Regulation of GI Function
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Transcript of Regulation of GI Function
1
Unit 06b Regulation of GI Functionregulation of GI function
long versus short reflexes, feedforwardparallels between enteric and central nervous systemsgut hormones – historical
cephalic phasemouth, swallowingtransition into stomach
gastric phasesecretions of gastric mucosaintegration of cephalic and gastric phasesmucus-bicarb barrier peptic ulcers
intestinal phaseintegration of gastric and intestinal phasessecretions into intestine activation of pancreatic enzymesabsorption in small intestinelarge intestine anatomy roles
diarrheacholera revisited
2
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!)
3
Cephalic phaseof digestion
(feedforward)
(sight, smell, etc.)
Sensoryreceptors
BrainSympathetic and parasympathetic neurons
Local stimuli:Distension
Presence of foodOsmolarity
Acid
Sensoryreceptors
andneurons
Inter-neurons
Neurons ofmyenteric
andsubmucosal
plexusesEnteric nervous system
Secretorycells of the
stomach andsmall
intestine
GI peptides
Smooth musclesor endocrine
cells of stomach,pancreas,intestine
• Changes in motility• Release of bile and pancreatic secretions• Enzyme, acid, and bicarb synthesis/release
BrainHunger/satiety
Endocrinepancreas
InsulinGlucagon
KEYStimulus
SensorIntegratingcentreOutput signal Long reflexes
Short reflexes
Tissue responseTarget
Fig 21.11 über slide
Integrated Control of GI Function
4
Small Intestine; Microanatomy
Villi
Crypt
MucosaMuscularis mucosae
Submucosa
Circular muscle
Longitudinal muscleSerosa
Peyer’s patch
Lymph vesselSubmucosalplexusMyentericplexus
Submucosalartery and vein
Muscularisexterna
Fig 21.3
5
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 (similar to astrocytes of CNS)
• diffusion barrier – capillaries surrounding ganglia are not very permeable (similar to blood-brain barrier)
• acts as integrating centre gut function can be regulated without CNS
6
Cephalic phaseof digestion
(feedforward)
(sight, smell, etc.)
Sensoryreceptors
BrainSympathetic and parasympathetic neurons
Local stimuli:Distention
Presence of foodOsmolarity
Acid
Sensoryreceptors
andneurons
Inter-neurons
Neurons ofmyenteric
andsubmucosal
plexusesEnteric nervous system
Secretorycells of the
stomach andsmall
intestine
Gutpeptides
Smooth musclesor endocrine
cells of stomach,pancreas,intestine
• Changes in motility• Release of bile and pancreatic secretions• Enzyme, acid, and bicarb synthesis/release
BrainHunger/satiety
Endocrinepancreas
InsulinGlucagon
KEYStimulus
SensorIntegratingcentreOutput signal Long reflexes
Short reflexes
Tissue responseTarget
Fig 21.11 über slide
Integrated Control of GI Function
7
stomach
pancreas
duodenum
Pavlov
• 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
• pancreas secretion was thought to be controlled only by vagus nerve
Beginnings of Endocrinology
8
tested hypothesis:
• collected lining of duodenum• added acid to it• injected it intravenously
pancreatic secretion
Beginnings of Endocrinology
stomach
pancreas
duodenum
Bayliss and Starling
• carefully dissected away all nerves surrounding pancreas and duodenum put acid in the duodenum pancreas still secreted
hypothesis:
acid caused release of signalfrom duodenum into blood
- factor from intestine that stimulated pancreatic secretion called secretin- general term coined for blood-borne regulators: HORMONES
9
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’
Fig 21.1210
KEYM: motilityS: secretionD: digestionA: absorption
upper esophageal
sphincter
loweresophageal
sphincter
pylorus
ileocecalvalve
rectumanal
sphincters
Mswallowing, chewingOral Cavity and Esophagus
Stomach
Small Intestine
Large Intestine
S saliva (salivary glands)D carbohydrates, fats (minimal)A none
Mmixing and propulsion (peristalsis)S HCl, pepsinogen and gastric lipase,
mucus and HCO3, gastrin, histamine
D proteins, fatsA lipid-soluble substances such as alcohol and aspirin
Mmixing and propulsion mostly by segmentationS enzymes, HCO3
and enzymes, bile, mucus, hormones: CCK, secretin, GIP, et al.
D carbohydrates, fats, polypeptides, nucleic acidsA peptides, amino acids, glucose, fructose
fats, water, ions, minerals, vitamins
Msegmental mixing; mass movement for propulsionS mucusD none (except by bacteria)A ions, water, minerals, vitamins, small organic
molecules produced by bacteria
Overview of GI Function
11
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)
12
Swallowing Reflex
Tongue pushes bolus against soft palate and back of mouth, triggering swallowing reflex.
