Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations

Abstract

Objective Ulcerative colitis (UC) is a chronic condition characterised by the relapsing inflammation despite previous endoscopic and histological healing. Our objective was to identify the molecular signature associated with UC remission. Design We performed whole-genome transcriptional analysis of colonic biopsies from patients with histologically active and inactive UC, and noninflammatory bowel disease (non-IBD) controls. Real-time reverse transcriptase-PCR and immunostaining were used for validating selected genes in independent cohorts of patients. Results Microarray analysis (n=43) demonstrates that UC patients in remission present an intestinal transcriptional signature that significantly differs from that of non-IBD controls and active patients. Fifty-four selected genes were validated in an independent cohort of patients (n=30). Twenty-nine of these genes were significantly regulated in UC-in-remission subjects compared with non-IBD controls, including a large number of epithelial cell-expressed genes such as REG4, S100P, SERPINB5, SLC16A1, DEFB1, AQP3 and AQP8, which modulate epithelial cell growth, sensitivity to apoptosis and immune function. Expression of inflammation-related genes such as REG1A and IL8 returned to control levels during remission. REG4, S100P, SERPINB5 and REG1A protein expression was confirmed by immunohistochemistry (n=23). Conclusions Analysis of the gene signature associated with remission allowed us to unravel pathways permanently deregulated in UC despite histological recovery. Given the strong link between the regulation of some of these genes and the growth and dissemination of gastrointestinal cancers, we believe their aberrant expression in UC may provide a mechanism for epithelial hyper-proliferation and, in the context of malignant transformation, for tumour growth.

Mucosal Transcriptomics Implicates Under Expression of BRINP3 in the Pathogenesis of Ulcerative Colitis

“…29 This suggests that low BRINP3 may identify a subgroup of patients within the general UC cohort and supports the previously reported heterogeneous genetic character of this disease. 53 Abnormal BRINP3 expression is specific for colonic mucosal tissue in UC and not a generic response to inflammation or therapy.…”

“…21,22 Numerous studies have therefore been conducted in UC using both mucosal biopsies and surgical resection specimens. [21][22][23][24][25][26][27][28][29] In the vast majority of these studies, the samples were obtained from chronically inflamed tissue such that transcriptomic differences observed have been dominated by the consequences of tissue damage and the presence of infiltrating inflammatory cells. 21,24,26,27 A recent meta-analysis of a number of these studies 23 identified the tight junction molecule, claudin 8 (CLDN8), to be the most underexpressed gene in the colon in individuals with IBD.…”

miR-20b, miR-98, miR-125b-1*, and let-7e* as new potential diagnostic biomarkers in ulcerative colitis

“…Previous studies have demonstrated different mRNA expression profiles of mucosal colonic biopsies from IBD patients and healthy individuals [34,35,46,47] . Furthermore, Olsen et al [34] demonstrated that active and inactive UC could be distinguished from CD patients and controls.…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…For instance, impaired butyrate oxidation has been associated with active mucosal inflammation. Apart from reduced butyrate oxidation itself, impaired butyrate uptake, most likely as a consequence of decreased MCT1 expression, was found in patients with active ulcerative colitis 45, 46. Moreover, density analyses from an open access genomewide association studies database revealed a dense cluster of associations for SLC16A7 (encoding for MCT2) variants with Crohn disease and high‐density lipoprotein (HDL) cholesterol levels, although functional validation is completely missing so far 47…”