Glossary of 6 - Intestinal secretions

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What are three functions of water in the GI tract?
1.Serves as a medium for the movement of food.
2.Facilitates the action of aqueous digestive enzymes
3.Hydration of mucin to form mucus
What are two ways that water enters the intestinal lumen, and what is the quantity of water that enters daily?
1.Dietary intake - 3L/day
2.Intestinal secretion (transfer from the body) - 6L/day
What powers the movement of water from the interstitium to the lumen?
*osmotic driving force set up by the presence of food particles in the lumen
*additionally, secreted electrolytes act as osmolytes to add to the driving force
What channel is used to allow the passage of water through the intestinal epithelium from the interstitium to the lumen?
Aquaporin 8 (AQP-8)
Give three examples of secreted electrolytes that can behave like osmolytes.
1.NaCl is secreted from crypt cells
2.NaHCO3 is secreted by the pancreas
3.HCl is released by gastric glands
In general, how is the flow of water reversed from secretion to absorption?
As nutrients (e.g. glucose and amino acids) are absorbed by intestinal epithelium, the osmotic gradient is reversed and water is also absorbed.
What two transporters can be found on the basolateral membrane of the crypt cells? What molecules do they move and in what direction?
1.Na+/K+ ATPase: Na+ out of cell, K+ into cell
2.Na+/K+/2Cl-: all three ions moved into the cell
What channels are found on the basolateral membrane of the crypt cells?
*K+ leak channels that allow efflux of K+ to the interstitium
*AQP-8 channels that allow the movement of water
What is the RMP of the basolateral membrane of the crypt cells? What purpose does this serve?
*RMP is negative and close to E-K+
*the negative RMP creates a driving force on Cl- to push it across the apical membrane and into the lumen when CFTR channels are open
Where in the intestine are CFTR channels found? How are they regulated?
*apical membrane of crypt cells
*activated by PKA, which activated by cAMP
*production of cAMP is stimulated by VIP and inhibited by somatostatin
Describe how the opening of CFTR channels will eventually result in the movement of water into the lumen.
*Cl- moves through CFTR and into the lumen
*as [Cl-] increases, Na+ runs down the electrical gradient through paracellular channels and into the lumen
*high [NaCl] creates a osmotic gradient that draws water through AQP-8 and into the lumen
What are the driving forces on Cl- which push it out of the crypt cells and into the lumen?
*there is a high intracellular [Cl-] created by the Na+/K+/2Cl- transporter
*there is an electrical driving force created by the negative RMP of the basolateral membrane
Describe how defective CFTR are pathogenic in cystic fibrosis.
The defective CFTR result in inadequate movement of water across epithelial surfaces. As a result, mucin is poorly hydrated and mucus remains very thick and viscous. This has a variety of effects depending on the affected tissue.
How is Na+ absorbed in the distal colon? What stimulates this action?
*ENaC is expressed on the apical membrane of the epithelia
*aldosterone stimulates absorption of Na+ through these channels
How does the distal colon help to regulate the body's K+ status?
*varied expression of K+ channels that allow secretion
*activation of K+/H+ ATPase which allows absorption of the ion
In general, how can the absorptive and secretory actions of the distal colon best be described?
*absorbs NaCl
*secretes KHCO3
Why are hypokalemia and acidosis often seen in diarrhea?
The fluid in the colon is high in K+ and HCO- so excessive loss of this fluid leads to the hypokalemia and acidosis.
What are the ingredients of an effective oral rehydration solution? Give the reason for the inclusion of each.
1.NaCl, glucose, and amino acids increase volume - as each is absorbed they create an osmotic gradient that draws water out of the lumen
2.NaHCO3 - raises pH to counter acidosis
3.KCl - replaces K+ to counter hypokalemia
What is the difference between malabsorptive and secretory diarrhea?
*malabsorptive is due to an inability to absorb nutrients from the lumen
*secretory is due to inappropriate secretion of material into the lumen
How does milk of magnesia work as a laxative?
Magnesium is poorly absorbed by the intestinal tract and thus can stimulate malabsorptive diarrhea.
Why is steatorrhea seen with Zollinger-Ellison disease?
The disease involves a gastrin-secreting tumor which stimulates heavy secretion of HCl into the gastric lumen. The high acidity inhibits the action of pancreatic enzymes and fats are thus poorly broken down and absorbed.
Why is malabsorptive diarrhea seen in Crohn's disease and ulcerative colitis?
The absorptive capacity of the intestinal mucosa is decreased by inflammatory processes.
How does the cholera toxin enter the intestinal epithelium?
It binds receptors on the basolateral membrane and is endocytosed.
How does the cholera toxin cause secretory diarrhea?
Once in the cell, it ribosylates G-proteins which then activate adenylate cyclase. As [cAMP] increases, there is heavy activation of CFTR and large amounts of Cl- move into the lumen. This draws Na+ and water into the lumen in a gross exaggeration of the normal process.
What is pancreatic cholera?
A non-islet tumor in the pancreas secretes large amounts of VIP which activates the CFTR pathway and results in massive efflux of Cl- into the lumen.
How can pancreatic cholera be treated medically?
A stable analog of somatostatin is given which has the dual action of inhibiting the CFTR pathway and release of VIP from the tumor.
Where on the intestinal epithelium does the heat-stabile toxin produced by E.coli bind? What is the effect of toxin binding? How does this cause diarrhea?
The toxin binds GCC receptors on the apical membrane which activates guanylate cyclase and cause and increase in cGMP. cGMP activates the CFTR pathway causing efflux of Cl- as in cholera.
What is guanylin? What is its proposed function?
A peptide that is secreted by goblet cells concurrently with mucin. It is thought that guanylin binds the GCC receptor and facilitates the movement of water into the lumen, thus ensuring the proper hydration of mucin.

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