GI fluids and electrolyte physiology

Question 1

Normal fluid balance in GI tract

Answer 1

• Ingest 2L and secrete 8L of fluids normally
• Absorb 9.9L, meaning there is .1L of fluid excretion
• If secretion is increased by 10%, up to 8.8L, and absorption remains at 9.9L then the net excretion is .9L (9x increase)
• This is b/c the volume of fluid secreted is 60-80x the volume of fluid excreted in stool (10% increase is 6-8x increase of fluid in stool)
• Likewise, volume absorbed is 70-100x volume of fluid excreted in stool
• Thus a 10% decrease of fluid absorbed is 7-10x increase of fluid in stool

Question 2

Leaky tight junctions of SI and osmotic diarrhea

Answer 2

• A non-absorbable solute (i.e. lactose in lactose intolerant individual) will trap water in the lumen of the SI via osmotic forces
• Since there are leaky tight junctions, NaCl will move into the lumen from ISF due to concentration gradient
• The movement of NaCl will pull more water out into the lumen (osmotically) and thus the cycle continues
• Increased volume in the SI increases peristalsis and thus transit time
• This will reduce the time allowed for absorption, and thus increase the volume and lead to a spiral of diarrhea

Question 3

Leaky tight junctions and maximizing Na-coupled absorption

Answer 3

• Leaky tight junctions allow there to be little voltage drop (-3mV) from lumen to ISF (b/c NaCl can move freely btwn the two)
• The voltage drop from cytosol to ISF is constantly -60mV
• Thus the voltage drop from lumen to cytosol is -57mV
• The goal is to get the voltage drop btwn lumen and cytosol as large a negative value as possible, so there is more energy in moving Na into the cell
• Freely moving Na btwn lumen and ISF also helps to ensure there is always Na within lumen for absorption of substrates
• Net amount of Na absorbed = net amount of Cl absorbed ([NaCl] in lumen = [NaCl] in ISF)

Question 4

NaCl absorption independent of other substrates

Answer 4

• There is Na/H exchanger (NHE) and HCO3-/Cl- (anion exchanger, AE) in apical membrane
• Na is absorbed for secretion of H+, and Cl- is absorbed for secretion of HCO3-
• This allows for absorption of Na and Cl independently of Na-coupled substrate absorption
• Na in cytosol is pumped to ISF via Na/K ATPase, Cl is pumped to ISF via KCC (K/Cl cotransporter)

Question 5

Epithelial water absorption 1

Answer 5

• The SI can absorb water even when the osmolarity of the lumen is equal to osmolarity of the ISF
• This is achieved by concentrating solutes (NaCl) in basolateral membrane infoldings (local osmosis)
• Reflection coefficients (probability of compounds moving through a layer) are large for apical membrane and small for basal lamina
• A lot of the NaCl that is absorbed is dumped out the later membrane into ISF pockets btwn cells that are in direct contact w/ basal lamina

Question 6

Epithelial water absorption 2

Answer 6

• When the NaCl (and water, following osmotic forces) is dumped out the later membrane, it is more likely to cross the basal lamina into plasma than cross the apical membrane b/c the reflection coefficient of basal lamina is smaller
• The water that’s in the intercellular spaces generates a high hydrostatic pressure and water is forced out of intercellular space across basal lamina and into circulation

Question 7

Colonic absorption of NaCl and H2O

Answer 7

• Colonic epithelial cells use NHE/AE apical transporters to absorb NaCl (similar to SI)
• The colon lacks leaky tight junctions (no paracellular movement of NaCl), which decreases the voltage drop btwn lumen and cytosol to -30mV, from -57mV
• This means that its favorable for both Na (via ENaC) and Cl (via CFTR) to move into the cell from the lumen, based only on electrochemical gradients (low [Cl] in cytosol)
• Water moves passively across membranes via AQP, following osmotic forces

Question 8

Colonic absorption of K and HCO3-

Answer 8

• Apical K channels allow K to flow from cytosol to lumen
• Apical CFTR channels allow HCO3 to flow from cytosol to lumen
• HCO3- also secreted via AE
• [K] and [HCO3] in stool are always constant, meaning that when there is 10x more water in stool there is 10x more K and HCO3
• This means during excessive excretion of fluids (diarrhea) there is also excessive excretion of K and HCO3
• Thus diarrhea leads to metabolic acidosis and hypokalemia

Question 9

Cholera toxin mechanism 1

Answer 9

• In the SI, the toxin ADP-ribosylates Ga subunit of a GPCR, locking it in an active state
• This leads to constitutively active AC, thus elevated cAMP and activated PKA
• PKA activates apical CFTR and basolateral NaCl influx mechanisms (NHE and NKCC)
• This results in transcellular secretion of Cl and paracellular secretion of Na, leading to increased H2O secretion

Question 10

Cholera toxin mechanism 2

Answer 10

• PKA also inactivates apical NHE, decreasing NaCl absorption (substrate-independent)
• This does not effect Na-coupled substrate absorption
• Thus, Na absorption can be increased by adding glucose and increasing flux thru SGLUT
• This also increases paracellular Cl absorption, and thus H2O absorption