Slc26a3 deficiency is associated with loss of colonic HCO3 (-) secretion, absence of a firm mucus layer and barrier impairment in mice

Acta Physiol (Oxf). 2014 May;211(1):161-75. doi: 10.1111/apha.12220. Epub 2014 Jan 31.


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.

Keywords: anion exchanger; bicarbonate; chloride-losing diarrhoea; intestinal barrier; mucin; sodium/hydrogen exchanger.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis / genetics
  • Acidosis / metabolism
  • Animals
  • Antiporters / genetics
  • Antiporters / metabolism*
  • Bicarbonates / metabolism*
  • Colon / metabolism*
  • Intestinal Mucosa / metabolism*
  • Ion Transport / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Mucin-2 / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism
  • Sulfate Transporters


  • Antiporters
  • Bicarbonates
  • Mucin-2
  • Slc26a3 protein, mouse
  • Slc9a3 protein, mouse
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sulfate Transporters