A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity.
Gastroenterology
; 160(4): 1240-1255.e3, 2021 03.
Article
en En
| MEDLINE
| ID: mdl-33189700
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 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.Palabras clave
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Enfermedades Inflamatorias del Intestino
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Antiportadores
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Antiportadores de Cloruro-Bicarbonato
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Disbiosis
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Transportadores de Sulfato
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Mucosa Intestinal
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Gastroenterology
Año:
2021
Tipo del documento:
Article