Altered colonic mucosal polyunsaturated fatty acid (PUFA) derived lipid mediators in ulcerative colitis: new insight into relationship with disease activity and pathophysiology

OBJECTIVES: Ulcerative 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.DESIGN: Study 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.RESULTS: 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.CONCLUSIONS: Our 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

Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease

Background: Crohn disease (CD) is associated with osteoporosis and other extraintestinal manifestations that might be mediated by cytokines from circulating (peripheral blood) mononuclear cells (PBMCs). Fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduces disease activity in patients with CD with raised laboratory markers of inflammation and in healthy subjects alters PBMC function. Objective: We investigated the effect of fish oil plus antioxidants on cytokine production by PBMCs from patients with CD with raised C-reactive protein concentrations (?6.9 mg/L) or erythrocyte sedimentation rates (?18 mm/h). Design: A randomized placebo-controlled trial of fish oil (2.7 g EPA and DHA/d; n = 31) or placebo (olive oil; n = 31) for 24 wk was conducted in patients with CD. The fish-oil group additionally received an antioxidant preparation (vitamins A, C, and E and selenium). Exclusion criteria included corticosteroid use. Fatty acid composition was measured by gas chromatography. Production of tumor necrosis factor ?, interferon ? (IFN-?), and prostaglandin E2 (PGE2) was measured by enzyme-linked immunosorbent assays after stimulation with mitogen and endotoxin (lipopolysaccharide). Results: Fish-oil plus antioxidant dietary supplementation was associated with higher EPA and DHA incorporation into PBMCs (P &lt; 0.001) and lower arachidonic acid (P = 0.006) and lower production of IFN-? by mitogen-stimulated PBMCs (P = 0.012) and of PGE2 by lipopolysaccharide-stimulated PBMCs (P = 0.047). Conclusion: Dietary supplementation with fish oil plus antioxidants is associated with modified PBMC composition and lower production of PGE2 and IFN-? by circulating monocytes or macrophages. The response of extraintestinal manifestations of CD should be investigated in a randomized controlled trial. <br/

Peripheral blood mononuclear cell fatty acid composition and inflammatory mediator production in adult Crohn's disease

Background &amp; aims: Crohn's disease (CD) is associated with nutritional deficiencies, altered plasma concentrations of polyunsaturated fatty acids (PUFA) and an anti-inflammatory response to fish oil that contains n-3 PUFA. This suggests that, in CD, immune cells may have altered n-3 PUFA composition with functional consequences. The aim of this study is to investigate n-3 and n-6 PUFA composition and synthetic function of peripheral blood mononuclear cells (PBMC) in the basal state.Methods: A case control study of 52 adult CD patients and healthy, age- and sex-matched controls. Composition of PBMC and plasma phospholipids were measured by gas chromatography and production of tumour necrosis factor-?, prostaglandin E2 (PGE2) and interferon-? (IFN-?) by PBMC were measured by ELISA.Results: CD was associated with higher concentrations of eicosapentaenoic acid and other n-3 PUFA, and lower arachidonic acid (AA) (n-6 PUFA) in PBMC. This was not explained by differences in dietary fat intake. Lower rates of production of PGE2 and IFN-? by PBMC were noted in quiescent and active CD, respectively, compared to controls.Conclusions: CD is associated with a greater availability, and not a deficiency, of n-3 PUFA in PBMC, but lower concentrations of AA, and lower rates of production of PGE2 and IFN-?, compared to healthy controls

Prostaglandin E2 production and T cell function after fish-oil supplementation: response to antioxidant cosupplementation

Background: prostaglandin E2 (PGE2) inhibits lymphocyte proliferation and the production of interferon-{gamma} (IFN-{gamma}) by peripheral blood mononuclear cells, but the effect of PGE2 on interleukin 4 (IL-4) production is unclear. Fish oil, which contains eicosapentaenoic and docosahexaenoic acids, inhibits production of PGE2. The effects of fish oil on lymphocyte proliferation and production of IFN-{gamma} and IL-4 are unclear and may be influenced by the availability of antioxidants.Objective: we investigated the effect of dietary fish oil with and without antioxidant cosupplementation on lymphocyte proliferation and the production of PGE2, IFN-{gamma}, and IL-4 by peripheral blood mononuclear cells.Design: sixteen healthy men received dietary fish-oil supplements providing 0.3, 1, and 2 g eicosapentaenoic acid plus docosahexaenoic acid/d for 4 consecutive weeks each (total of 12 wk). All subjects were randomly assigned to daily cosupplementation with either antioxidants (200 µg Se, 3 mg Mn, 30 mg RRR-{alpha}-tocopheryl succinate, 90 mg ascorbic acid, 450 µg vitamin A) or placebo.Results: fish-oil supplementation decreased PGE2 production and increased IFN-{gamma} production and lymphocyte proliferation from baseline values. Cosupplementation with antioxidants did not affect cytokine production or lymphocyte proliferation.Conclusion: dietary fish oil modulates production of IFN-{gamma} and lymphocyte proliferation in a manner consistent with decreased production of PGE2, but this effect is not modified by antioxidant cosupplementation

Gomes histological classification of UC.

<p>1A: Gomes 0 (normal); 1B: Gomes 1 (mild oedema and inflammation in lamina propria with cryptitis); 1C: Gomes 2 (crypt abscess formation and inflammation); 1D: Gomes 3 (destructive crypt abscesses +/− granulomata); 1E–F: Gomes 4 (active ulceration and formation of granulation tissue with neoangiogenesis).</p

Lipid mediator concentrations (pg/mg tissue) in colonic mucosa (inflamed and non-inflamed) in UC patients.

€<p>Data are median ± IQR.</p>*<p>Wilcoxon signed rank pair analysis.</p

O2PLS model showing computed prediction of disease severity based on lipid mediator profile.

<p>6A: Plot showing O2PLS regression score plots; 6B: plot showing actual vs. predicted GOMES score based on lipid mediator profile.</p

Variable importance plot in O2PLS analysis demonstrates relative contribution of lipid mediators to separation between histological grades of severity.

<p>(Fig. 6).</p

Variable importance plot in O2PLS-DA analysis demonstrates relative contribution of lipid mediators to separation between inflamed and non-inflamed mucosa.

<p>(Fig. 4).</p