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CAPS 423
Gastrointestinal Motility
• Dr. Eric Accili
• Department of Cellular & Physiological Sciences
• University of British Columbia
• [email protected]
• Life Sciences Building, Rm 2320, (2nd floor west
tower)
• www.canalionique.wordpress.com
Teaching 2016
Password = Fisiology
Objectives
• Functional Anatomy
– GI tract, smooth muscle cells
• Smooth Muscle Properties
– slow waves, contraction
• Innervation of the GI Tract
– parasympathetic, sympathetic, enteric
– sensory neurons, interneurons, motor neurons
• Passage of Food
– peristalsis, migrating myoelectric complex
• GI Motility Disorders
– symptoms
"The alimentary canal is a musculo-membrane
tube, about 30 ft! in length, extending from the
mouth to the anus."
Gray's Anatomy.
Pennsylvania: Running Press, 1974
30 feet!
Anatomy of the GI Tract
Structure of the GI Tract
Submucosal Plexus
Myenteric Plexus
GI Smooth Muscle Cells
Longitudinal Muscle
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Thin muscle coat
Contraction shortens intestine and expands
radius
Innervated by excitatory motor neurons
Few gap junctions to adjacent fibres
Ca2+ influx from outside important in
excitation-contraction coupling
Circular Muscle
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Thick muscle coat
Contraction lengthens intestine and shortens
radius
Innervated by excitatory and inhibitory motor
neurons
Many gap junctions to adjacent fibres
Intracellular Ca2+ release important in
excitation-contraction coupling
GI Smooth Muscle Cells
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~ 500 M long, 5 to 20 M across
Resting membrane potential -40 to -80 mV
Circular layer better electrically coupled than
longitudinal layer via frequent gap junctions
Exhibit slow waves
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oscillating membrane potential
triggered by influx of Ca2+
~3/min in stomach to ~12/min in duodenum
generated by interstitial cells located between
longitudinal and circular layers of muscularis
externa
spread through each segment of GI tract
amplitude can be modulated by intrinsic and
extrinsic nerves and hormones
sympathetic decreases and parasympathetic
increases amplitude
action potentials triggered if threshold reached,
enhance contractile force
Smooth Muscle Cells
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Spontaneously active (myogenic)
Stretch induces active tension
Myogenic activity modulated by nerves
No structured neuromuscular junctions
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Not spontaneously active
Not activated by stretch
Activated by multiple motor neurons
Structured neuromuscular junctions
Motor Axon Varicosities
There are no structured nerve-muscle junctions, transmitter release is diffuse.
Action potentials do not trigger release of transmitter from every varicosity
Varicosities can migrate along nerve fibres
Different Wave Frequencies
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Frequency of electrical activity determines the frequency of contractions.
-~3/min in the antrum, ~12/min in the duodenum. ~6-10/min in the colon
Slow Waves and Contraction
10-20 msec long
1 - 10 per sec
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Extent of depolarization and frequency can be altered by hormones and nerves.
Slow Waves Without APs
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Contractions are small or nonexistent in the absence of action potentials.
Slow Waves With APs
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Phasic contractions occur when action potentials appear on slow waves.
Santiago Ramon y Cajal
Physician, Pathologist
(1 May 1852 – 17 October 1934)
Interstitial Cells of Cajal
Martínez et al Nature Reviews Cancer 5, 904-909 (November 2005)
Interstitial Cells of Cajal
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Interstitial cell networks are the pacemakers for intestinal electrical slow waves.
Interstitial cells of Cajal are non-neuronal cells of mesenchymal origin.
Excitatory and inhibitory neurotransmitters spread diffusely from axonal
varicosities to the interstitial cell networks.
Gap Junctions Connect Cells
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Gap junctions transfer electrical current from cell-to-cell in smooth muscle,
generating a functional electrical syncytium.
Information Transfer Routes
Neurocrine
Synaptic transmission, paracrine signalling and hormonal signalling are forms of
chemical information transfer in the digestive tract.
Regulation of GI Functions
• Much of the hormonal and neural
regulation is intrinsic to the GI tract.
• Some extrinsic regulation, mediated by
non resident endocrine cells and
neurons.
• Overlap allows for subtle and precise
control of GI functions.
