Unit 06b Regulation of GI Function

regulation of GI function
long versus short reflexes, feedforward
parallels between enteric and central nervous systems
gut hormones historical
cephalic phase
mouth, swallowing
transition into stomach
gastric phase
secretions of gastric mucosa
integration of cephalic and gastric phases
mucus-bicarb barrier peptic ulcers
intestinal phase
integration of gastric and intestinal phases
secretions into intestine activation of pancreatic
enzymes
absorption in small intestine
large intestine
anatomy
roles
diarrhea

Regulation of GI Function
long reflexes, integrated in CNS
sensory info from GI tract to CNS
feedforward reflexes that originate outside GI tract
include cephalic reflexes in response to sight, smell, thought
of food, effects of emotion
efferent limb always autonomic
parasympathetic excitatory
sympathetic generally inhibitory
short reflexes, integrated within gut, in enteric nervous system
neurons in submucosal plexus receive signals from lumen,
regulate secretion
neurons in myenteric plexus regulate motility
reflexes involving gut peptides
can act locally (paracrine) or travel via blood (endocrine)
effects on motility altered peristalsis, gastric emptying, et al.
effects on both exocrine and endocrine secretion
some gut peptides also act on brain (some even produced there!)
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Integrated Control of GI Function

Cephalic phase
of digestion
(feedforward)
(sight, smell, etc.)

KEY
Stimulus
Sensor

Target
Tissue response

Integrating Short reflexes

centre
Output Long reflexes
signal

Sensory
receptors
Brain
Sympathetic and
parasympathetic
neurons

Local stimuli:

Changes in motility
Neurons ofSmooth muscles
Sensory
Distension
myenteric or endocrine Release of bile and
Interreceptors
Presence of food
and
cells of stomach, pancreatic secretions
neurons
and
Osmolarity
submucosal pancreas, Enzyme, acid, and
neurons
Acid
bicarb synthesis/release
plexuses
intestine
Enteric nervous system
Secretory
cells of the
stomach and
small
intestine

Fig 21.11 ber slide

GI peptides

Brain
Endocrine
pancreas

Hunger
/satiety
Insulin
Glucagon

Small Intestine; Microanatomy

Villi
Crypt
Peyers patch
Mucosa
Muscularis mucosae
Submucosa
Circular muscle
Muscularis
externa
Longitudinal muscle
Serosa

Lymph vessel
Submucosal
plexus
Myenteric
plexus

Submucosal
artery and vein

Fig 21.3

Parallels between Enteric and Central Nervous

Systems
has intrinsic neurons that lie entirely within gut
(similar to interneurons of CNS)
autonomic neurons that bring signals from CNS
to gut are extrinsic neurons

releases more than 30 different neurotransmitters

and neuromodulators
not norepinephrine / epinephrine / acetylcholine
but otherwise similar to molecules used in CNS
has glial support cells
CNS)

(similar to astrocytes of

diffusion barrier capillaries surrounding ganglia

are not very permeable
(similar to bloodbrain barrier)

Integrated Control of GI Function

Cephalic phase
of digestion
(feedforward)
(sight, smell, etc.)

KEY
Stimulus
Sensor

Target
Tissue response

Integrating Short reflexes

centre
Output Long reflexes
signal

Sensory
receptors
Brain
Sympathetic and
parasympathetic
neurons

Local stimuli:

Changes in motility
Neurons ofSmooth muscles
Sensory
Distention
myenteric or endocrine Release of bile and
Interreceptors
Presence of food
and
cells of stomach, pancreatic secretions
neurons
and
Osmolarity
submucosal pancreas, Enzyme, acid, and
neurons
Acid
bicarb synthesis/release
plexuses
intestine
Enteric nervous system
Secretory
cells of the
stomach and
small
intestine

