UC San Diego

Non-typhoidal Salmonella is the most burdensome foodborne illness worldwide, yet despite its prevalence, the mechanism through which Salmonella causes diarrhea is not entirely known. Intestinal ion transporters play important roles in water absorption in the intestine, and can be a therapeutic target in Salmonella induced diarrhea, but there is not a complete understanding of which ion transporters Salmonella regulates. We have previously shown that infection with Salmonella causes decreased expression of the chloride/bicarbonate exchanger SLC26A3 (DRA; Down-Regulated in Adenoma) in the colonic tissues of mice. To better understand the mechanism

of Salmonella infection in intestinal epithelial cells, we developed an enteroid model that mimics the crypt-villus axis of the intestines, and contains the four different cell subtypes found in the intestines (enterocytes, enteroendocrine, goblet, and Paneth cells). These enteroids were converted to enteroid-derived monolayers (EDM) to allow access to the apical membrane. With this model, we looked at changes in the Wnt/NOTCH signaling pathways responsible for controlling cell fate commitment in the intestines in addition to changes in DRA in both colonic and small intestinal EDM. We hypothesized that EDM would show similar decreases in DRA to those seen in vivo, in addition to alterations in Wnt/NOTCH signaling that may be linked to DRA down-regulation. We found that expression of both DRA and NICD (of the NOTCH signaling pathway) were decreased 6 h post infection. Our work shows the possibility of using EDM as a model to uncover mechanisms that can be targeted for therapeutic developments against diarrhea caused by Salmonella infection.