Dataset Information

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease.

ABSTRACT:

Background

E-cadherin, a major actor of cell adhesion in the intestinal barrier, is encoded by the CDH1 gene associated with susceptibility to Crohn Disease (CD) and colorectal cancer. Since epigenetic mechanisms are suspected to contribute to the multifactorial pathogenesis of CD, we studied CpG methylation at the CDH1 locus. The methylation of the CpG island (CGI) and of the 1st enhancer, two critical regulatory positions, was quantified in surgical specimens of inflamed ileal mucosa and in peripheral blood mononuclear cells (PBMC) of 21 CD patients. Sixteen patients operated on for a non-inflammatory bowel disease, although not normal controls, provided a macroscopically normal ileal mucosa and PBMC for comparison.

Results

In ileal mucosa, 19/21 (90%) CD patients vs 8/16 control patients (50%) (p < 0.01) had a methylated CDH1 promoter CGI. In PBMC, CD patients with methylated CGI were 11/21 (52%) vs 7/16 controls (44%), respectively. Methylation in the 1st enhancer of CDH1 was also higher in the CD group for each of the studied CpGs and for their average value (45 ± 17% in CD patients vs 36 ± 17% in controls; p < 0.001). Again, methylation was comparable in PBMC. Methylation of CGI and 1st enhancer were not correlated in mucosa or PBMC.

Conclusions

Methylation of several CpGs at the CDH1 locus was increased in the inflamed ileal mucosa, not in the PBMC, of CD patients, suggesting the association of CDH1 methylation with ileal inflammation. Longitudinal studies will explore if this increased methylation is a risk marker for colorectal cancer.

SUBMITTER: de Ponthaud C

PROVIDER: S-EPMC10865720 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease.

de Ponthaud Charles C Abdalla Solafah S Belot Marie-Pierre MP Shao Xiaojian X Penna Christophe C Brouquet Antoine A Bougnères Pierre P

Clinical epigenetics 20240214 1

<h4>Background</h4>E-cadherin, a major actor of cell adhesion in the intestinal barrier, is encoded by the CDH1 gene associated with susceptibility to Crohn Disease (CD) and colorectal cancer. Since epigenetic mechanisms are suspected to contribute to the multifactorial pathogenesis of CD, we studied CpG methylation at the CDH1 locus. The methylation of the CpG island (CGI) and of the 1st enhancer, two critical regulatory positions, was quantified in surgical specimens of inflamed ileal mucosa a ...[more]

PMID: 38355645

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Project description:BACKGROUND:Crohn's disease (CD) is a complex disorder resulting from the interaction of genetic, environmental, and microbial factors. The pathogenic process may potentially affect any segment of the gastrointestinal tract, but a selective location in the terminal ileum was reported in 50% of patients. AIM:To characterize clinical sub-phenotypes (colonic and/or ileal) within the same disease, in order to identify new therapeutic targets. METHODS:14 consecutive patients undergoing surgery for ileal CD were recruited for this study. Peripheral blood samples from each patient were collected and the main polymorphisms of the gene Card15/Nod2 (R702W, G908R, and 1007fs) were analyzed in each sample. In addition, tissue samples were taken from both the tract affected by CD and from the apparently healthy and disease-free margins (internal controls). We used a multiplex gene assay in specimens obtained from patients with ileal localization of CD to evaluate the simultaneous expression of 24 genes involved in the pathogenesis of the disease. We also processed surgery gut samples with routine light microscopy (LM) and transmission electron microscopy (TEM) techniques to evaluate their structural and ultrastructural features. RESULTS:We found a significant increase of Th17 (IL17A and IL17F, IL 23R and CCR6) and Th1 (IFN-γ) gene expression in inflamed mucosa compared to non-inflamed sites of 14 CD patients. DEFB4 and HAMP, two genes coding for antimicrobial peptides, were also strongly activated in inflamed ileal mucosa, suggesting the overwhelming stimulation of epithelial cells by commensal microbiota. IFN-γ and CCR6 were more expressed in inflamed mucosa of CD patients with ileal localization compared with patients with colonic localization suggesting a more aggressive inflammation process in this site. Morphological analysis of the epithelial lining of Lieberkün crypts disclosed enhanced release activity from goblet mucocytes, whereas the lamina propria contained numerous cells pertaining to various lines. CONCLUSION:We observed that the expression of ileal genes related to Th1 and Th17 activity is strongly activated as well as the expression of genes involved in microbiota regulation.

Project description:To formulate therapy goals, we aimed to define the relationship between fecal calprotectin and health-related quality of life in inflammatory bowel diseases (IBDs). This retrospective single-center cross-sectional study included ambulatory IBD patients who had completed standardized questionnaires comprising items of health-related quality of life (Short Inflammatory Bowel Disease Questionnaire) and clinical disease activity scores, and who had provided stool samples for calprotectin determination within 30 days of questionnaire completion. Correlation analyses were performed between the indicated parameters. Post hoc analysis was conducted, taking into account only data from patients with fecal calprotectin concentrations measured within 3 days of questionnaire completion. One hundred ninety-seven patients with Crohn disease and 111 patients with ulcerative colitis were enrolled in the study. Lower fecal calprotectin concentrations were associated with better health-related quality of life. The correlations were weak, but stronger if only fecal calprotectin concentrations measured within 3 days of questionnaire completion were included (results for 3 days; Crohn disease: n = 86, rS = -0.419, P < 0.001; ulcerative colitis: n = 43, rS = -0.432, P = 0.004). In Crohn disease, a significant correlation between fecal calprotectin concentration and health-related quality of life was found in patients with colonic involvement (n = 59, rS = -0.470, P < 0.001), but not in patients with purely ileal disease (n = 27, rS = -0.268, P = 0.18). Correlations between fecal calprotectin concentrations and clinical disease activity were also only weak to moderate. Owing to its moderate correlation with fecal calprotectin concentrations in IBD patients with colonic involvement, health-related quality of life should be used in combination with other markers for IBD management. This is even more important in isolated ileal Crohn disease, where no significant correlation between fecal calprotectin concentration and health-related quality of life was found. Especially for use in research studies, care should be taken to keep the time between clinical evaluation of IBD patients and the determination of fecal calprotectin concentrations as short as possible.

Dataset Information

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease.

Background

Results

Conclusions

Publications

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease.

Similar Datasets

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