Fig 21.11 ber slide

Gut
peptides

Brain

Endocrine
pancreas

Hunger
/satiety
Insulin
Glucagon

Beginnings of Endocrinology
Pavlov
stomach

acid chyme passing into

duodenum pancreatic juice
secreted
mechanism?
vagal afferents from duodenum
to brain vagal efferents from
brain to pancreas pancreatic
juice secreted into duodenum

duodenum

pancreas
pancreas secretion was thought
to be controlled only by vagus
nerve

Beginnings of Endocrinology
Bayliss and Starling

stomach

carefully dissected away all

nerves surrounding pancreas and
duodenum
put acid in the duodenum
pancreas still secreted

duodenum

hypothesis:
acid caused release of signal
from duodenum into blood
pancreas

tested hypothesis:

collected lining of duodenum

added acid to it
injected it intravenously
pancreatic secretion

tor from intestine that stimulated pancreatic secretion called secre

neral term coined for blood-borne regulators: HORMONES 8

Families of Gut Hormones

gastrin family - includes gastrin, CCK, et al.
major targets are stomach (gastrin), intestine and accessory organs
(CCK)

secretin family
secretin, vasoactive intestinal peptide (VIP), gastric inhibitory peptide
(GIP), glucagon-like peptide-1 (GLP-1)
both endocrine and exocrine targets

motilin
acts on gut smooth muscle
regulates migrating motor complexes

content in Table 21.1 will be referred to as needed

Overview of GI Function

KEY
M: motility
S: secretion
D: digestion
A: absorption
upper
esophageal
sphincter
lower
esophageal
sphincter

pylorus

ileocecal
valve
rectum
anal
sphincters

Fig 21.12

Oral Cavity and Esophagus

swallowing,
chewing
M
saliva
S (salivary glands)
carbohydrates,
fats (minimal)
D
Anone
Stomach
mixingMand propulsion (peristalsis)
S pepsinogen and gastric lipase,
HCl,
mucus and HCO3, gastrin, histamine
proteins,
fats
D
lipid-soluble
A substances such as alcohol and aspirin
Small Intestine
mixingMand propulsion mostly by segmentation
S
enzymes,
HCO3 and enzymes, bile, mucus,
hormones: CCK, secretin, GIP, et al.
carbohydrates,
fats, polypeptides, nucleic acids
D
A
peptides,
amino acids, glucose, fructose
fats, water, ions, minerals, vitamins
Large Intestine
segmental
M mixing; mass movement for propulsion
S mucus
noneD (except by bacteria)
A
ions, water,
minerals, vitamins, small organic
molecules produced by bacteria
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Digestion begins in the mouth.

saliva secretion under autonomic control
softens and lubricates food
digestion: salivary amylase, some lipase
antimicrobial: lysozyme, immunoglobulins
chewing (mastication)
transfer to stomach (deglutition)

11

Swallowing Reflex
Breathing inhibited as bolus
passes closed airway.

pushes bolus against soft palate

k of mouth, triggering swallowing reflex.

Soft palate elevates,

closing off nasopharynx.
Hard palate.
Tongue
Epiglottis folds down to help keep
Bolus
swallowed material out of airways
Epiglottis
Glottis
Upper esophageal sphincter relaxes.
Larynx moves up and forward.
Tonically contracted
upper esophageal sphincter. Food moves downward into
esophagus, propelled by
peristaltic waves and aided by gravity.

swallowing reflex integrated in

medulla
sensory afferents in cranial nerve IX
and somatic motor and autonomic
neurons mediate reflex
Fig 21.14

12

Transition into the Stomach

lower esophageal sphincter guards entry into stomach
tonically contracted muscle
if LES not closed, acid from stomach can splash up into
lower esophagus
during respiration (when intrathoracic pressure drops)
during churning of stomach
= gastroesophageal reflux disease (GERD) =
heartburn

13

Control of GI Function: Cephalic and

Gastric Phases
Food!

anticipation of food /
presence of food in mouth

Medulla
oblongata
Stomach

Lumen of
stomach

activation of neurons in medulla

Preganglionic efferent signals to salivary glands

parasympathetic
autonomic signals via vagus to enteric
neuron in vagus
nerve
Gastric
mucosa

motility and
LONG
REFLEXstomach, intestine,

secretion in
accessory organs

Sensory
Enteric
input
plexus
SHORT
Distention
REFLEX
or peptides and
Postganglionic
amino acids
parasympathetic
initiate short
and intrinsic
Target
reflexes.
enteric neurons
cells
Secretion
and motility

