes Barrier Dysfunction
• This reorganization of cytoskeletal and tight
junctional proteins is associated with an
increase in paracellular permeability
– Allowing for antigens to cross the epithelium
• Barrier dysfunction is caused by parasite-
dependent activation of myosin light chain
kinase (MLCK)
• Importantly, barrier dysfunction may be
predisposing for immune activation in the gut
Pathophysiology of Giardiasis
Causes diffuse microvillus shortening
– Some infections lead to villus atrophy as well
– Pathology occurs shortly AFTER barrier dysfunction

Control Infected

 Decreased digestion of proteins, carbohydrates & fats

– Digestive enzymes are attached to the epithelium
 Reduced absorption of electrolytes, glucose & water
Pathophysiology of Giardiasis
• Microvillous brush border injury
– Mostly diffuse shortening across the entire
intestinal surface
– May be accompanied by local
areas of complete microvillus
ablation in areas
– A 60% loss of intestinal surface
area
• Ultimately leading to a
maldigestive and
malabsorptive diarrhea
– Crypt hyperplasia may also be
present causing hypersecretion
 Amoebiasis

Trophozoit
 Amoebiasis

• After Malaria, Chagas disease and

Leishmaniose, fourth most fatal protozoan
caused disease
• 100,000 cases of death/year
• 500,000,000 new infections/year
Geographical Distribution
The Organism

• Facultative pathogen, since also infections with

asymptomatic course of disease are known
• Two species are known
– Morphologically and genetically very similar:
Entamoeba dispar:
- Relatively harmless, causes diarrhea
Entamoeba histolytica:
- Amoebiasis and abscesses of liver

Problems with diagnose!

Infection Cysts of
Entamoeba histolytica
• In regions with low sanitary
standards a very high risk of
fecal-oral infection:
• Drinking water and food (e.g.
salad, fruits and vegetables are
washed with infected water)
• Direct contact with feces
• Sometimes brought from a
vacation.
 Life cycle Entamoeba histolytica
Intestinal Form
of disease

Excystation (small intestine)

1 trophozoite with 4 nuclei emerges,
and produces in the end 8
trophozoites from each cyst

Entamoeba histolytica life cycle-en.svg

 Life cycle Entamoeba histolytica

Invasive Form of
disease:
Trophozoites
breaking through the
intestinal wall and Invasive infection
enter the blood through bloodstream,
stream infecting liver, brain,
lungs

 Severe state of
disease, death
 Dead end road for
parasite !

Entamoeba histolytica life cycle-en.svg

 Tools of Invasion

1. Amoeba secretagogues causes a massive (> 300 %)

activation of goblet cell mucus secretion  exhaustion
2. Invasion is a contact-dependent process with 3
molecules important to cross the intestinal wall:

Lectins  adhesion to mucus

- Adhesion to glycoproteins in target cells
Amoebapores  pore forming molecules
- Influx of ions and water  Lysis

Proteases  degradation of tissue

collagen, laminin, glycoproteines, fibronectin,
hemoglobinase  hemoglobin
 Treatment and Prevention
Treatment:
• Tissue active: Metronidazol (active agent)

• Lumen active: Diphetarson (active agent)

Prophylaxe (most important!):

• Proper sanitation
• Sterilization of water (e.g. boiling)