Protective Role of Intestinal Epithelial Cell (IEC) Specific Slc26a3 Overexpression in Experimental Colitis

Background: DRA (Down Regulated in Adenoma) or Slc26a3 is the key chloride-absorbing transporter in the mammalian intestine. DRA KO mice (global) exhibit compromised barrier integrity, microbial dysbiosis and increased susceptibility to DSS colitis. Multiple GWAS studies in IBD cohorts have recently established DRA, as a novel IBD susceptibility gene. However, the impact of Intestinal epithelial cell (IEC) specific DRA overexpression on gut inflammation has not been investigated. Given that DRA function or expression is decreased in IBD patients and models of colitis, we hypothesized that IEC-specific overexpression of DRA will confer protection against acute DSS colitis. Methods: We generated a novel, inducible IEC-specific DRA overexpressing mouse model (DRA O/E). WT and DRA O/E mice were divided into 4 groups: (1) WT; (2) WT + DSS; (3) DRA O/E and (4) DRA O/E + DSS. DSS and DRA O/E + DSS groups were challenged with 3.5% DSS in drinking water for 7 days to induce acute colitis. H&E staining, Myeloperoxidase (MPO) activity, calprotectin and cytokine levels were examined to assess tissue histology and gut inflammation. Results: Tamoxifen treatment resulted in induction of DRA-V5 protein expression (utilizing V5 antibody) in the intestine of DRA O/E mice but not in tamoxifen treated control mice. Importantly, liver tissue from these DRA O/E mice did not show any DRA-V5 expression, confirming that the overexpression of DRA was inducible, and was restricted only to the intestine. Interestingly, after DSS treatment, DRA O/E group mice exhibited significant attenuation in the increase in colonic weight/length ratio and showed reduced disease activity index (~62% decrease) compared to WT + DSS mice. In addition, histological analysis of distal colon demonstrated that DRA O/E + DSS mice showed significantly less damage in surface-crypt architecture, neutrophil infiltration, ulceration/erosion and goblet cell depletion compared to WT+ DSS mice. Moreover, DRA O/E + DSS mice demonstrated a significantly lower induction in the MPO enzyme activity (~40% decrease), and markedly lower fecal calprotectin levels (~55% decrease), compared to WT + DSS mice. In addition, DRA O/E + DSS mice also showed significantly lower induction in the mRNA levels of proinflammatory markers, IL-1ß (~70% decrease), IL-17 (~50% decrease) and NLRP-3 (~50% decrease) compared to WT+DSS mice. In addition, DRA O/E + DSS mice showed a significant attenuation in STAT-3 phosphorylation levels (~70% decrease) in the colon compared to WT+ DSS mice. Conclusion: We established a novel IEC-specific DRA O/E mouse model and showed that DRA O/E mice were less susceptible to acute DSS colitis and further support the key role of DRA dysregulation in IBD pathogenesis. Funded by Department of Veterans Affairs and NIH/NIDDK) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.