Unit 6B: Regulation of GI fucntion

long reflexes integrated in CNS

1. sensory info from GI tract to CNS

2. “feed forward” reflexes that originate outside GI tract

3. efferent limb always autonomic

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

excitatory → excitatory

sympathetic → generally inhibitory

short reflexes, integrated within gut, in “enteric nervous system”

1. neurons in submucosal plexus receive signals from lumen, regulate secretion

2. neurons in myenteric plexus regulate motility

reflexes involving gut peptides

1. can act locally (paracrine) or travel via blood (endocrine)

   • effects on motility 0 altered peristalsis, gastric emptying et al.

   • effects on both exocrine and endocrine secretion

2. some gut peptides also act on brain (some even produced there)

parallels between enteric and central nervous system

1. 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

2. releases more than 30 different neurotransmitters and neuromodulators

   • not norepinephrine/ epinephrine/acetylcholine but otherwise similar to moelcules used in CNS

3. has glial support cells (similar to astrocytes of CNS)

4. diffusion barrier

   • capillaries surrounding ganglia are not very permeable (similar to blood-brain barrier)

5. act as integrating centre

   • gut function can be regulated without CNS

Beginnings of Endocrinology Pavlov

1. acid chyme passing into duodenum → pancreatic juice secreted

2. vagal afferents from duodenum to brain → vagal efferents from brain to pancreas → pancreatic juice secreted into duodenum

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

beginnings of Endocrinology Bayliss and Starling

1. carefully dissected away from all nerves surrounding pancreas and duodenum

   • put acid in the duodenum

   • pancreas still secreted

2. hypothesis: acid caused release of signal from duodenum

3. tested hypothesis: collected lining of duodenum, added acid to it, injected it intravenously → pancreatic secretion

factor from intestine that stimulated pancreatic secretion called

secretin

general term coined for blood-borne regulators

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

motility overview

1. swallowing, chewing

2. mixing and propulsion (peristalsis)

3. mixing and propulsion mostly by segmentation

4. segmental mixing mass movement for propulsion

saliva - secretion under autonomic control

• softens and lubricates food

• digestion: salivary amylase, some lipase

• antimicrobial: lysozyme, immunoglobins

chewing

mastication

transfer to stomach

deglutition (swallowing)

digestion begins in the mouth

1. saliva

2. chewing

3. transfer to stomach

swallowing reflex

1. tongue pushes bolus against soft palate and back of mouth swallowing reflex

2. breathing inhibited as bolus passes 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

lower esophageal sphincter guards entry into stomach

tonically contracted ring of smooth muscle

if LES not closed, acid from stomach can splash up into lower esophagus

1. during respiration (when intrathoracic pressure drops)

2. during churning of stomach = gastroesophageal reflux disease (GERD) = heartbern

Control of GI Function: Cephalic and Gastric Phase

1. anticipation of food/presence of food in mouth

2. activation of neurons in medulla

3. efferent signals to salivary glands, autonomic signals via vagus to enteric NS

4. increased motility and secretion in stomach, intestine, accessory organs

initiated with long vagal reflex

cephalic phase

once food enters stomach, series of short reflexes

gastric phase

three functions of the stomach

1. storage

2. digestion

3. protection

1. 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”

2. stomach digestion

mechanical and chemical processing into chyme

• secretions begin before food arrives..

  • enzymes, acid, hormones

3. stomach protection

against microbes → acid

• self protection → mucus bicarbonate barrier

secretory cells of gastric mucosa

1. parietal cells

2. chief cells

3. enterochromaffin-like cell

4. G cells

5. D cells

parietal cells secrete gastric acid and intrinsic factor

• 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 reflexes

• multiple roles…

somatostatin from D cells

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

ph at stomach lumen

gastric juice pH ~ 2

pH at mucus layer

bicarb - chemical barrier pH ~ 7 at cell surface

breakdown of mucus-bicarb barrier

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

main treatment for peptic ulcers

antacids - substances that neutralized gastric acid like tums

more modern approaches for treatment of peptic ulcers

1. H2 receptor antagonists → block histamine action (pepcid)

2. proton pump inhibitors → block H+/K+ - ATPase (prilosec)

concentration of H+ in lumen vs parietal cell

lumen can be as low as pH , parietal cell is ~ 7.2, so [H+] a million times higher in lumen

acid secretion by parietal cells

as H+ secreted from apical side, bicarb (from CO2 + OH) is absorbed into blood - “alkaline tide” from stomach can be measured after a meal

stimulation of parietal cell acid secretion

resting parietal cell, gastrin, histamine, Ach → acid-secreting parietal cell

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

bicarb from pancreas (duct cells) stimulated by

neural, secretin to neutralize chyme

mucus from goblet cells stimulated by

increase of inflammation to protect and lubricate

bile from gall bladder liver) stimulated by

CCK (presence of fats, protein) for fat digestion

enzymes (as zymogens) from pancreas (acini) brush border stimulated by

neural, CCK, distension (presence of food) for digestion

bile salts can be

recycled multiple times within a meal

bile salts are released into duodenum then,

absorbed in terminal ileum, enter portal circulation, travel back to liver

activation of pancreatic zymogens

1. pancreatic secretions (include inactive zymogens) from pancreatic duct

2. enteropeptidase in brush border activates trypsin (trypsinogen → trypsin)

3. activates zymogens to enzymes

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)

motility: segmental contractions with little forward movement except when mass movements occur (3-4 times per day)

wave of contractions that send bolus forward, trigger distention of rectum → defecation reflex

diarrhea is bc

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 (b/c losing bicarb)

NaCl Secretion (small itnestine, colon, salivary glands)

1. Na+, K+, and Cl- enter via NKCC transporter

2. Cl- enters lumen through CFTR channel

3. Na+ is reabsorbed by Na+/K+ atpase

4. Negative Cl- in lumen attracts Na” by paracellular pathway, water follows

crypt cells in small intestine and colon secrete

“isotonic saline” that mixes with mucus secreted by goblet cells to lubricate gut contents

cholera intestinal infection, vibrio cholerae need to ingest

~ 100 million bacteria - lower doses can cause infection in

• people with reduced gastric acidity

• young children

• immune suppressed individuals

vibrio cholerae bacteria must survive acidity of stomach

then reach small intestine → attach to and invade intestinal epithelial cells → produce toxin

effect of cholera toxin on inactivation of G alpha subunit

cholera toxin prevents inactivation of G alpha subunit causing persistent activation of adenylyl cyclase blocking GTP hydrolysis

intracellular trafficking of cholera toxin

1. enters cell via pentameric B subunits

2. travels in retrograde direction through Golgi

3. sequence on A2 subunit recognized as signal to be shuttled to ER

4. mimics a misfolded protein and gets dumped out into cytosol (normally to be degraded)

5. instead, A1 subunit (enzyme) modifies G alpha subunit - bound to GTP

6. persistent activation of adenylyl cyclase

7. persistent activation of cAMP

8. sustained activation of CFTR channel

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???

cholera epidemics did not strike northern europe until

19th century

CFTR channels involved in other diseases that were around earlier

coliform diarrhea, bronchial asthma, typhoid…