Aim Downregulated in adenoma (DRA, Slc26a3) is a member of the solute carrier family 26 (SLC26), family of anion transporters, which is mutated in familial chloride‐losing diarrhoea (CLD). Besides Cl−‐rich diarrhoea, CLD patients also have a higher‐than‐average incidence of intestinal inflammation. In a search for potential explanations for this clinical finding, we investigated colonic electrolyte transport, the mucus layer and susceptibility against dextran sodium sulphate (DSS)‐induced colitis in Slc26a3−/− mice. Methods HCO3− secretory (JHCO3−) and fluid absorptive rates were measured by single‐pass perfusion in vivo and in isolated mid‐distal colonic mucosa in Ussing chambers in vitro. Colonocyte intracellular pH (pHi) was assessed fluorometrically, the mucus layer by immunohistochemistry and colitis susceptibility by the addition of DSS to the drinking water. Results HCO3− secretory (JHCO3‐) and fluid absorptive rates were strongly reduced in Slc26a3−/− mice compared to wild‐type (WT) littermates. Despite an increase in sodium/hydrogen exchanger 3 (NHE3) mRNA and protein expression, and intact acid‐activation of NHE3, the high colonocyte pH in Slc26a3−/− mice prevented Na+/H+ exchange‐mediated fluid absorption in vivo. Mucin 2 (MUC2) immunohistochemistry revealed the absence of a firm mucus layer, implying that alkaline secretion and/or an absorptive flux may be necessary for optimal mucus gel formation. Slc26a3−/− mice were highly susceptible to DSS damage. Conclusions Deletion of DRA results in severely reduced colonic HCO3− secretory rate, a loss of colonic fluid absorption, a lack of a firmly adherent mucus layer and a severely reduced colonic mucosal resistance to DSS damage. These data provide potential pathophysiological explanations for the increased susceptibility of CLD patients to intestinal inflammation.