Fig 21.13

14

Control of GI Function: Gastric Phase

initiated with long vagal reflex cephalic phase
once food enters stomach, series of short reflexes gastric
phase
three functions of the stomach:
storage - neurally mediated receptive relaxation of upper
stomach
importance of storage function has been more apparent as
gastric surgeries have become more popular
gastric dumping syndrome
digestion mechanical and chemical processing into chyme
secretions begin before food arrives
enzymes, acid, hormones
protection against microbes acid
self-protection mucus-bicarbonate barrier
15

Secretory Cells of Gastric Mucosa

gastric
gland
opening

Fig 21.15

FUNCTION
STIMULUS
CELL TYPES SUBSTANCE
OF
SECRETION
FOR RELEASE
SECRETED
Tonic secretion; with
Physical barrier btw
mucus
irritation
of
mucosa
lumen and epithelium
mucous
neck cell
Secreted with Buffers gastric acid to
prevent epithelial
bicarbonate
mucus
damage.
Activates pepsin;
gastric
acid
(HCl)
Acetylcholine,
kills bacteria
parietal
gastrin,
histamine
Complexes with vit
cells intrinsic factor
B12 to permit absorption
enterochromaffinAcetylcholine, Stimulates gastric
histamine
acid secretion
gastrin
like cell
chief cells pepsin(ogen) Acetylcholine, acidDigests proteins
Digests fats
gastric lipase secretion
Inhibits gastric acid
D cells somatostatin Acid in the stomach
secretion
Acetylcholine,
Stimulates gastric
G cells gastrin
peptides,
acid secretion
and amino acids

16

Functions of Gastric Secretory Products

parietal cells acid

activates pepsin

denatures proteins makes them more accessible to pepsin

anti-microbial

chief cells pepsinogen ( pepsin)

endopeptidase
particularly effective on collagen (meat digestion)

chief cells gastric lipase

minor contribution to fat digestion (co-secreted with pepsinogen)

enterochromaffin-like (ECL) cells histamine

binds to H2 receptors on parietal cells - promotes acid secretion

gastrin from G cells

triggered by both long and short loop reflexes ...

multiple roles ...

somatostatin from D cells

shuts down secretion of acid and pepsinogen (-ve regulator)

17

Integration of Cephalic and Gastric

Phases
Food or cephalic Input via
Food
reflexes initiate vagus nerve
gastric secretion.

Lumen of
stomach
Amino acids
or peptides

Gastric mucosa
Enteric
sensory
neuron
G cell

GastrinGastrin stimulates acid

secretion by direct action
on parietal cells or indirectly
through histamine.
Somatostatin release by H+
D
cell
Somatostatin

is feedback signal that

modulates acid and
pepsin release.
Negative feedback
ECL
pathway
Histaminecell
Parietal
Acid stimulates H+
cell
short reflex
Enteric
secretion of
Enteric
pepsinogen.
plexus
sensory
neuron
Pepsin
Pepsinogen Chief
cell

Fig 21.16

18

Mucus-Bicarbonate Barrier in Stomach

stomach
lumen

gastric juice pH 2

Mucus layer - physical barrier

HCO3

HCO3
HCO3
HCO3
Bicarb - chemical barrier

mucus
layer

pH 7 at cell surface
mucus
droplets

gastric mucous cells

capillary

breakdown of mucus-bicarb barrier:

peptic ulcer acid and pepsin damage mucosal surface,
creating holes that extend into submucosa and
19
muscularis
layers
Fig 21.15

Prevention / Treatment of Peptic Ulcers

main treatment was antacids
substances that neutralized gastric acid

more modern approaches include

H2 receptor antagonists block histamine
action

proton pump inhibitors block H+/K+-ATPase

20

Acid Secretion by Parietal Cells

H ATP
K
Cl

H2O

Capillary

Lumen of
stomach

Interstitial
fluid

H OH
CA
K
HCO3
CO2
Cl
Cl
Parietal cell

HCO3
Cl

lumen can be as low as pH 1, parietal cell is ~7.2, so

[H+] a million times higher in lumen!
as H+ secreted from apical side, bicarb (from CO2 + OH-)
is absorbed into blood
alkaline tide from stomach can be measured after a
21
Fig 21.5 meal

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Stimulation of Parietal Cell Acid

