16 Small Bowel Physiology Part 1

Question 1

Small bowel (p.3)

• measures/
• many/
• provides/
• interface between/
  
  • chyme
• Proper function requires/

Answer 1

• measures about 4 m in length.
• many macro- and microscopic invaginations,
• provides a large surface for absorption of ingested water, minerals and nutrients.
  
  • absorbs at least 7 liters of fluid
• interface between the various constituents of the chyme (ingested materials) and the body.
  
  • chyme contains potentially antigenic substances or pathogenic organisms.
• Proper function requires
  
  • an intact epithelium,
  • normal regulation of epithelial function, blood flow and intestinal motility, which mixes and propels luminal contents.

Question 2

Polarity within the Small Bowel:
Crypt-villous axis (p.4-5)

• The basic functional unit responsible for the absorptive capacity of the intestine
• ​polarity
• Cells
  
  • divide/
  • slowly migrate/
  • during this migration/
• Enterocytes

Answer 2

• The basic functional unit responsible for the absorptive capacity of the intestine is the epithelial cell.
• polarity
  
  • It is polar with an apical surface, facing the lumen, and a basolateral surface.
  • microvilli increase the surface area and, thereby, absorptive capacity at the luminal side.
  • differential expression of molecules
• Cells
  
  • divide in the base of the crypt
  • slowly migrate to the villus tip, where they eventually undergo apoptosis.
  • During this migration, cellular characteristics change from primarily secretory to more absorptive properties
• Enterocytes
  
  • Proliferation: crypts
  • Migration to villus tip (4 – 7 days)
  • Paneth cells (lysozymes, defensin)
  • Enteroendocrine cells (hormones)

Question 3

Polarity within the Small Bowel:
Another axis exists along the entire length of the small intestine (p.6-7)

• Differences in the epithelium
• the expression of enzymes and transporters involved in glucose uptake/
  
  • iron, calcium, folate uptake and absorption of fat-soluble vitamins/
  • bile acids and vitamin B12/
• Proximal small bowel
• Distal small bowel
• Entire small bowel

Answer 3

• The epithelium is more permeable (‘leaky’) proximally and shows a progressive increase in transepithelial resistance as one looks more distally.
  
  • There are also differences in absorptive pathways.
• the expression of enzymes and transporters involved in glucose uptake is highest proximally and decreases aborally
  
  • iron, calcium, folate uptake and absorption of fat-soluble vitamins in the proximal gut,
  • bile acids and vitamin B12 are preferentially taken up in the ileum.
• Proximal small bowel:
  
  • Active calcium uptake
  • Folate
  • Thiamine
  • Niacin
  • Fat-soluble vitamins
  • Iron
• Distal small bowel:
  
  • Passive calcium uptake
  • Magnesium
  • Bile acids
  • Vitamin B12
• Entire small bowel:
  
  • Vitamin C

Question 4

Pathways of Transport (p.8)

• The epithelium constitutes a barrier for/
  
  • Solutes and water/
  • Tight junctions/
  • The lipid bilayer/
    
    • specialized transport systems/
  • Pinocytosis
• Fluxes across the semi-permeable epithelium are/
  
  • The energy determining the direction of these fluxes may be/
  • specialized molecules typically/

Answer 4

• The epithelium constitutes a barrier for the exchange of water and solutes between the two different sides of the gut wall (luminal and ‘serosal’).
  
  • Solutes and water can cross this barrier by passing in between (paracellular transport) or through (transcellular transport) cells
  • Tight junctions limit and regulate the permeability of paracellular transport.
  • The lipid bilayer functions as a significant barrier for fluxes of water and water-soluble substances.
    
    • specialized transport systems evolved to facilitate and regulate transport of these substances.
  • Pinocytosis (incorporation of substances by endocytosis of vesicles) plays only a minor role in intestinal absorption.
• Fluxes across the semi-permeable epithelium are directed (i.e. in the case of absorption move from mucosal to serosal side) and require driving forces.
  
  • The energy determining the direction of these fluxes may be concentration gradients, electrical potentials or may require direct energy expenditure to move molecular against a gradient.
  • specialized molecules typically break down ATP as they transport molecules into or out of the cell.

Question 5

Pathways of Transport:
Much of the transepithelial flux can be viewed as a two step process (p.9)

Answer 5

• One step involves the flux across the membrane following a favorable electrochemical gradient.
  
  • As the permeability of the lipid bilayer for hydrophilic substances is low, specialized transmembrane proteins (ion channels, transporters) typically enhance this flux.
• On the contralateral site of the cell, an active (= ATP consuming) transport process takes place, thus maintaining the gradient allowing the first step.
  
  • These transport processes in series are often referred to as pump-leak sequence

Question 6

Antiporter / Exchangers (p.10-18)

• Several specialized transporters have been identified in epithelial cells.
• the Na+/H+ exchanger
• Deletion of one subtype of the antiporter/
• A chloride/bicarbonate exchanger/

Answer 6

• Several specialized transporters have been identified in epithelial cells.
  
