title: Slc26a3 deficiency is associated with loss of colonic HCO3 (-) secretion, absence of a firm mucus layer and barrier impairment in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: F
authors.initials: F
authors.lastname: Xiao
authors.forename: Q
authors.initials: Q
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: M E V
authors.initials: ME
authors.lastname: Johansson
authors.forename: A K
authors.initials: AK
authors.lastname: Singh
authors.forename: W
authors.initials: W
authors.lastname: Xia
authors.forename: B
authors.initials: B
authors.lastname: Riederer
authors.forename: R
authors.initials: R
authors.lastname: Engelhardt
authors.forename: M
authors.initials: M
authors.lastname: Montrose
authors.forename: M
authors.initials: M
authors.lastname: Soleimani
authors.forename: D A
authors.initials: DA
authors.lastname: Tian
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: G C
authors.initials: GC
authors.lastname: Hansson
authors.forename: U
authors.initials: U
authors.lastname: Seidler
mesh_terms: D000138:Acidosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D017136:Ion Transport / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2 / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000076988:Sulfate Transporters
chemical_list: D017920:Antiporters; D001639:Bicarbonates; D055262:Mucin-2; C489860:Slc26a3 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters
keywords: anion exchanger; bicarbonate; chloride-losing diarrhoea; intestinal barrier; mucin; sodium/hydrogen exchanger