Project 1: Probiotic bacteria stimulate intestinal nutrient/ion absorption and counteract dysregulated ion transport in IBD and infectious diarrhea: Inhibition of electrolyte (NaCl) absorption is a hallmark of IBD and infectious diarrhea. Our studies delineated novel mechanisms underlying the beneficial effects of the probiotic Lactobacillus acidophilus in enhancing intestinal nutrient/ion absorption and counteract pathogen infection. We have partially characterized the L. acidophilus-secreted factors that stimulate intestinal Cl^- absorption and counteract Citrobacter rodentium infection-induced diarrhea. My NIH-funded current research utilizes crypt-derived human intestinal organoids to delineate the molecular pathophysiology of cryptosporidiosis, a widespread diarrheal disease caused by Cryptosporidium infection and an emerging global health problem. Utilizing this novel ex vivo model as well as in vivo mouse models, our studies, for the first time, have demonstrated that Cryptosporidium infection disrupts intestinal epithelial barrier function via downregulation of key tight junction proteins and inhibits Cl^- absorption by downregulating the expression of DRA (DownRegulated in Adenoma, SLC26A3), the apical membrane Cl^-/HCO₃^- exchanger protein responsible for Cl^- absorption. Our results implicate that dysregulated ion transport and impaired barrier function could be major contributing factors to cause cryptosporidiosis. Our subsequent studies will investigate the mechanisms of Cryptosporidium infection in immunocompromised hosts, such as HIV patients, in which the parasite is known to cause fatal diarrhea.