Project Summary / Abstract Diarrhea causes monovalent (e.g., Na+, K+, Cl- and HCO3-) and divalent (e.g., Zn2+, Ca2+) ion losses. Unlike the losses of monovalent ions which are large and are therefore replaced through rehydration therapy, the losses of divalent ions are relatively small in osmoles and are often overlooked during diarrheal treatment. Studies now suggest that despite divalent ions contributing relatively few osmoles in the stool, their effects are large due to the presence of divalent ion-sensing receptors (e.g., Zn2+-sensing receptor, ZnSR; Ca2+-sensing receptor, CaSR) and their amplifying effects in the gut. As a result, losses of these divalent ions without replacement may affect the magnitude of, or recovery from acute diarrheal illnesses. Without replacement of Zn2+ and restoration of ZnSR anti-diarrheal function, diarrhea is more severe and protracted; adding back Zn2+ and correcting ZnSR defect reduce the severity and duration of diarrhea. This is well documented. However, information on the role of Ca2+ and CaSR in diarrhea is limited. The PI’s laboratory at the University of Florida was the first to report the presence of a potent Ca2+/CaSR-based antidiarrheal mechanism in the gastrointestinal tract. After demonstrating Ca2+/CaSR action in childhood diarrhea in laboratory animals, the PI and his coworkers presented clinical evidence in few cases of children with diarrheal diseases. These preliminary studies in humans show that, like Zn2+, without correcting negative Ca2+ balance, diarrheal symptoms were more severe or more protracted and that, with replacement of Ca2+, diarrhea was both promptly and dramatically reduced in both animals and humans. Based on this, it is hypothesized that an ideal diarrhea replacement therapy will be a solution that replaces both monovalent ions and divalent minerals, particularly Ca2+. However, so far, no formal randomized controlled trials (RCTs) on Ca2+ replacement in diarrheal patients have been performed. This proposed study represents the first of such efforts. In this initial study, we propose to obtain pilot data to demonstrate the safety and effect size of Ca2+ replacement on clinical outcomes (stool output and diarrhea duration) in adults with acute infectious diarrhea before more powerful and expensive RCTs are conducted, including in infants and young children. We anticipate that prompt replacement of Ca2+ will significantly reduce the severity and shorten the duration of diarrhea symptoms.