Soft palate elevates,closing off nasopharynx.Hard palate.TongueBolusEpiglottisGlottisLarynx moves up and forward.Tonically contractedupper esophageal sphincter.
Fig 21.14
Epiglottis folds down to help keep swallowed material out of airways.
Upper esophageal sphincter relaxes.
Breathing inhibited as boluspasses closed airway.
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
13
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’
14
Food!
Stomach
Medullaoblongata
Preganglionicparasympatheticneuron in vagus
nerve
Postganglionicparasympathetic
and intrinsicenteric neurons
Entericplexus
Sensoryinput
Targetcells
Distentionor peptides and
amino acidsinitiate short
reflexes.
Secretionand motility
Lumen ofstomach
Gastricmucosa
LONGREFLEX
SHORTREFLEX
Fig 21.13
anticipation of food / presence of food in mouth
activation of neurons in medulla
efferent signals to salivary glandsautonomic signals via vagus to enteric NS
motility and secretion instomach, intestine, accessory organs
Control of GI Function: Cephalic and Gastric Phases
15
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
16
Secretory Cells of Gastric MucosaCELL TYPES SUBSTANCE
SECRETEDSTIMULUS
FOR RELEASEFUNCTION
OF SECRETIONgastricgland
openingmucousneck cell
parietalcells
chief cells
D cells
G cells
mucus
bicarbonate
gastric acid (HCl)
intrinsic factor
histamine
pepsin(ogen)gastric lipase
somatostatin
gastrin
Tonic secretion; withirritation of mucosa
Secreted withmucus
Acetylcholine,gastrin, histamine
Acetylcholine,gastrinAcetylcholine, acidsecretion
Acid in the stomach
Acetylcholine,peptides,and amino acids
Physical barrier btwlumen and epitheliumBuffers gastric acid toprevent epithelialdamage.Activates pepsin;kills bacteriaComplexes with vitB12 to permit absorptionStimulates gastricacid secretionDigests proteinsDigests fats
Inhibits gastric acidsecretionStimulates gastricacid secretion
enterochromaffin-like cell
Fig 21.15
17
Functions of Gastric Secretory Productsparietal 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)
18
Lumen ofstomach
Gastric mucosaAmino acidsor peptides
FoodFood or cephalic reflexes initiate gastric secretion.
Input viavagus nerve
Entericsensoryneuron
G cellGastrin Gastrin stimulates acid
secretion by direct actionon parietal cells or indirectlythrough histamine.
D cell Somatostatin Somatostatin release by H+
is feedback signal thatmodulates acid and pepsin release.
Entericplexus
ECLcellHistamineParietal
cell
Entericsensoryneuron
Acid stimulatesshort reflex secretion ofpepsinogen.
H+
Negative feedbackpathway
Pepsin Pepsinogen Chiefcell
Fig 21.16
Integration of Cephalic and Gastric Phases
19
Mucus-Bicarbonate Barrier in Stomach
breakdown of mucus-bicarb barrier:• peptic ulcer – acid and pepsin damage mucosal surface, creating
holes that extend into submucosa and muscularis layers
gastric juice pH 2
Mucus layer - physical barrier
stomachlumen
mucuslayer
mucusdropletsgastric mucous cells
HCO3 HCO3
pH 7 at cell surface
capillary
HCO3 HCO3
Bicarb - chemical barrier
Fig 21.15
20
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
21
Acid Secretion by Parietal Cells
• 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 meal
Parietal cell
ATP
Cl Cl Cl Cl
K
K
H
H2O
HCO3HCO3
CO2
H OH
Lumen ofstomach
Capillary
Interstitialfluid
CA
Fig 21.5
22
Stimulation of Parietal Cell Acid Secretion
H+/K+-ATPase
23
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
24
Integration of Gastric and Intestinal Phases
PancreasInsulin
secretionPancreatic
enzymesecretion
Pancreaticbicarbonate
secretion
Stomach
Smallintestine
? Endocrinecell
Hyper-osmoticsolution
Fats,proteins
Chymeinto smallintestine
Entericnervoussystem
Food intostomach
Acid secretion
Pepsin and lipase secretion
Gastric motility
Carbs Acid
GIP GLP-1 CCK Secretin
Fig 21.17
25
Summary of Secretions during Intestinal PhaseSubstance 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
26
• bile salts are released into duodenum, absorbed in terminal ileum, enter portal circulation, travel back to liver– recycled several times during a meal!
Enterohepatic Circulation of Bile Salts
27
Fat Absorption (revisited)
• 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(short fatty acids can travel solo, entering capillaries rather than lymph)
Fig 21.9
Bilesalts
Bile saltsrecycle
Bile salts coat fatdroplets.
