Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells

Abstract

Cholera is a global health problem with no targeted therapies. The Ca 2+ -sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca 2+ is considered its main agonist. We found that increasing extracellular Ca 2+ had a minimal effect on forskolin-induced Cl – secretion in human intestinal epithelial T84 cells. However, extracellular Mg 2+ , an often-neglected CaSR agonist, suppressed forskolin-induced Cl – secretion in T84 cells by 65% at physiological levels seen in stool (10 mM). The effect of Mg 2+ occurred via the CaSR/Gq signaling that led to cAMP hydrolysis. Mg 2+ (10 mM) also suppressed Cl- secretion induced by cholera toxin, heat-stable E . coli enterotoxin, and vasoactive intestinal peptide by 50%. In mouse intestinal closed loops, luminal Mg 2+ treatment (20 mM) inhibited cholera toxin–induced fluid accumulation by 40%. In a mouse intestinal perfusion model of cholera, addition of 10 mM Mg 2+ to the perfusate reversed net fluid transport from secretion to absorption. These results suggest that Mg 2+ is the key CaSR activator in mouse and human intestinal epithelia at physiological levels in stool. Since stool Mg 2+ concentrations in patients with cholera are essentially zero, oral Mg 2+ supplementation, alone or in an oral rehydration solution, could be a potential therapy for cholera and other cyclic nucleotide–mediated secretory diarrheas.

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

“…The solutions were aerated with 95% O2 /5% CO2 and maintained at 37°C during experiments. Short-circuit current (Isc) was measured using an EVC4000 multichannel voltage clamp (World Precision Instruments, Sarasota, FL, USA) via Ag/AgCl electrodes and 3 M KCl agar bridges as previously described (54).…”