Can We Treat Diarrhea by Stimulating Na+ Absorption?

Drugs designed to increase intestinal absorption of sodium might be the best approach for treatment of diarrheal diseases, according to the Advances in Translational Science article in the January issue of Clinical Gastroenterology and Hepatology.

Acute diarrheal diseases are the second leading cause of of death in children under 5 years old. Worldwide, there are an estimated 1.7 billion cases, and diarrhea is responsible for killing approximately 760, 000 children every year. In the US,  adults experience 99 million episodes of acute diarrhea or gastroenteritis, resulting in about 8 million physician visits and more than 250,000 hospital admissions each year (1.5% of adult hospitalizations).

There are some drugs for treatment of diarrhea, including opiates, which only moderately decrease stool output; racecadotril, which has inconsistent effects on acute diarrhea in children; and crofelemer—a CI^– channel inhibitor approved by the FDA for treatment of HIV-associated diarrhea.

However, oral rehydration solutions still account for the greatest reductions in mortality among children in developing countries. These solutions rehydrate patients but don’t necessarily reduce stool output or length of illness. More effective drugs are needed.

Diarrheal diseases develop via altered intestinal transport of electrolytes and water. Epithelial cells in the villus of the small intestine or surface and upper crypt of the colon mostly absorb Na⁺, whereas those in the lower crypt primarily secrete Cl^– and HCO₃^– . Infectious agents that cause diarrhea alter electrolyte transport and intestinal permeability by inhibiting Na⁺ absorption and stimulating anion and K⁺ secretion (see figure).

The plasma membrane of each intestinal epitheial cell is divided into the apical (brush border) and basolateral membrane. Specific membrane transport proteins segregate to either side of these cells, and are required for electrolyte transport (absorption and secretion), which contributes to intestinal Na+ absorption. Reagents are needed to either reverse the changes in transport that occur in diarrhea and/or stimulate other transport processes to compensate for these changes.

Varsha Singh et al. review drugs that might be used to treat diarrhea by stimulating intestinal Na⁺ absorption. They describe the molecular mechanisms by which intestinal water and Na⁺ are absorbed in healthy people and how those processes change during development of diarrhea.

Singh et al. discuss the therapeutic potential of agents designed to stimulate intestinal absorption of Na+. These would alter activities of the brush border Na+/H+ exchanger (NHE3), the Cl–/HCO3– exchanger SLC26A3 (DRA), the Na+ D-glucose linked co-transporter 1 (SGLT1), or the epithelial Na+ channel (ENaC).

Another approach to increase intestinal absorption of Na+ involves addition of zinc to oral rehydration solutions—zinc inhibits stimulated Cl^– secretion to reduce the duration of diarrhea. Furthermore, the intestinal calcium-sensing receptor (CaSR) regulates intestinal secretion and absorption. Stimulating the CaSR with either calcium or sensitizing (calcimimetic) compounds reverses changes in colonic Na+ absorption and Cl– secretion caused by bacterial toxins.

Singh et al. explain that drugs currently approved to stimulate NaCl absorption are restricted to analogues of physiologic regulators including mu agonist opiates, somatostatin, and clonidine (an alpha₂ adrenergic receptor agonist). These agonists have all been used to treat diarrhea but are limited by side effects, high costs, requirement for parenteral administration, or limited potency. Although modifications of these classes of drugs might be developed, new ways to stimulate Na⁺ absorption are needed.

However, the authors conclude that drug development is a slow process, and no lead compounds that stimulate neutral NaCl absorption are likely to emerge as useful treatments of diarrhea any time soon.