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)

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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

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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

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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

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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

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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, …