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Clostridium difficile Toxins A and B Decrease Intestinal SLC26A3 Protein Expression

Coffing, HP;Priyamvada, S;Natarajan Anbazhagan, A;Salibay, C;Engevik, MA;Versalovic, J;Yacyshyn, MB;Yacyshyn, BR;Tyagi, S;Saksena, S;Gill, RK;Alrefai, WA;Dudeja, PK;

Clostridium difficile infection is the primary cause of nosocomial diarrhea in the United States. While C. difficile toxins A and B are the primary mediators of CDI, the overall pathophysiology underlying C. difficile associated diarrhea remains poorly understood. Studies have shown that both NHE3 (Na+/H+ exchanger) and DRA (Down Regulated in Adenoma, Cl-/HCO3- exchanger) resulting in decreased electrolyte absorption are implicated in infectious and inflammatory diarrhea. Furthermore, studies have shown that NHE3 is depleted at the apical surface of intestinal epithelial cells and down-regulated in patients with CDI, but the role of DRA in C. difficile infection remains unknown. In the current studies, we examined the effects of C. difficile toxins TcdA and TcdB on DRA protein and mRNA levels in intestinal epithelial cells (IECs). Our data demonstrates that DRA protein levels were significantly reduced in response to TcdA and TcdB in IECs in culture. This effect was also specific to DRA, as MCT1 , an intestinal butyrate transporter, protein levels were unaffected by TcdA and TcdB. Contrary to other inflammatory and infectious models of diarrhea,Additionally, purified TcdA and TcdA + TcdB, but not TcdB, resulted in a decrease in colonic DRA protein levels in a toxigenic mouse model of CDI. Finally, patients with recurrent CDI also exhibited significantly reduced expression of colonic DRA protein. Together, these findings indicate that C. difficile toxins markedly downregulate intestinal expression of DRA which may contribute to the diarrheal phenotype of CDI.