Gastrointestinal Hormones
Location of endocrine cells
Hormone
that produce the hormone
Stomach
Gastrin
Somatostatin
Duodenum or jejunum
Secretin
Cholecystokinin (CCK)
Motilin
Gastric inhibitory polypeptide (GIP)
Somatostatin
Pancreatic islets
Pancreatic polypeptide
Amylin
Ileum or colon
Glucagon-like peptide-1 (GLP-1)
Peptide YY
Somatostatin
Gut Hormone
Communication Routes
Enteroendocrine cells are 1-2% of
epithelial cell lining. Sense sigals in
lumen and release peptide hormone.
Innervation of the GI Tract
Autonomic Nervous System
Parasympathetic
Typically stimulates
motor and secretory
activity.
Vagus control to level of
transverse colon,
remainder from pelvic
nerves.
Sympathetic
Typically inhibits motor
and secretory activity,
induces contraction of
muscularis mucosae
and some sphincters.
Celiac, Superior and
inferior mesenteric
Sympathetic input
shunts blood away from
gut during exercise or
stress ~20% CO
The Enteric Nervous System
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Contains about 108 neurons, ~ same as in spinal cord.
Includes motor neurons, sensory receptors, and interneurons.
Can coordinate activity in the absence of extrinsic innervation (reflex arcs).
Receives extrinsic innervation from sympathetic and parasympathetic.
Neuronal cell bodies of the myenteric plexus encricled by sympathetic postganglionic nerves
Blue – “auto-fluorescence” of
myenteric neuronal cell bodies
Green – fluorescence of antibody for
tyrosine hydroxylase
‘en passant’ terminals –release
neurotransmitter along their length
‘en passant’ terminals
release neurotransmitter along their
length
Enteric nerves of the human myenteric plexus
Groups of cell bodies = “Ganglion”
Connections of ENS Neurons
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Control by ENS, modulation by ANS
Plexuses consist of ganglia
interconnected by tracts of fine
unmyelinated nerve fibres
Effector neurons to muscle cells,
secretory cells, blood vessels
Interneurons to integrate sensory
input and formulate output
Extensive branching in ENS, each
axon may innervate many muscle cells
Afferent fibres are abundant, carry
signals from chemosensitive and
mechanosensitive nerve endings
Most myenteric neurons are motor,
submucosal regulate secretion
Multiple neurotransmitters like CNS
Excitatory motor neurons release Ach
or Sub. P, inhibitory release VIP, NO
Integrated Circuits
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The brain and the enteric nervous system have integrated circuits.
Microcircuits of the ENS
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Gut behavior is programmed by the enteric microcircuits.
Local and Central Reflexes
Intestine and Colon Reflexes
• Law of the intestine
– a bolus in the intestine causes contraction behind and
relaxation ahead.
• Intestinointestinal reflex, colonocolonic reflex
– over distension of one segment causes intestinal relaxation.
• Gastroileal reflex, gastrocolic reflex
– elevated stomach secretory and motor function increase ileal
and colonic motility.
Intrinsic Reflexes
Excitatory potentials are
mediated by substance P or
acetylcholine release from motor
neurons
Localized mechanical or
chemical stimulation of the
intestinal mucosa elicits
contraction above and
relaxation below
Inhibitory potentials are
mediated by nitric oxide or
vasoactive intestinal peptide
release from motor neurons
Intestine Reflex Pathway
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Sympathetic prevertebral ganglia are pathways for rapid transfer of signals
between separated regions of bowel.
The transganglionic pathways bypass synaptic delays inherent in the enteric
nervous system in signal transfer over long distances.
Gastric Reflexes
GASTRIC RECEPTIVE RELAXATION
NODOSE
GANGLION
DORSAL
INTEGRATIVE MOTOR
PATHWAYS NUCLEUS
ACCOMMODATION OF PROXIMAL STOMACH
NODOSE
GANGLION
DORSAL
INTEGRATIVE MOTOR
PATHWAYS NUCLEUS
VAGUS
VAGUS
VAGUS
VAGUS
MECHANORECEPTOR
MECHANORECEPTOR
INHIBITORY
NEURON
FOOD
BOLUS
ESOPHAGUS
CIRCULAR
SMOOTH
MUSCLE
INTERNEURON
VIP/NO
PROXIMAL
STOMACH
FOOD
BOLUS
STOMACH
CIRCULAR
SMOOTH
MUSCLE
INHIBITORY
NEURON
VIP/NO
PROXIMAL
STOMACH
Inhibitory Motor Neurons
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Activity of a subpopulation of inhibitory motor neurons to the intestinal circular
muscle tonically inhibits contraction.
