Introduction: Diarrhea is still a leading cause of death in children and the elderly worldwide, especially during antibiotic therapy in transplant/immunosuppressed patients. The incidence and the severity of diarrhea has been reduced using oral rehydration solution (ORS), but it does not directly reduce intestinal secretion and may paradoxically worsen diarrhea. Consequently, new alternative anti-diarrheal therapies are needed. The calcium-sensing receptor (CaSR) is localized in numerous body tissues, but its function in the small intestine and in the colon, is still not clear. Fluid and electrolyte homeostasis (secretion and absorption) is controlled primarily in the intestine. We demonstrate the function of the CaSR in the small intestine and the colon using calcium and calcium nanoparticles solution to activate the intestinal CaSR and prevent cyclic nucleotide-induced diarrhea.
Materials and Methods: Male Sprague-Dawley rats’ small intestinal and colon segments were isolated and connected into an ex vivo bowel perfusion device. Extraluminally, the segments were perfused with HEPES buffer. Intraluminally, the small intestines were perfused with different concentrations of calcium (1.0, 5.0, and 7.0 mM) and the colon segments were perfused with and without calcium nanoparticles. The experiments were conducted both in presence and absence of Forskolin, a potent secretagogue. Secretory-absorptive function was assessed based on nanospectrophotometric measurements of FITC-Inulin, a non-absorbable fluorescent marker bound to a biologically inert sugar.
Results and Discussion: Elevated levels of luminal calcium perfusion reduced intestinal secretion, and, at higher concentrations, led to moderate absorption. Elevation of the luminal calcium concentration to 7.0 mM abolished the classical Forskolin-induced secretion. The 7.0 mM calcium-perfusate demonstrated enhanced absorption from the proximal to distal portions of the small intestine, with an approximate two-fold increase in the absorptive rate when compared to the proximal and distal small intestine perfusated with 1.0 mM and 5.0 mM of calcium. In the colon, the Forskolin perfusion rapidly induced considerable secretion. The addition of calcium nanoparticles to the perfusate resulted in a return to a normal secretion profile, indicating prevention/abatement of cyclic nucleotide-induced diarrhea.
Conclusion: The present study provides evidence of the functional activity of apical CaSR from the proximal to the distal portions of the small intestine and the colon segments. Furthermore, CaSR activation through calcium nanoparticles abates Forskolin induced fluid secretion and can lead to absorption of fluid at higher concentrations, despite continued presence of the cyclic nucleotide activator. Calcium and calcium nanoparticles can mitigate secretagogue-induced diarrhea. These results suggest that the use of nanoparticles may be a potential treatment or a prophylactic therapy of diarrhea.