Is Eicosapentaenoic Acid Useful in the Treatment of Ulcerative Colitis in Children?

There is evidence that n-3 long chain polyunsaturated fatty acids (LC-PUFAs) are beneficial in chronic inflammatory diseases. The beneficial effects appear to relate to the ability of n-3 LC-PUFAs, particularly eicosapentaenoic acid (20:5 n-3, EPA) to antagonize the production of inflammatory eicosanoid mediators from arachidonic acid (20:4 n-6). In addition, n-3 PUFAs regulate the production of some inflammatory cytokines and downregulate the expression of a number of genes involved in inflammation (1). The study of Shimizu et al. (2) evaluates the impact of 1.8 g of highly purified eicosapentaenoic acid ethyl ester (EPA-E) given daily for 2 months to children with ulcerative colitis (UC) in relapse. Clinical symptoms as well as erythrocyte fatty acid composition and LTB4 production by leukocytes and colonic mucosa were monitored. No patients showed symptoms of worsening clinical relapse during the study period and there were no significant differences in the histologic scores before and 2 months after the EPA-E treatment. The LTB4 production from leukocytes and rectal mucosa after 2 month of EPA-E treatment was significantly lower than before treatment. Because the authors did not include a control group without EPA-E treatment, it is difficult to ascertain whether or not the absence of relapses for the study period is attributable to the administration of EPA-E. However, this study does suggest that the daily administration of EPA-E to children with UC may be important in the management of the disease. Medical therapy with pharmacologic agents is undeniably useful for induction of remission of UC; however, in the long term medical therapies may result in adverse side effects. Dietary management options may provide effective therapy in UC without the adverse effects of either surgery or medications. Few clinical studies suggest a significant influence of diet or nutritional supplementation in UC probably because the cause of UC is multifactorial and individual therapeutic effects are difficult to isolate. There is however, some evidence to indicate that a high intake of n-3 fats, such as EPA, may have an anti-inflammatory effect (3). The fatty acid composition of lymphocytes and other immune cells is affected according to the fatty acid composition of the diet, and therefore diet may alter the immunoregulatory functions of these cells (4,5). Although not all studies agree, it appears that EPA downregulates the T-helper 1-type (TH-1) response, which is associated with chronic inflammatory disease. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of pro-inflammatory cytokines (6,7). The study by Shimizu et al. (2) did not evaluate the influence of the intake EPA-E on cytokines but focused only on the changes of the eicosanoid LTB4. However, additional studies in children should aim to determine how the capacity of immunoregulation is influenced by EPA-E in children with UC. Fish oil is the most common and important source of n-3 PUFA, although the use of purified EPA as ethyl ester may have some advantages in the treatment of UC, particularly in children, because it can be administered in a single capsule with or after each meal. Most of the studies performed to evaluate the anti-inflammatory properties of n-3 LC-PUFA have been done in adults. McCall et al. (8) treated six patients with active UC with 3 to 4 g/d of EPA for 12 weeks and observed an improvement in their symptoms and an amelioration of intestinal mucosa histologic findings associated with a lower LTB4 production by neutrophils. Salomon et al. (9) also reported that administration of 2.7 g/d of EPA and 1.8 g/d of DHA to 10 patients with UC for 8 weeks led to an improvement in all indicators of clinical activity for 7 patients, although the amelioration in the other 3 patients was unimpressive. Lorenz-Meyer et al. (10) treated 10 patients with active UC for 7 months using a crossover model with olive oil and fish oil, and they found promising results. In 1992, Hawthorne et al. (11) published the first double-blind controlled study to evaluate the effects of oral administration of n-3 PUFA in UC. They treated 96 patients with UC in different degrees of activity with 4.5 g/d of EPA. In patients with active UC, a significant decrease in corticosteroid use was observed. Likewise, the production of LTB4 by neutrophils decreased by more than 50%. Stenson et al. (12), in a controlled study in which patients with active UC received 5.4 g/d of n-3 PUFA for 4 months, reported good patient weight gains, improved colon histology, and a 60% decrease in LTB4 production by rectal dialysates. A similar study in which 4.2 g/d of n-3 PUFA was administered for 3 months to 17 patients with active UC, there was a 72% decrease in the amount of steroid required to control disease (13). Loeschke et al. (14), in a study of 64 patients with UC in remission, compared the results of 2 years treatment with either 5.1 g n-3 PUFA daily or the equivalent amount of corn oil. After 3 months, patients receiving the n-3 supplement experienced fewer relapses. More recently, it has been shown that in patients with proctocolitis receiving n-3 PUFA supplementation, there is evidence of suppression of immune reactivity concurrent with reduction in disease activity. These findings may have important implications for therapy in patients with UC (15,16). A word of caution is sounded by one study, however, in which greater disease activity occurred in 10 UC patients receiving 5.4 g/d of fish oil for 2 months (17). In conclusion, the administration of n-3 LC-PUFA to patients with UC and, more specifically, the administration of EPA-E to children with UC may provide a tool to ameliorate the course of the disease because of the anti-inflammatory properties of these lipids. The mechanisms by which n-3 PUFA influences the systemic and the gut-associated lymphoid tissue immune response remain to be ascertained. In addition, potential adverse side effects caused by increased oxidation should be carefully evaluated before the these compounds are recommended for routine use.