microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts

Abstract

CD (coeliac disease) is a frequent autoimmune disorder of the small bowel, which is characterized by an immunological reaction against gluten and transglutaminase in genetically predisposed subjects. However, the molecular determinants underpinning CD pathogenesis are yet to be fully elucidated and little data are available about the involvement of miRNAs (microRNAs) in CD. In the present study, the duodenal mucosa miRNA expression was profiled in adult untreated CD presenting with a classic phenotype or iron-deficiency anaemia, treated patients with or without duodenal normalization, and non-CD subjects as controls. Deregulation of seven miRNAs (miR-31-5p, miR-192-3p, miR-194-5p, miR-551a, miR-551b-5p, miR-638 and miR-1290) was determined in a larger series of CD patients with different clinical phenotypes compared with non-CD subjects. These seven microRNAs were then analysed in duodenal fibroblasts obtained from CD patients and incubated with gliadin peptides (13- and 33-mer). The miRNA cluster miR-192/194, involved in matrix remodelling, was deregulated in CD according to the different clinical presentations, and miR-192-3p levels were modulated by gliadin peptides in vitro. In conclusion, the analysis of miRNAs deserves further consideration for its potential use in the treatment and management of CD.

The genetics of celiac disease: A comprehensive review of clinical implications

“…In small intestinal biopsies of CD patients, the observed over-expression of miRNAs-449a has been linked to deregulation of the NOTCH pathway, important in the maintenance of normal gut function [63]. Furthermore, the observed deregulation of several other miRNAs in CD patients is recovered after GFD, supporting the potential role for miRNAs in the treatment and management of CD [65].…”

“…A second study investigated the microRNA profile (377 human miRNAs with subsequent validation of 36 miRNAs) in the small bowel of adult CD patients and control subjects [65]. Four groups of patients were considered: two with active CD but differing in clinical parameters (classical presentation or iron-deficiency anemia as the main extraintestinal sign) and two on a GFD but with different mucosal healing (one composed by patients showing mucosal recovery (M0) and negativization of specific antibodies and another group composed by patients still showing intestinal atrophy).…”

Genetics of celiac disease

“…This miRNA is known to target and reduce the levels of NOTCH1 and KLF4, which were shown to correlate with a lower number of goblet cells in the small intestine of CeD patients [40]. The differences in the levels of miRNAs were not only related with the disease status (healthy or affected), but also with the phenotype expression: for example, miR-194-5p and miR-368 were found to be differentially expressed in anemic CeD patients [41].…”

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

“…35 Moreover, gene expression and alternative splicing are not only dependent on the tissue, but also on epigenetic factors, 21 and changes in the expression of intestinal genes have been found to be related to the inhibition of histone deacetylation 36 and an increased DNA methylation, 37 Several epigenetic mechanisms have been found to be differently regulated in the intestinal mucosa of patients with celiac disease, IBD and colorectal cancer. [38][39][40] Interestingly, the IL-15 gene is hypomethylated in IBD. 41 In summary, five novel isoforms of IL-15Ra have been identified in human intestinal epithelial cells, which are commonly distributed through the cytoplasmic and endoplasmic reticulum compartments.…”