Micelles
Emulsion
Large fatdroplets from
stomach
Pancreatic lipaseand colipase breakdown fats intomonoglyceridesand fatty acidsstored in micelles.
Lumen of small intestine Enterocytes
Monoglycerides and fattyacids diffuse from micellesand cross cell membranes.
Cholesterol istransportedinto cells.
Absorbed fats combinewith cholesterol andproteins in intestinalcells to form chylomicrons.
cholesterol triglycerides protein
ChylomicronGolgiapparatus
SmoothER
Chylomicrons removed by lymphatic system.
Capillary
Lactealto
vena cava
Interstitial fluid
28
Activation of Pancreatic Zymogens
Pancreatic secretions(include inactive
zymogens)
Enteropeptidasein brush border
activates trypsin.
Trypsinogen
Trypsin
ACTIVATED ENZYMES
• Chymotrypsin• Carboxypeptidase• Colipase• Phospholipase
• Chymotrypsinogen• Procarboxypeptidase• Procolipase• Prophospholipase
ZYMOGENS
Lumen of small intestine Pancreatic duct
activates
Intestinalmucosa
Fig 21.17
29
Absorption in Small Intestine
Aorta
Inferior vena cava
Hepatic artery
Hepatic portal vein
Liver
Nutrients
Sinusoidsof liver Hepatic
vein
GI tract arteries
capillaries of GI tractFig 21.18
– most absorbed nutrients move into capillaries in villi, then into hepatic portal vein
• fats go into lymphatic system rather than blood
• xenobiotics must first pass through liver before reaching systemic circulation
• most fluid is absorbed in small intestine– transport of organic nutrients and ions creates osmotic gradient
30
Small Intestine; Microanatomy
Villi
Crypt
MucosaMuscularis mucosae
Submucosa
Circular muscle
Longitudinal muscleSerosa
Peyer’s patch
Lymph vesselSubmucosalplexusMyentericplexus
Submucosalartery and vein
Muscularisexterna
Fig 21.3
31
Gross Anatomy of the Large Intestine
Fig 21.19
Hepatic portal vein
Inferior vena cava
Transverse colon
Aorta Tenia coli
Ascendingcolon
Food enterslarge intestine via
ileocecal valve.Cecum
Appendix
Ileum
Sigmoid colon
Haustra
Descendingcolon
Rectum
32
Large Intestine, a closer look
Lymphoidnodule
Intestinal glandsare the site offluid secretion.
Muscularismucosae
Submucosa
Longitudinal layer(tenia coli)
Circular muscle
Defecation reflexbegins with distensionof rectal wall.
internal anal sphincter
external anal sphincter
anus
Rectum
Fig 21.19
33
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
34
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- secretione.g. cholera
• diarrhea can be adaptive (flushing out infection), but can also lead to dehydration, metabolic acidosis
35
NaCl Secretion (Small Intestine, Colon, Salivary Glands)
Negative Cl in lumenattracts Na byparacellular pathway.Water follows.
Na isreabsorbed.
Na , K, andCl enter viaNKCC transporter.
Cl enterslumen throughCFTR channel.
Lumen Interstitialfluid
ATP
Na,H2O
Na,H2O
Na
Na
K
K
K
Cl Cl 2 Cl
Fig 21.5
• crypt cells in small intestine and colon secrete ‘isotonic saline’ that mixes with mucus secreted by goblet cells to lubricate gut contents
NOTE: similar to pancreatic duct cells, Cl- secretion pulls Na+ and water into lumen– similar mechanism used in salivary glands
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
Cholera Toxin (CT)
37Vanden 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 editionFigs 15-26, 15-28
Gα-subunit turns itself off by hydrolyzing GTP.
source: Alberts (free online)Molecular Biology of the Cell, 4th editionFig 15-29
How long does a G-protein signal last?• as long as the and subunits are free …
– which is as long as the Gα-subunit is bound to GTP– normally it hydrolyzes GTP GDP within a few seconds and re-
associates with βγ-subunits
There are serious consequences of disruptions in Gα activation or inactivation.
Effect of Cholera Toxin on Inactivation of Gα Subunit
source: Lodish, et al. (free online)Molecular Cell Biology, 4th editionFig 20-17
42
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 Gα subunit – remains bound to GTP
• persistent activation of adenylyl cyclase• persistent elevation of cAMP
• sustained activation of CFTR channel
modification of Gα subunit
link to source
43
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 Cl- secretion during infection?• survive to pass on the gene to offspring??
BUT:• cholera epidemics did not strike Northern Europe until 19th century
RESPONSE:• CFTR channels involved in other diseases that were around earlier
– bronchial asthma, typhoid fever, …