Secretion
H+/K+-ATPase

22

Control of GI Function: Intestinal Phase

stomach produces chyme by actions of acid, pepsin,
peristalsis
intestinal phase begins with controlled entry of chyme into
small intestine
sensors in duodenum feed back to stomach to control
delivery of chyme, feed forward to intestine to promote
digestion, motility and nutrient utilization

23

Integration of Gastric and Intestinal

Phases
Stomach

Food into
stomach

Acid secretion
Pepsin and lipase secretion
Gastric motility
Small
intestine

Hyperosmotic
solution

Chyme
into small
intestine

Carbs

? Endocrine GIP GLP-1

cell

Pancreas

Fig 21.17

Fats,
proteins
CCK

Insulin Pancreatic
secretion enzyme
secretion

Enteric
nervous
system

Acid
Secretin

Pancreatic
bicarbonate
secretion

24

Summary of Secretions during Intestinal

Phase
Substance

Source

Stimulus for
Release

Function

bicarb

pancreas (duct
cells)

neural, secretin

neutralize
chyme

mucus

goblet cells

can be increased by
inflammation

protection,
lubrication

bile

gall bladder
(liver)

CCK (presence of
fats, protein)

fat digestion

enzymes
(as
zymogens)

pancreas (acini)
brush border

neural, CCK,
distension
(presence of food)

digestion

25

Enterohepatic Circulation of Bile Salts

bile salts are released into duodenum, absorbed in terminal ileum,

enter portal circulation, travel back to liver
recycled several times during a meal!
26

Fat Absorption (revisited)

Bile
salts

Bile salts
recycle
Micelles

Bile salts
coat fat
droplets.

Absorbed fats combine

Lacteal
Cholesterol is
with cholesterol and
to
transported proteins in intestinal
into cells. cells to form chylomicrons.
vena cava
cholesterol triglycerides protein

Emulsion

Chylomicrons
removed by
lymphatic system.

Golgi
Chylomicron
apparatus
Smooth
ER

Pancreatic lipase
and colipase break
Monoglycerides and fatty
down fats into
acids diffuse from micelles
monoglycerides and cross cell membranes.
Large fat and fatty acids
droplets fromstored in micelles.

stomachLumen of small intestine

Enterocytes

Capillary
Interstitial fluid

lipid components of micelles diffuse across apical membrane

(some evidence that cholesterol crosses via transporter)
monoglycerides and free fatty acids recombine into
triglycerides in smooth ER
triglycerides, cholesterol, proteins form chylomicrons, which
are packed into vesicles and exocytosed
27

Fig 21.9

Activation of Pancreatic Zymogens

Lumen of small intestine

Pancreatic duct
Pancreatic secretions
(include inactive
zymogens)

Trypsinogen

ZYMOGENS

Chymotrypsinogen
Procarboxypeptidase
Procolipase
Prophospholipase

Enteropeptidase
in brush border
activates trypsin.
Trypsin

activates
ACTIVATED ENZYMES

Fig 21.17

Chymotrypsin
Carboxypeptidase
Colipase
Phospholipase

Intestinal
mucosa

28

Absorption in Small Intestine

most fluid is absorbed in small intestine
transport of organic nutrients and ions creates
osmotic gradient

most absorbed nutrients move into

capillaries in villi, then into hepatic
portal vein
fats go into lymphatic system
Sinusoids
rather than blood
of liver
xenobiotics must first pass
through liver before reaching
systemic circulation
Liver

Aorta

Hepatic
vein
Inferior
vena cava
Hepatic artery

Hepatic portal vein

GI tract arteries

Fig 21.18

capillaries of GI tract

29

Small Intestine; Microanatomy

Villi
Crypt
Peyers patch
Mucosa
Muscularis mucosae
Submucosa

Lymph vessel
Submucosal
plexus
Myenteric
plexus

Circular muscle
Muscularis
externa
Longitudinal muscle
Serosa
Submucosal
artery and vein

Fig 21.3

i
em

r
e
nd
30

Gross Anatomy of the Large Intestine

Hepatic portal vein

Aorta

Tenia coli

Inferior vena cava

Transverse colon

Ascending
colon
Descending
colon

Food enters
large intestine via
ileocecal valve.
Cecum

Ileum

Haustra
Sigmoid colon

Appendix

Rectum

Fig 21.19

31

Large Intestine, a closer look

Intestinal glands
are the site of
fluid secretion.
Lymphoid
nodule
Muscularis
mucosae
Submucosa

