MacLean CH, Mojica WA, Newberry SJ, Pencharz J, Garland RH, Tu W, Hilton LG, Gralnek IM, Rhodes S, Khanna P, Morton SC. American Journal of Clinical Nutrition, 2005;82:611–619. DOI: Not provided.
Available data insufficient to support n-3 fatty acid efficacy in inflammatory bowel disease
Background & Rationale
n-3 fatty acids have been proposed as a therapeutic intervention in inflammatory bowel disease based on their immunomodulatory properties demonstrated in cell culture and animal models. These essential fatty acids modulate eicosanoid synthesis and exert eicosanoid-independent inhibitory effects on proinflammatory cytokine interleukin-1. Population-based epidemiological studies suggest a role for fatty acids in inflammatory bowel disease pathogenesis. Studies examining fatty acid profiles have demonstrated decreased total serum polyunsaturated fatty acids in inflammatory bowel disease patients and specific n-3 fatty acid deficiencies in patients with Crohn disease. At the cellular level, inflammatory bowel disease is characterised by elevated concentrations of interleukin-1 and proinflammatory leukotriene B4, which is synthesised from n-6 fatty acids. The authors conducted a systematic review to synthesise published and unpublished evidence on the effects of n-3 fatty acids on clinical outcomes in inflammatory bowel disease.
Study Design
The authors performed a systematic review of controlled trials assessing n-3 fatty acid interventions in inflammatory bowel disease. Computerised databases including MEDLINE (1966–2003), PREMEDLINE, EMBASE (1980–2003), Cochrane Central Register of Controlled Trials, CAB Health (1973–2003), and Dissertation Abstracts (1961–2002) were searched without language restrictions. Industry experts were contacted for unpublished data, though none were identified. Two independent reviewers screened 366 citations and abstracts, reviewed 180 full-text articles, and identified 13 controlled trials meeting inclusion criteria. Data were abstracted on outcomes of interest, patient characteristics, intervention details, adverse events, and methodological quality. Study quality was assessed using the Jadad score, which ranges from 0 to 5, with scores of 3 or higher indicating high methodological quality. Reviewers resolved disagreements through consensus.
Patient Population
The 13 articles described 12 unique studies enrolling patients with Crohn disease or ulcerative colitis. Sample sizes ranged from 11 to 204 participants. Study duration ranged from 3 to 24 months. All studies used fish oil as the n-3 fatty acid source, with doses ranging from 5.1 to 20 grams daily or 6 to 18 capsules daily. Control groups received various comparators including olive oil, corn oil, sunflower oil, vegetable oil, or evening primrose oil. Seven of the 12 studies achieved Jadad scores of 3 or higher; the mean Jadad score was 3.2. Concealment of allocation was reported in only 3 of the 12 studies. Most trials were deemed to be of good methodological quality.
Key Findings
Clinical scores for ulcerative colitis were assessed in five studies using various indices. Three studies reported statistically significant improvement with n-3 fatty acids at one or more time points. One study reported improvement at 3 months and another at 6 months. However, one of these three studies showed no effect at the predetermined study endpoint. Two studies found no significant differences between groups. One study in Crohn disease found no significant difference in clinical scores between n-3 fatty acids and olive oil.
Endoscopic scores for ulcerative colitis were reported in three studies. Two studies restricted to ulcerative colitis patients reported statistically significant improvement with n-3 fatty acids. A third study including both ulcerative colitis and Crohn disease patients showed significant improvement with n-3 fatty acids when all patients were combined, but not when analyses were restricted to either disease separately.
Histologic scores for ulcerative colitis were reported in three studies. Two studies found no significant difference between groups, whilst one reported statistically significant improvement with n-3 fatty acids. No studies reported histologic scores for Crohn disease.
Relapse rates showed mixed findings. Seven of eight trials examining remission or relapse found no effect of n-3 fatty acids. The single positive study used enteric-coated capsules designed to deliver n-3 fatty acids to the small bowel and found significantly lower relapse rates in Crohn disease patients (28% versus 69%). Five studies in ulcerative colitis found no significant differences in relapse rates.
Three studies assessed corticosteroid requirements in ulcerative colitis. One study reported greater reduction in median daily prednisolone dose with n-3 fatty acids compared with placebo. Another study found fewer patients treated with n-3 fatty acids required prednisolone enemas or systemic corticosteroids. A third study showed lower mean prednisone doses with n-3 fatty acids, though changes within groups were not significant.
Discussion
The available data are insufficient to draw firm conclusions about n-3 fatty acid effects on clinical, endoscopic, or histologic scores, induced remission, relapse rates, or immunosuppressive therapy requirements in inflammatory bowel disease. Many individual studies were underpowered to detect clinically significant effects. Viewing outcomes collectively, only three studies reported significant benefits on two or more assessed outcomes, and methodological quality was suboptimal in two of these. The observed efficacy in the single study using enteric-coated capsules warrants attention, as this delivery system differed from other trials and may have delivered n-3 fatty acids directly to diseased bowel segments. The findings regarding corticosteroid requirements suggest n-3 fatty acids may reduce corticosteroid needs or enable dose reduction, though statistical significance was demonstrated in only one study. Important limitations include lack of information on dose-response relationships, absence of dietary n-6 and n-3 fatty acid intake assessment in most studies, and inability to distinguish whether effects resulted from increased n-3 intake or reduced n-6 intake, as most studies substituted n-6 with n-3 fatty acids.
Authors’ Conclusions
The authors concluded that the available data are insufficient to draw conclusions about the effects of n-3 fatty acids on clinical, endoscopic, or histologic scores or remission or relapse rates in inflammatory bowel disease. However, consistent findings across three studies suggested that n-3 fatty acids may reduce corticosteroid requirements, although statistical significance was demonstrated in only one of these studies. The authors noted that fewer than six studies assessed effects on any single outcome, precluding meta-analysis. They emphasised that future studies should assess n-3 fatty acid effects on clinical outcomes in inflammatory bowel disease, including corticosteroid requirements, and should incorporate assessment of baseline dietary fatty acid intake, dose-response relationships, and delivery methods.
Reference
MacLean CH, Mojica WA, Newberry SJ, Pencharz J, Garland RH, Tu W, Hilton LG, Gralnek IM, Rhodes S, Khanna P, Morton SC. Systematic review of the effects of n-3 fatty acids in inflammatory bowel disease. Am J Clin Nutr. 2005;82(3):611-619.