Mucosal DNA methylation reveals immune-related methylation profile and correlates with crohn’s disease status

Altered DNA methylation (DNAm) patterns have been proven to play a key role in Crohn's disease (CD) pathogenesis. However, DNAm and its association with disease status in Chinese CD remain unclear. This study systematically examines DNAm patterns in Chinese patients with CD and their association with disease status. By elucidating specific DNAm alterations involved in CD pathogenesis, it aims to provide a molecular foundation for early diagnosis, prognosis assessment, and personalized treatment strategies. In this study, 24 adult treatment-naïve patients with CD were enrolled between January 2022 and May 2023. We performed reduced representation bisulfite sequencing (RRBS) on paired inflamed and non-inflamed intestinal mucosa samples from these patients, and inflammation-specific and disease severity-specific differential methylation signatures were identified. A total of 17,097 differentially methylated sites (DMCs) and 2,687 differentially methylated regions (DMRs) were identified in inflamed mucosa. Biological association analysis revealed that inflammation-associated DMRs were enriched in immune function, with 123 DMRs annotating 89 genes involved in immune cell function while 173 DMRs annotating 117 genes participated in cell adhesion function. Analysis of DNAm profiles of inflamed mucosal samples by disease severity revealed that 389 DMRs were associated with the Simple Endoscopic Score for Crohn's Disease (SES-CD) and 327 DMRs with the Crohn Disease Activity Index (CDAI). Of these, six genes, KDM4B, CLDN15, PGGHG, SLC25A10, KIAA2013, and N4BP1, were significantly associated with inflammation, SES-CD and CDAI. Hence, DNAm reflects immunological changes in the gut of CD patients and discriminates patients based on disease severity, highlighting its potential as a predictive marker for disease management.