  • These antiporters generally exchange one intracellular ion (e.g. H+) against a similarly charged extracellular ion (e.g.Na+).
  • This process does not require energy and can go in both directions.
  • However, concentration differences will favor movement in one direction, leading to net fluxes.
• the Na+/H+ exchanger is responsible for sodium uptake.
  
  • As sodium and other solutes drag along water, decrease or lack of this molecule should result in diarrhea.
• Deletion of one subtype of the antiporter increases stool weight (= diarrhea) and increases stool pH
  
  • rare inherited diarrheal diseases are due to mutations of these antiporters.
  • the expression of these molecules changes during inflammation, thereby contributing to diarrhea.
  • upregulation of these exchangers may increase absorption and may contribute to the adaptation seen in patients with short gut syndrome.
• A chloride/bicarbonate exchanger transports chloride into the cell and typically acts in parallel to the Na+/H+ exchanger.
  
  • These two antiporters together get NaCl into the cell.
  • If the anion antiporter is absent, one would also expect diarrhea.
  • patients with a rare genetic form of diarrhea (“congenital chloride diarrhea”) do not express this molecule.

Question 7

Pumps (p.19-22)

• leak-pump sequence.
• the importance of blockers (‘digitalis’) in managing cardiac diseases.
• Diarrhea/
• inflammation/

Answer 7

• leak-pump sequence.
  
  • The antiporter facilitates sodium entry.
  • As more and more sodium moves into the cell, the concentration gradient is lost.
  • To maintain this gradient and allow ongoing absorption, the cell has to actively move (‘pump’) sodium out of the cell at the basolateral side.
  • The N+/K+ ATPase performs this task.
• the importance of blockers (‘digitalis’) in managing cardiac diseases.
  
  • Ouabain has been tested in the gut.
  • the inhibition of the pump does not allow extrusion of sodium at the basolateral side.
    
    • The resulting decrease in the electrochemical gradient for sodium impairs sodium absorption from the lumen
• Diarrhea is not a common side effect of clinically used Na+/K+ ATPase inhibitors (largely due to other dose limiting side effects).
• inflammation decreases the expression of this molecule, which may contribute to a resulting diarrhea.

Question 8

Ion Channels (p.23)

• Epithelial cells express several ion channels, which are important in/
• They can be seen as/
• Channels have different /

Answer 8

• Epithelial cells express several ion channels, which are important in absorption and / or secretion.
• They can be seen as a regulated pore that will open (=flux) or close (=no flux) depending on tight regulatory processes, such as the generation of intracellular messengers (e.g., calcium or cyclic nucleotides).
• Channels have different selectivity for ions.
  
  • Some may be rather promiscuous, other highly selective.

Question 9

Ion Channels:
Potassium channels (p.24)

• intracellular potassium concentration
• potassium ions will/
• The net efflux of positively charged potassium ion leaves the cell/

Answer 9

• intracellular potassium concentration is high.
• potassium ions will leave the cell through these channels.
• The net efflux of positively charged potassium ion leaves the cell negatively charged, which drives sodium influx and thus provides an important driving force for absorptive processes in the gut.

Question 10

Ion Channels:
Chloride channels (p.25-30)

• regulated by/
• cystic fibrosis transmembrane conductance regulator (CFTR).
  
  • cystic fibrosis (CF)
  • the CFTR channel
  • Normally, hormones/
• Cholera toxin
  
  • activates/
  • patients with cholera develop/
  • cholera toxin vs. CFTR

Answer 10

• regulated by different intracellular signals.
• cystic fibrosis transmembrane conductance regulator (CFTR).
  
  • cystic fibrosis (CF)
    
    • a gut disease.
    • The earliest manifestation is the delayed passage of meconium or even an obstruction due to meconium.
    • something is wrong with intestinal secretion.
  • the CFTR channel
    
    • important in secretion.
    • activated by cAMP.
  • Normally, hormones (e.g., VIP) activate a G protein-coupled receptor, which in turn triggers activation of adenylate cyclase, generation of cAMP and phosphorylation of the channel, which in turn opens the pore and allows chloride fluxes.
• Cholera toxin
  
  • activates a G protein alpha subunit that generates cAMP.
  • patients with cholera develop profound secretory diarrhea.
  • cholera toxin is not quite as bad when CFTR is mutated.

Question 11

Ion Channels:
Aquaporins (p.31-34)

• allow/
• water will move/
• osmotically active substances/
• This mechanism also accounts for/

Answer 11

• allow passive flow of water, which can not easily cross the lipid membrane of cells.
• water will move wherever there are more solutes (=osmotic forces).
• osmotically active substances increase stool volume.
• This mechanism also accounts for osmotic diarrhea you see in malabsorption.

Question 12

Clinical Context (p.35-36)