Abstract
ObjectivesUlcerative colitis (UC) is a relapsing inflammatory disorder of unconfirmed aetiology, variable severity and clinical course, characterised by progressive histological inflammation and with elevation of eicosanoids which have a known pathophysiological role in inflammation. Therapeutic interventions targetting eicosanoids (5-aminosalicylates (ASA)) are effective first line and adjunctive treatments in mild-moderate UC for achieving and sustaining clinical remission. However, the variable clinical response to 5-ASA and frequent deterioration in response to cyclo-oxygenase (COX) inhibitors, has prompted an in depth simultaneous evaluation of multiple lipid mediators (including eicosanoids) within the inflammatory milieu in UC. We hypothesised that severity of inflammation is associated with alteration of lipid mediators, in relapsing UC.DesignStudy was case-control design. Mucosal lipid mediators were determined by LC-MS/MS lipidomics analysis on mucosal biopsies taken from patients attending outpatients with relapsing UC. Univariate and multivariate statistical analyses were used to investigate the association of mucosal lipid mediators, with the disease state and severity graded histologically.ResultsLevels of PGE2, PGD2, TXB2, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems.ConclusionsOur approach of capturing inflammatory mediator signature at different stages of UC by combining comprehensive lipidomics analysis and computational modelling could be used to classify and predict mild-moderate inflammation; however, predictive index is diminished in severe inflammation. This new technical approach could be developed to tailor drug treatments to patients with active UC, based on the mucosal lipid mediator profile.
Highlights
Ulcerative colitis (UC) is a chronic, relapsing intestinal inflammatory disorder of the colonic mucosa, with variable distribution but limited to the distal bowel in 60% of cases [1]
Levels of PGE2, PGD2, TXB2, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems
Reported metabolites included eicosanoids derived from arachidonic acid (AA)
Summary
Ulcerative colitis (UC) is a chronic, relapsing intestinal inflammatory disorder of the colonic mucosa, with variable distribution but limited to the distal bowel (distal colitis and proctitis) in 60% of cases [1]. Despite advances in medical treatments, including biologics that target cytokine-led inflammatory responses for severe disease, long term control of UC is variable with available therapeutic interventions [3,4,5], with 57% of all patients following a relapsing and remitting clinical course [6,7]. In mild to moderate relapsing disease only, a limited therapeutic repertoire is available to patients principally as oral or topical 5-aminosalicylic acid (5-ASA) and corticosteroids. Mucosal inflammation in UC is characterised by an infiltrate of neutrophils, plasma cells and eosinophils, which correlate with disease severity and are predictors of disease relapse [8,9,10]. Mucosal inflammation in UC responds to therapeutic interventions that target eicosanoid production such as 5-ASA [13,14]. The understanding of both the pathophysiology of UC and pharmacotherapeutic effects of 5-ASA is limited, which has inhibited the development of new therapeutic interventions
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