- Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn 2+ acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn 2+ we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn 2+ and ZnR/GPR39 are both required for a beneficial effect of Zn 2+ in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl − transport, a critical factor in diarrhea, by upregulating K + /Cl − cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl − absorption pathway. Finally, inhibition of KCC-dependent Cl − transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn 2+ acting via ZnR/GPR39 has a direct role in controlling Cl − absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.