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http://purl.uniprot.org/citations/33189700http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33189700http://www.w3.org/2000/01/rdf-schema#comment"

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 investigate 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."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.org/dc/terms/identifier"doi:10.1053/j.gastro.2020.11.008"xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Ge Y."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Kumar A."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Zhao N."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Patel M."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Saksena S."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Dayal A."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Chatterjee I."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Alrefai W.A."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Dudeja P.K."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Gill R.K."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Singhal M."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Mohamadzadeh M."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Zadeh M."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Anbazhagan A.N."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Priyamvada S."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Jayawardena D."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/author"Zadeh K."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/name"Gastroenterology"xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/pages"1240-1255.e3"xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/title"A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity."xsd:string
http://purl.uniprot.org/citations/33189700http://purl.uniprot.org/core/volume"160"xsd:string
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