Crohn disease (CD) is an inflammatory condition of the gastrointestinal tract associated with extraintestinal manifestations that include altered bone turnover and poor nutritional status. The mechanism through which localized inflammation in the CD-affected gastrointestinal tract is associated with systemic manifestations remains unconfirmed but can
involve activated mononuclear cells that migrate by way of the peripheral blood (PBMCs) to bone, muscle, liver, and other tissues. PBMCs release inflammatory mediators, including tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2), and interferon a (IFN- a), with independent effects on bone turnover or nutritional status. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 polyunsaturated fatty acids (PUFAs), whereas arachidonic acid (AA) is an n-6 PUFA. These PUFAs are acquired directly from the diet or by metabolism of dietary essential fatty acids and are substrates for the production of the eicosanoid family of inflammatory mediators (prostaglandins and leukotrienes) by mononuclear cells. Fish oil is a rich source of EPA and DHA and, in healthy subjects, alters the n-3 PUFA composition of PBMCs. The proportions of EPA and DHA in plasma phospholipid and PBMCs are altered in patients with CD compared with healthy subjects but can also be influenced by CD activity. Evidence exists that fish oil inhibits clinical disease relapse in patients with CD with raised laboratory markers of systemic inflammation [that is, erythrocyte sedimentation rate (ESR)]. This response is accompanied by a significant reduction in inflammatory markers, consistent with a systemic anti-inflammatory effect. The present study investigated the effect of fish oil plus antioxidants on cytokine production by PBMCs from patients with CD with raised C-reactive protein concentrations (e"6.9 mg/L) or erythrocyte sedimentation rates (e"18 mm/h).
This was a randomized, double-blind, placebo-controlled trial of the effect offish oil plus antioxidants compared With placebo on the composition and function of PBMCs. Patients consumed nine capsules of fish oil/d or placebo oil in addition to their habitual diet. The placebo was olive oil containing the monounsaturated fatty acid (MUFA), oleic acid (OA). The fish-oil intervention was equivalent to an additional intake of 2.7 g EPA and DHA/d. Patients in the fish-oil group additionally received a compound antioxidant dietary supplement containing 200 [micro]g selenium, 3 [micro]g manganese, 30 mg vitamin E as d-alpha-tocopheryl succinate, 450 [micro]g vitamin A (300 [micro]g RE as retinol and 150 pg RE as [beta]-carotene), and 90 mg vitamin C as ascorbic acid. The placebo group received an identical capsule containing maltose and lactose. Patients were assessed at baseline and at 8, 16, and 24 wk for treatment compliance and side effects, laboratory markers of disease activity, plasma and mononuclear cell fatty acid composition, and PBMC function and for issuing of fresh capsules. Compliance to the study was assessed by direct questioning and confirmed by analysis of plasma phospholipid composition.
A total of 77 patients were recruited and randomly assigned to fish oil plus antioxidants or placebo. Fifteen patients were excluded from the outcome analysis. Six patients withdrew from the study (two in the fish-oil plus antioxidant group and four in the placebo group). Nine patients were retrospectively identified with laboratory markers of inflammation (ESR or CRP) that were within the locally accepted normal ranges for the healthy population and, therefore, below the threshold for recruitment. There were no reported serious side effects of treatment with either fish oil plus antioxidants or placebo. Values for CDAI, CRP, and ESR were comparable between the two groups and consistent with mild-to-moderate disease activity, but there was evidence of a higher body mass index in the fish-oil plus antioxidants group. No significant differences were observed between fish-oil plus antioxidants and placebo groups in dietary fat or antioxidant intake, quantitatively or qualitatively, or baseline plasma vitamin E, vitamin A, selenium, zinc, or copper. No significant differences were observed in the response to fish oil plus antioxidants compared with placebo of CDAI, CRP, or ESR. Six patients in the fish-oil plus antioxidants group (19.4%) and 7 patients in the placebo group (22.6%) required corticosteroid medication during the intervention period. No significant differences were observed in the response to fish oil plus antioxidants compared with placebo of plasma vitamin A, vitamin E, or copper at 24 wk. However, plasma selenium was higher in the fish-oil plus antioxidants group than in the placebo group. Fish oil plus antioxidants was associated with significantly greater incorporation of EPA, docosapentaenoic acid, and DHA within PBMCs than with placebo and a significantly lower incorporation of AA.
Fish-oil plus antioxidant dietary supplementation was associated with greater incorporation of the long chain n-3 PUFAs, EPA, DPA, and DHA, and lower incorporation in the n-6 PUFA, AA, in PBMCs (and plasma phospholipid). Dietary supplementation with fish oil plus antioxidants results in altered fatty acid composition of PBMCs and plasma phospholipid in CD and in lower production of IF2q-alpha and PGE2 by stimulated PBMCs, activated T cells, and monocytes, respectively. The clinical effects of decreasing IFN- alpha or PGE2 production by PBMCs in CD are uncertain but could be relevant to the management of extraintestinal manifestations and, in particular, bone turnover. This response should be investigated further within an intervention study.
T Trebble, N Arden, S Wootton, P Calder, M Mullee, D Fine, M Stroud. Fish oil and antioxidants alter the composition and fimction of circulating mononuclear cells in Crohn disease. Am J Clin Nutr 80(5):1137-1144 (November 2004) [Correspondence: TM Trebble, Institute of Human Nutrition, School of Medicine, University of Southampton, Tremona Road, Southampton S016 6YD, United Kingdom. E-mail: tt2@soton.ac.uk.]
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