Neural blockade or inhibition of NO synthase removes inhibition.
Provides added level of control over muscle tone.
Inhibitory Motor Neurons
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Strength of circular muscle contraction evoked by each slow wave cycle is a
function of the number of inhibitory motor neurons in an inactive state.
Inhibitory Motor Neurons
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Inhibitory innervation of gastrointestinal sphincters is transiently activated for
timed opening and passage of luminal contents.
Inhibitory Motor Neurons
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Inhibitory motor innervation of the intestinal circular muscle is continuously
active and is transiently inactivated to permit muscle contraction.
Gut Sensory Receptors
• Mechanoreceptors
– muscle (stretch, tension, length)
– mucosal
• Chemoreceptors
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acid
osmotic
amino acid
lipid
glucose
• Thermoreceptors
Enterochromaffin Cells
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Release of serotonin (5-HT) from enterochromaffin cells is an early step in
transduction of sensory information.
Enteroendocrine Cells
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Enteroendocrine cells are the first step in the transduction of chemoreceptive
sensory information.
Acid Chemoreceptors
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Chemoreceptors for acid in the gastric or duodenal mucosa evoke firing in vagal
afferents.
Distension Response
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Distension of the esphagus evokes firing in vagal afferent fibres.
Abdominal Pain
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Distension is the principal stimulus for pain and discomfort in the digestive tract.
Balloon distension in the colon evokes pain in specific regions
Most noxious stimuli (burning, cutting, caustic substances) do not evoke painful
sensations in the GI tract
Irritable Bowel Syndrome
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Individuals with irritable bowel syndrome have increased sensitivity to balloon
distension in the large intestine.
A similar phenomenon occurs in the small intestine.
Mechanism unclear
Chewing (Mastication)
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Both voluntary and reflex.
Lubricates food with salivary mucus.
Amylase breaks down starch.
Mechanically chops food into smaller pieces.
Swallowing
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1) Oral
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2) Pharyngeal
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voluntary phase, tongue moves food up and back
into the pharynx, where it stimulates receptors
that initiate a reflex controlled by the swallowing
centre in the medulla and lower pons
in less than 1 sec, soft palate moves to open a
narrow passage to the pharynx.
the larynx is moved against the epiglottis to
prevent food entering the trachea.
the upper esophageal sphincter relaxes.
the pharynx contracts to force the bolus deeply
into the pharynx.
a peristaltic wave is initiated to force the bolus
through the UES.
During this phase, respiration is inhibited.
3) Esophageal
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the UES constricts.
a primary peristalsis travels at 3 to 5 cm/sec
down the entire esophagus in less than 10 sec.
secondary peristalsis occurs if food remains.
pharynx
larynx
Pressures During Swallowing
Note resting pressure at the sphincters
Esophageal Function
• A conduit to move food from the pharynx to
stomach.
• The UES and LES prevent entry of air and
gastric contents, respectively.
• In the absence of peristalsis the LES remains
tightly closed to prevent esophagitis
(heartburn).
• Failure to relax during swallowing = achalasia.
Esophageal Peristalsis
Lower Esophageal Sphincter
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The lower esophageal sphincter is innervated by both vagal excitatory fibers
(VEF) and vagal inhibitory fibers (VIF).
Gastric Motility
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1) Allows the stomach to serve as a reservoir.
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2) Breaks food into smaller particles and mixes
food with gastric secretions.
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can accommodate volumes of up to 1.5L without a
great increase in intragastric pressure = receptive
relaxation.
contents may remain unmixed for 1 hr after eating.
fats gather at the top and are last to be emptied.
contractions are vigorous in the antrum.
generates ‘chyme’.
3) empties gastric contents into duodenum at a
controlled rate.
