Abstract
Mucosal healing determined by endoscopy is currently the remission standard for ulcerative colitis (UC). However, new criteria for remission are emerging, such as histologic normalization, which appears to correlate better to the risk of relapse. Here, we study mucosal healing on a molecular and functional level in quiescent UC. We obtained endoscopic biopsies from 33 quiescent UC patients and from 17 controls. Histology was assessed using Geboes score. Protein and mRNA levels were evaluated for the tight junction proteins claudin-2, claudin-4, occludin, and tricellulin, as well as Cl−/HCO3− exchanger DRA, and cyclo-oxygenase enzymes (COX-1, COX-2). The mucosal activity of COX-1 and COX-2 enzymes was assessed in modified Ussing chambers, measuring electrogenic ion transport (short-circuit current, SCC). Chronic inflammation was present in most UC patients. The protein level of claudin-4 was reduced, while mRNA-levels of claudin-2 and claudin-4 were upregulated in UC patients. Surprisingly, the mRNA level of COX-1 was downregulated, but was unaltered for COX-2. Basal ion transport was not affected, while COX-2 inhibition induced a two-fold larger decrease in SCC in UC patients. Despite being in clinical and endoscopic remission, quiescent UC patients demonstrated abnormal mucosal barrier properties at the molecular and functional level. Further exploration of mucosal molecular signature for revision of current remission standards should be considered.
Highlights
Ulcerative colitis (UC) is an idiopathic chronic inflammatory bowel disease (IBD), characterized by latent periods exacerbated by sudden relapses of activity with abdominal discomfort, increased stool frequency and rectal bleeding [1].The primary objective of current management is to alleviate patient symptoms by achieving clinical remission
We examined mucosal healing at the molecular and functional level by determining mucosal barrier integrity (TJ protein complex profile and subcellular localization), COX-enzyme activity and ion transport capacity as compared to clinical, endoscopic and histologic findings in UC patients with quiescent disease
We examined the cellular and subcellular localization of Cl−/HCO3−-exchanger DRA as well as tight junction (TJ) proteins occludin and claudin-4 in colonic biopsies from 11 UC patients and 11 controls using fluorescent immunohistochemistry
Summary
Ulcerative colitis (UC) is an idiopathic chronic inflammatory bowel disease (IBD), characterized by latent periods exacerbated by sudden relapses of activity with abdominal discomfort, increased stool frequency and rectal bleeding [1]. The primary objective of current management is to alleviate patient symptoms by achieving clinical remission. The second objective is to achieve endoscopic mucosal healing (eMH), since endoscopic remission is believed to correlate with improved long-term outcome and lower risk of relapse. The third objective is to maintain steroid-free remission [1,2]. It is difficult to predict long-term outcomes and relapse of UC with the current remission standards and available biomarkers. Better and/or complimentary dynamic, predictive and prognostic biomarkers are needed
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