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  • 1
    Abstract: OBJECTIVE: Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established. Our aims were (1) to identify miRNAs differentially expressed in the small bowel mucosa of patients with IBS-D and (2) to explore putative target genes specifically involved in epithelial barrier function that are controlled by specific dysregulated IBS-D miRNAs. DESIGN: Healthy controls and patients meeting Rome III IBS-D criteria were studied. Intestinal tissue samples were analysed to identify potential candidates by: (a) miRNA-mRNA profiling; (b) miRNA-mRNA pairing analysis to assess the co-expression profile of miRNA-mRNA pairs; (c) pathway analysis and upstream regulator identification; (d) miRNA and target mRNA validation. Candidate miRNA-mRNA pairs were functionally assessed in intestinal epithelial cells. RESULTS: IBS-D samples showed distinct miRNA and mRNA profiles compared with healthy controls. TJ signalling was associated with the IBS-D transcriptional profile. Further validation of selected genes showed consistent upregulation in 75% of genes involved in epithelial barrier function. Bioinformatic analysis of putative miRNA binding sites identified hsa-miR-125b-5p and hsa-miR-16 as regulating expression of the TJ genes CGN (cingulin) and CLDN2 (claudin-2), respectively. Consistently, protein expression of CGN and CLDN2 was upregulated in IBS-D, while the respective targeting miRNAs were downregulated. In addition, bowel dysfunction, perceived stress and depression and number of mast cells correlated with the expression of hsa-miR-125b-5p and hsa-miR-16 and their respective target proteins. CONCLUSIONS: Modulation of the intestinal epithelial barrier function in IBS-D involves both transcriptional and post-transcriptional mechanisms. These molecular mechanisms include miRNAs as master regulators in controlling the expression of TJ proteins and are associated with major clinical symptoms.
    Type of Publication: Journal article published
    PubMed ID: 28082316
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  • 2
    ISSN: 1573-2568
    Keywords: hydrogen breath test ; d-xylose test ; d-xylose breath test ; celiac disease ; intestinal malabsorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The hydrogen breath test (H2BT) with d-xylose has proven valid in both early recognition and follow-up of intestinal malabsorption. To further evaluate the specificity of the H2BT with d-xylose in the diagnosis of intestinal malabsorption as compared to the conventional urinary d-xylose test, we analyzed the result in 49 patients referred to our unit with a clinical diagnosis of intestinal malabsorption. These patients had an abnormal 25-g d-xylose H2BT but a normal conventional urinary d-xylose test. Jejunal biopsy with Watson capsule was performed in all patients. H&E staining was prepared from each biopsy specimen, and histological changes were classified according to the Marsh criteria. Jejunal biopsy showed mucosal atrophy in 5 patients (10%), hyperplastic lesion in 11 (22.5%), infiltrative lesion in 14 (28.5%), and normal appearance in 19 (39%). G. lamblia infection was additionally diagnosed in two patients. Histological changes were independent of the presence of diarrhea, weight loss, abdominal pain, or anemia. H2 excretion, assessed as increase over baseline and area under the curve, was similarly independent of the histological pattern. In conclusion, performance of a d-xylose H2BT in patients with a normal urinary test reveals a significant number of patients with intestinal mucosal atrophy who might otherwise remain undiagnosed.
    Type of Medium: Electronic Resource
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