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several mechanisms adjust the rate of gastric
emptying.
liquids are emptied before solid foods.
Gastric Emptying Rates
Plastic spheres 7 mm
Gastric Motility
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Gastric contractions usually start in the
middle of the stomach and travel toward
the pylorus.
They increase in force and velocity as they
approach the gastroduodenal junction.
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thus the majority of mixing occurs in the
antrum.
As the peristaltic wave reaches the pylorus,
a small amount of food exits before the
pyloric sphincter closes.
The rapid contraction of the antrum also
propels chyme back = retropulsion.
Fed contractions are ~3/min
During fasting, quiescence periods of 75-90
min are followed by 5-10 min of strong
antrum contractions with a relaxed pylorus.
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part of the migrating myoelectric complex.
pacemaker zone
Gastric Motility
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Gastric peristaltic waves occur at
about the frequency of the gastric
slow waves that are generated by
the pace-maker zone.
They occur at ~3/min and travel
towards the pylorus.
Smooth muscle contracts when the
depolarization during the slow wave
exceeds the threshold for
contraction.
The greater the depolarization the
greater the force of contraction.
Acetylcholine and gastrin increase
the amplitude and duration of
contractions, norepinephrine does
the opposite.
Action potentials notable
in antrum and pylorus
Gastroduodenal Junction
• The pylorus separates the gastric antrum from the
duodenal bulb and functions as a sphincter.
• The electrical rhythm of the duodenum is 10-12 slow
waves per min.
• Allows for regulated emptying of gastric contents at rate
the duodenum can process the chyme.
– too rapid can cause duodenal ulcers.
• Prevents regurgitation of duodenal contents to stomach.
– can cause gastric ulcers.
• Is densely innervated by vagal and sympathetic fibers.
– sympathetic fibers increase constriction, vagal may constrict or
relax, depending upon the neurotransmitter.
• CCK, GIP, and secretin all constrict the pylorus.
Regulating Gastric Emptying
-Rate at which fat empties doesn’t exceed rate at which it can be emulsified by bile
-Acid is not dumped into the duodenum more rapidly than it can be neutralized
Vomiting
• The oral expulsion of gastric (and sometimes duodenal) contents.
• Preceded by retching, in which gastric contents are forced into the
esophagus, but do not enter the pharynx.
• Reflex behavior coordinated by vomiting centre in medulla oblongata.
• Stimulated by distension of stomach and duodenum, tickling back of
throat, emetics (e.g. ipecac).
• Wave of reverse intestinal peristalsis.
• Pyloric sphincter and stomach relax to receive contents.
• A forced inspiration occurs against a closed glottis along with
contraction of abdominal muscles to elevate intra-abdominal pressure
and drive gastric contents into the esophagus.
• The LES relaxes, the stomach contracts, the UES relaxes, vomitus
enters the mouth.
• Closure of the glottis and inhibition of respiration prevent entry into
the trachea.
Small Intestine Motility
• ~5 m in length, takes 2 - 4 hrs for chyme to transverse.
• Duodenum, jejunum, ileum, where most digestion and
absorption occurs.
• Movements mix chyme with digestive secretions, bring
chyme into contact with microvilli, propel to colon.
• Most frequent movement is segmentation.
• Peristalsis is the progressive contraction of circular smooth
muscle in an orthograde direction.
– timing determined by the slow waves.
• Slow waves decline along length, 11-13/min to 8-9/min.
– may or may not be accompanied by action potential spikes.
– excitability is enhanced by parasympathetic nerves and inhibited
by sympathetic nerves.
Migrating Myoelectric Complex
• The pattern of motility during fasting, stomach to colon.
• Bursts of intense electrical and contractile activity separated by longer
quiescent periods.
• Repeats every 75 to 90 min in humans.
– about the time that MMC reaches distal ileum, new one begins.
• Sweep the small bowel clean and empty contents to colon.
• Inhibits migration of colonic bacteria into the ileum.
• Substances released by bacteria may stimulate secretion of NaCl &
water by epithelium, causing diarrhea
Migrating Myoelectric Complex
feeding triggers a
switch to a different
pattern, with both
segmental
contractions &
peristaltic
contractions
Muscularis Mucosae Contraction
• Contract irregularly at ~3/min.