Circular muscle Longitudinal layer

(tenia coli)
Rectum

Defecation reflex
begins with distension
of rectal wall.

internal anal sphincte

external anal sphincte

Fig 21.19

anus

32

Role of the Large Intestine

removes most of remaining water formation of
feces
motility:
ileocecal valve relaxes each time a peristaltic wave
reaches it
also relaxes when food leaves stomach
(gastroileal reflex)
segmental contractions with little forward
movement except when mass movements occur
(3-4 times per day)
wave of contractions that send bolus forward
trigger distension of rectum defecation
reflex
33

Diarrhea
imbalance between intestinal absorption and secretion
osmotic diarrhea - unabsorbed osmotically active solutes
undigested lactose, sorbitol or Olestra (fake fat)
osmotic laxatives
secretory diarrhea bacterial toxins increase Cl - secretion
e.g. cholera
diarrhea can be adaptive (flushing out infection), but can
also lead to dehydration, metabolic acidosis

34

NaCl Secretion (Small Intestine, Colon, Salivary

Glands)
Lumen
Interstitial
fluid

Cl enters
lumen through
CFTR channel.
Cl

Cl
Na
Na is
reabsorbed.

Na,
H2O
Negative Cl in lumen
attracts Na by
paracellular pathway.
Water follows.

Na , K, and

KCl
enter via

2 NKCC
Cl
transporter.
Na
ATP

K
Na,
H2O

crypt cells in small intestine and colon secrete isotonic saline

that mixes with mucus secreted by goblet cells to lubricate gut
contents

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Fig
21.5 similar to pancreatic duct cells, Cl- secretion pulls Na+ and
NOTE:

Cholera
intestinal infection, Vibrio cholerae
contaminated food (developed countries)
contaminated water (developing countries)
need to ingest ~100 million bacteria
lower doses can cause infection in
people with reduced gastric acidity
young children
immune suppressed individuals
100,000-130,000 deaths per year
bacteria must survive acidity of stomach reach
small intestine attach to and invade intestinal
epithelial cells produce toxin
36

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Cholera Toxin (CT)

37

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nden Broeck, Horvath & De Wolf 2007 Int J Biochem Cell Biol 2007;39:1771-5

Activation of a G-Protein Coupled Receptor

GPCR)

source: Alberts (free online)

Molecular Biology of the Cell, 4th edition
Figs 15-26, 15-28

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G-subunit turns itself off by hydrolyzing GTP.

1
t
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source: Alberts (free online)n
U

Molecular Biology of the Cell, 4th edition

Fig 15-29

How long does a G-protein signal last?

as long as the and subunits are free
which is as long as the G-subunit is bound to GTP
normally it hydrolyzes GTP GDP within a few
seconds and re-associates with -subunits

There are serious consequences of disruptions in

G activation or inactivation.

1
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Effect of Cholera Toxin on Inactivation of G

Subunit

1
t
i
source: Lodish, et U
al. (free
n online)
Molecular Cell Biology, 4th edition
Fig 20-17

Intracellular Trafficking of Cholera Toxin

(CT)
enters cell via pentameric B subunits
travels in retrograde direction through
Golgi
sequence on A2 subunit recognized as
signal to be shuttled to ER
mimics a misfolded protein and gets
dumped out into cytosol (normally to
be degraded)
instead, A1 subunit (enzyme) modifies
G subunit remains bound to GTP
persistent activation of adenylyl
cyclase
persistent elevation of cAMP

modification
of G subunit

sustained activation of CFTR channel

link to source

42

CFTR, Cholera and Cystic Fibrosis

CF is the most common fatal recessive single-gene
disorder of northern Europeans and their descendants
1 in 2,000 4,000 individuals affected

Why is the frequency of this fatal disease so

high?
suggestion:
CF heterozygotes have some advantage over `non-CF'
homozygotes
heterozygotes have ~ 50% functional CFTRs
enough for normal function but allows them to
resist death by cholera due to reduced Clsecretion during infection?
survive to pass on the gene to offspring??
BUT:

43