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A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity.

Abstract：

BACKGROUND & AIMS:The down-regulated in adenoma (DRA) protein, encoded by SLC26A3, a key intestinal chloride anion exchanger, has recently been identified as a novel susceptibility gene for inflammatory bowel disease (IBD). However, the mechanisms underlying the increased susceptibility to inflammation induced by the loss of DRA remain elusive. Compromised barrier is a key event in IBD pathogenesis. The current studies were undertaken to elucidate the impact of DRA deficiency on epithelial barrier integrity and to define underlying mechanisms. METHODS:Wild-type and DRA-knockout (KO) mice and crypt-derived colonoids were used as models for intestinal epithelial response. Paracellular permeability was measured by using fluorescein isothiocyanate-dextran flux. Immunoblotting, immunofluorescence, immunohistochemistry, and ribonucleoprotein immunoprecipitation assays were performed. Gut microbiome analysis was conducted to show the impact of DRA deficiency on gut microbial communities. RESULTS:DRA-KO mice exhibited an increased colonic paracellular permeability with significantly decreased levels of tight junction/adherens junction proteins, including ZO-1, occludin, and E-cadherin. A similar expression pattern of occludin and E-cadherin was observed in colonoids derived from DRA-KO mice and short hairpin RNA-mediated DRA knockdown in Caco-2 cells. Microbial analysis showed gut dysbiosis in DRA-KO mice. However, cohousing studies showed that dysbiosis played only a partial role in maintaining tight junction protein expression. Furthermore, our results showed increased binding of RNA-binding protein CUGBP1 with occludin and E-cadherin genes in DRA-KO mouse colon, suggesting that posttranscriptional mechanisms play a key role in gut barrier dysfunction. CONCLUSIONS:To our knowledge, our studies demonstrate a novel role of DRA in maintaining the intestinal epithelial barrier function and potential implications of its dysregulation in IBD pathogenesis.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Kumar A,Priyamvada S,Ge Y,Jayawardena D,Singhal M,Anbazhagan AN,Chatterjee I,Dayal A,Patel M,Zadeh K,Saksena S,Alrefai WA,Gill RK,Zadeh M,Zhao N,Mohamadzadeh M,Dudeja PK

doi

10.1053/j.gastro.2020.11.008

subject

Has Abstract

pub_date

2020-11-13 00:00:00

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(20)35396-8

pub_type

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A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity.