Question

Cholera and other diarrheal diseases cause nearly 2 billion cases of diarrhea annually. Cholera toxin and other bacterial toxins cause the intestine to secrete fluid into the lumen of the gut, depleting the extracellular fluid (ECF) volume. If fluid loss is not matched with fluid intake (law of mass balance), the result is severe dehydration, circulatory collapse, and even death. Drinking a rehydration solution is the most rapid and effective way to replace the large volumes of water lost by diarrhea, and the World Health Organization (WHO) includes packets of oral rehydration powders in its list of essential medicines.

But how was the formula for oral rehydration powders developed? In one of those happy coincidences, researchers Stan Schultz and Ralph Zalusky at Brooks Air Force Base in San Antonio, TX, were studying sodium uptake by the rabbit intestine and added glucose to the saline solution in the lumen. The setup for this isolated intestine experiment is shown in Figure 1. A section of isolated intestine is tied into a sac, filled with saline (NaCl solution), and suspended in a saline bath. The inside of the sac is the lumen of the intestine, also known as the mucosal surface.

Figure 1. Intestinal sac preparation for studying intestinal transport

After measuring Na⁺ transport with only a NaCl solution inside the sac, Schultz and Zalusky added glucose to the sac of saline. The results are shown in Figure 2.

Figure 2. The effect of added glucose on sodium transport

Part A - Glucose and sodium transport

What effect did the addition of glucose have on Na⁺ transport?

Na⁺ transport increased.

Na⁺ transport did not change.

Na⁺ transport decreased.

Part B - Glucose and water absorption

What effect would adding glucose to the NaCl solution in the lumen have on water absorption by the intestine?

Water absorption would decrease.

Water absorption would not change.

Water absorption would increase.

Part C - Directional transport  

What would happen to Na⁺ transport if glucose was added only to the solution bathing the outside (ECF side) of the gut sac, as shown in Figure 2?

Na⁺ transport would not change.

Na⁺ transport would decrease.

Na⁺ transport would increase.

Part D - Fructose transport   

Schultz and Zalusky repeated the experiment shown in Figure 2, but this time they added fructose to the sac instead of glucose. Based on the model shown in Figure 3, what do you think happened to Na⁺ transport when they added fructose?

Na⁺ transport increased.

Na⁺ transport did not change.

Na⁺ transport decreased.

Part E - Intestinal transport terminology

Drag these terms into the correct label on the figure.

Mucosal solution
Plasma
Serosal solution
Apical membrane
Basolateral membrane

Part F - Effect of ouabain on sodium transport  

Why would adding ouabain to the serosal side of the sac decrease Na⁺ transport, but adding it to the mucosal side had little effect? (Transport normally declines slowly over time in isolated tissue preparations.)

Ouabain decreases the sodium transport by decreasing the ATP production in the cell.

Ouabain is inactivated in the mucosal membrane.

Ouabain inhibits the active transport of sodium out of the cell, which is necessary to keep Na⁺ concentrations in the cell low.

These studies by Schultz and Zalusky provided the definitive link between glucose absorption and salt and water absorption by the intestine. It was not long after publication of their work that researchers put the basic principle of Na⁺-linked glucose transport into clinical practice.

One of the first controlled studies investigated how administration of various fluids would affect diarrhea output in cholera patients. During an outbreak of cholera in Bangladesh in the 1960s, N. Hirschhorn and colleagues placed tubes into the gastrointestinal tracts of patients. Through these tubes they could deliver measured volumes of solutions to the patients’ intestines. The solutions contained electrolytes such as Na⁺, K⁺, Cl⁻, and HCO₃⁻ , with or without varying concentrations of sugars. The researchers then measured stool (feces) output volume over time. They were able to calculate a net stool output rate from the difference in stool output volume and fluid input volume per unit time.

Part G - Net stool output

Recall that cholera toxin causes a secretory diarrhea, where the fluid in the diarrhea (stool output) has been transported from the ECF to the lumen of the gut. What would a negative net stool output rate mean?

Stool output/time exceeds fluid input/time.

Fluid input/time exceeds stool output/time.

Stool output decreased.

No solution was being administered through the tube.

Some of Hirschhorn et al.’s results from administering solutions with varying concentration of glucose are shown in Figure 5.

Figure 5. Effect of increasing concentrations of glucose in perfusion solutions on net stool output rate. Figure developed from data in Hirschhorn et al., 1968.

Part H - Effect of added glucose on stool output in cholera

Which statement best explains the effect of increasing glucose concentration in the perfusion solution on net stool output rate?

Glucose had no effect because electrolytes administered through the tube always decreased the net stool output rate, regardless of the glucose levels.

Absorbing a greater quantity of glucose increased fluid absorption and thereby decreased the net stool output rate.

More glucose in the perfusion solution meant that there was less water in the solution to make stool with.

Stool production was decreasing over time as the patients recovered from cholera, and adding glucose did not change the rate of this decrease.

Part I - Comparing glucose, galactose, and fructose

Why didn’t net stool output rate decrease significantly with fructose?

Fructose absorption does not bring as much water because fructose has a smaller molecular weight than glucose and galactose.

Fructose can’t be absorbed without glucose in the intestine.

Fructose absorption doesn’t require sodium transport and results in a lower solute transport and lower water absorption.

GLUT transporters only transport hexose sugars, and fructose has a 5-carbon ring, not a 6-carbon ring.

GLUT transporters only transport sugars that start with G.

Answer 1

Part A
Na transport increase

sodium absorption from oral rehydration solution is increased by both glucose-sodium cotransport and solvent drag

Part b
Increase water absorption

In the small intestine, water absorption is brought about by the creation of suitable osmotic gradients that promote net uptake of water from the intestinal lumen. The absorption of solute, especially that brought about by active carriers, are highly effective in creating the osmotic gradients that promote net water uptake. The activation of these transporters also increases the permeability of the mucosa which helps absorption. Moderate hypotonicity of the luminal contents potentiates solute-induced water absorption while hypertonicity slows fluid absorption. Dilute hypotonic glucose-sodium solutions are highly effective oral rehydration solutions
The co-transport of glucose into epithelial cells via the SGLT1 protein requires sodium. Two sodium ions and one molecule of glucose (or galactose) are transported together across the cell membrane via the SGLT1 protein. Without glucose, intestinal sodium is not absorbed. This is why oral rehydration salts include both sodium and glucose. For each cycle of the transport, hundreds of water molecules move into the epithelial cell to maintain osmotic equilibrium. The resultant absorption of sodium and water can achieve rehydration

Part c
Na transport does not change

cell can't import glucose for free using diffusion, because the natural tendency of the glucose will be to diffuse out rather than flowing .it's transport along with Na .carrier protein lets sodium ions move down their gradient, but simultaneously brings a glucose molecule up its gradient and into the cell. The carrier protein uses the energy of the sodium gradient to drive the transport of glucose molecules.