Altered Colonic Mucosal Polyunsaturated Fatty Acid (PUFA) Derived Lipid Mediators in Ulcerative Colitis: New Insight into Relationship with Disease Activity and Pathophysiology

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.

Quantitative Profiling of Hydroxy Lipid Metabolites in Mouse Organs Reveals Distinct Lipidomic Profiles and Modifications Due to Elevated n-3 Fatty Acid Levels

“…A study demonstrated significant changes in the formation of LOX-derived 5-HETE, 12-HETE and 15-HETE with an association of higher levels and worse post-transplant graft function outcome in human kidney transplantation, indicating a critical role of lipid metabolites in the pathophysiology of post-transplantation organ dysfunction [18]. This is further supported by another study that found significantly elevated 5-HETE, 11-HETE, 12-HETE and 15-HETE levels in colonic mucosal biopsies from ulcerative colitis patients correlating with inflammation severity [19]. …”

The role of PGE2 in intestinal inflammation and tumorigenesis

“…Although there is evidence that exogenous PGE 2 administration can attenuate DSS-induced damage [49], the effects of PGD 2 treatment is unknown. We also examined levels of HETEs given that they have been shown to impact upon the inflammatory process [50] and 5-HETE in particular has been found to be elevated in mucosal biopsies from colitis patients[51]. Interestingly, 5-HETE was increased in the colons of mPGES-1 −/− mice following DSS administration, an effect not observed in wild-type mice.…”

Involvement of CYP1B1 in interferon γ‐induced alterations of epithelial barrier integrity

“…Interestingly, while the expression of the other CYP1 family members, CYP1A1 and CYP1A2, is generally down‐regulated by inflammation (Morgan, ), CYP1B1 expression is induced by inflammatory cytokines (Piscaglia et al, ; Bleau et al, ; Umannová et al, ). Moreover, CYP1B1 also metabolizes endogenous compounds such as arachidonic acid to give hydroxyeicosatetraenoic acids (HETEs), which are involved in inflammation in general and inflammatory bowel diseases in particular (Masoodi et al, ). This oxidation of arachidonic acid by CYP1B1 is of biological significance as CYP1B1‐produced mid‐chain HETEs have been recently implicated in doxorubicin‐induced cardiotoxicity (Maayah et al, ).…”