Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea

ABSTRACT Hydroxylases are oxygen‐sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl− secretion, the driving force for fluid secretion, is dependent on O2 availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short‐circuit current changes across voltage‐clamped monolayers of T84 cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca2+‐ and cAMP‐dependent secretory responses in voltage‐clamped T84 cells to 20.2 ± 2.6 and 38.8 ± 6.7% (n= 16; P