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.
Higher AA, AA:EPA ratio, DPA and DHA and lower LA, α-LNA and EPA are seen in inflamed mucosa in UC and correlate with severity of inflammation. This suggests an alteration in fatty acid metabolism in the inflamed gut mucosa, which may offer novel targets for intervention and should be considered if nutritional strategies are used.
Our findings suggest that IL-8 is elevated and TGFβ is reduced in distal colitis. Lower concentration of IFNγ, IL-4 and IL-17A were also noted. TNFα levels were unchanged. These findings suggest that the inflammatory response in UC may predominantly involve IL-8 mediated neutrophil infiltration and failure of TGFβ mediated tissue healing.
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