• Alter pattern of ridges and folds of mucosa and mix
luminal contents.
• Villi also contract irregularly to help empty central
lacteals of villi and increase intestinal lymph flow.
• Lacteals = intestinal lymphatic that takes up chyle and
passes it to they lymph circulation, which passes to the
blood
Motility of the Colon
• Receives 500 to 1500 ml chyme per day.
• Most salts and water are absorbed.
– feces normally contains only 50 to 100 ml water per day.
• The progress of colonic contents is slow (5-10 cm/hr).
• Mass movement occurs 1-3 times per day.
– differs from peristalsis by prolonged contraction.
– push contents within a significant length of colon.
• Stimulation of sympathetic nerves stop movements,
vagal nerves cause segmental contractions in proximal
portion, pelvic nerves control distal colon.
Gut Stress Response
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Alterations in large intestinal motility and blood flow occur in response to acute
stress in humans.
Rectum and Defecation
• The rectum is typically empty.
• Mass movement of the sigmoid colon fills rectum.
– causes reflex relaxation of the internal and constriction of the
external anal sphincters, urge to defecate.
• If defecation is postponed, the urge to defecate
subsides.
• May voluntarily relax external sphincter.
• Descending and sigmoid colon contract.
• Intra-abdominal pressure is elevated to aid expulsion of
feces.
GI Disorders That Impact Motility
• Irritable Bowel Syndrome (IBS)
– most common GI disorder - 10% to 20% of adults.
– abnormal function of the colon
– abdominal pain, bloating, constipation and diarrhea
• Crohn’s Disease
– inflammation of the small intestine
– abdominal pain and diarrhea
• Celiac Disease
– intolerance to gluten (wheat, rye, barley)
– immune mediated damage to small intestine
– abdominal pain, diarrhea, weight loss, fatigue
• Social and economic costs are enormous.
• These disorders remain poorly understood and there are
few effective treatments.
GI Motility Disorders
• Gastroesophageal Reflux Disease
– ~15% of population
– chronic but treatable, lifestyle, medication, surgical procedures
• Constipation
– infrequent bowel movements (<3/week)
– decreased number of propagating contractions (slow transit)
• Diarrhea
– Frequent loose or watery stools
– Excessive number of propagating contractions (rapid transit)
• Gastroparesis
– stomach takes too long to empty
– nausea, vomiting, early feeling of fullness
• Achalasia
– lack of peristalsis in the esophagus, LES doesn’t relax
– difficulty swallowing, chest discomfort, weight loss
Hirschsprung's Disease
Hirschsprung's Disease
• Nerve cells in latter part of the colon are missing
(both myenteric and submucous plexi).
• Muscles in that region do not relax, hence
contractions of muscle that normally push food
through that part of the colon do not occur.
• Region of intestine above the “aganglionic” region
swells resulting in constipation, swollen belly etc.
• 1 case per 5400-7200 newborns
Hirschsprung's Disease
In the absence of the enteric nervous system, how do
the muscles of the colon end up contracted?
Muscles themselves are naturally more contracted
AND/OR
Parasympathetic nervous system provides some basal
input to contract muscles
Enteric nervous system provides resting relaxation.
May be due to the absence of a neurotransmitter;
e.g. Vasoactive Intestinal Peptide (VIP)
• peptide neurotransmitter found in neurons of the
colon
• when applied to colonic smooth muscle, causes
relaxation
VIP in the human myenteric plexus
Groups of cell bodies = “Ganglion”
Hirschsprung's Disease – current therapy
• Corrected by surgery – but there can be issues,
does not always work well.
• Laxatives, high fibre diet to correct constipation
Hirschsprung's Disease - research
• Gene directed therapy – re-create enteric neurons.
• Stem cell therapy – re-create enteric neurons.
• Botulinum Toxin (Botox)! – decrease acetylcholine
release at the neuromuscular junction, relax
muscle in colon. Limited success.
Enteric Nervous System of Mouse
Normal
EDN-3 (endothelin)
mutant
Enteric nervous system (ENS)
phenotypes observed in
various mouse mutant strains
commonly used as models for
Hirschsprung's disease
Nature Reviews Neuroscience 8, 466-479, 2007