Effects of Omega-3 Fatty Acids on Immune Cells

Fatty acids and bipolar disorder

1 - Omega-3 Fatty Acids in Health and Disease

Polyunsaturated omega-3 and omega-6 fatty acids are essential fatty acids that cannot be produced by the body itself and therefore must be provided through nutrition. Omega-6 and particularly omega-3 fatty acids have important roles in the organism, contributing to the maintenance and promotion of health. The optimal proportion of omega-6/omega-3 fatty acids is 2:1, or even better 1:1. They are involved in normal growth and development, play a role in the prevention of coronary and cardiovascular diseases, of diabetes mellitus, of arterial hypertension, arthritis and cancer. Omega-3 fatty acids mainly have an anti-inflammatory effect, but also act as hypolipidemic and antithrombotic agents. A potential role of omega-3 fatty acids is that of increasing physical performance. Their role in the physical activity refers on one side to the global health of athletes and on the other side to their anti-inflammatory effect, as high intensity physical exercise induces increased free-radical production and microtraumas, with the induction of an inflammatory status. The anti-inflammatory effect of these fatty acids manifests through an increased production of endogenous antioxidant enzymes, through decreasing the production of prostaglandins metabolites, decreasing the production of leukotriene B4, etc. They are also effective on reducing muscle pain post eccentric exercise and on decreasing the severity of bronchoconstriction induced by exercise, as well as improving pulmonary function variables. In conclusion it seems that supplementing diets with omega-3 fatty acids, apart from having benefic effects on health and on the prevention and management of certain affections, proves to be a beneficial for physical activity and athletic performance.

Fatty acids play a very important role in human physiology. Except for the fact that fatty acids in stored triglycerides can be used for energy production, fatty acids from dietary lipids are transported in plasma and built into various cellular structures. The fatty acid profile of cell membrane phospholipids plays a determining role in the cell membrane in that it influences fluidity, receptor function and the type of eicosanoids that can be synthesised from it. Fatty acids also have highly differentiated inputs in cellular transduction mechanisms and regulation of gene transcription. In this, the steric conformation plays a large role: the straight-chain saturated and trans-fatty acids, when compared with the unsaturated fatty acids with progressively more bent chains, lead to a variety of mechanisms that have less positive effects on our health. In this regard, the two most important families of polyunsaturated fatty acids, the so-called omega-3 and omega-6 fatty acids, also lead to different effects. Changes in the pattern of dietary fatty acid intake through the ages have lead to an increased intake of saturated, trans- and omega-6 fatty acids relative to omega-3 fatty acids. Clinical trials during the past twenty years have shown that dietary supplementation with omega-3 fatty acids can lead to an improvement of the symptoms of certain lifestyleassociated disorders. Atherosclerosis, obesity, type 2 diabetes mellitus, depression, schizophrenia, Alzheimer’s disease, attention deficit hyperactivity disorder in young children, certain types of cancer, osteoporosis in the elderly and some dermatological disorders are amongst the conditions that can be addressed in this manner.

In developing countries, approximately 30-40% of school-age children suffer from iodine and iron deficiencies. Poverty and consumption of monotonous diets are underlying causes of inadequate intakes of micronutrients and omega-3 fatty acids and may have severe consequences for children’s cognitive development. Multiple micronutrient interventions have shown to benefit mental performance of children, but a systematic evaluation of the evidence is currently lacking. The omega-3 fatty acid, -linolenic acid (ALA) is converted into docosahexaenoic acid (DHA), a major structural component of the brain, which is important for normal development and maintenance of brain function. At present, it is unclear whether additional intake of omega-3 fatty acids improves cognitive performance in children.The aim of this thesis was to investigate the role of multiple micronutrients and omega-3 fatty acids on cognitive performance in school-age children living in deprived environments, thereby addressing three main research questions.The first query concerned the investigation of the size of effects of multiple micronutrient interventions on different cognitive domains. Findings of our meta-analysis comprising 17 studies in children 5-16 years of age, suggested that multiple micronutrients were beneficial for fluid intelligence (i.e. reasoning abilities) (0.14 SD; 95% CI: -0.02, 0.29) and academic performance (0.30 SD; 95% CI: 0.01, 0.58). Crystallized intelligence (i.e. acquired knowledge) seemed not affected (-0.03 SD; 95% CI: -0.21, 0.15) and for the other cognitive domains data were too limited to draw firm conclusions.Secondly, we examined the role of omega-3 fatty acids on children’s cognitive development, for which a literature review was conducted. Associations between omega-3 fatty acid status or dietary intake and cognitive performance were investigated by cross-sectional analysis using baseline data of a randomized controlled trial in 598 Indian schoolchildren (see below for details). We found no evidence for a beneficial effect of additional intake of omega-3 fatty acids, and of DHA in particular, on cognitive development in school-age children. Neither there was a significant relationship between omega-3 fatty acid status and cognitive performance.Lastly, we studied the effect of different doses of micronutrients and omega-3 fatty acids, and their interaction, on cognitive performance. For that purpose, a randomized controlled trial in 598 Indian schoolchildren aged 6-10 years was conducted from November 2005 until March 2007. Children received either 15% or 100% of the Recommended Dietary Allowance of micronutrients in combination with either a low (140 mg ALA) or high dose (900 mg ALA plus 100 mg DHA) of omega-3 fatty acids for 12 months. Cognitive function was measured at baseline, 6 and 12 months. Our results showed that with some small differential effects on short term memory at 6 months (0.11 SD; 95% CI: 0.01-0.20) and fluid intelligence at 6 months (-0.10 SD; 95% CI: -0.17, -0.03) and 12 months (-0.12 SD; 95% CI: -0.20, -0.04), the high and low dose of micronutrients were as effective for improving retrieval ability, cognitive speediness and overall cognitive performance. Neither there were differences between the omega-3 fatty acid treatments, nor an interaction between micronutrients and omega-3 fatty acids on cognitive outcomes.In conclusion, although multiple micronutrients may benefit intellectual performance of schoolchildren, development of public health guidelines is currently premature. Further investigation on doses and composition of micronutrients would be needed to identify a cost-effective micronutrient supplement to optimize cognitive performance in children. Presently, no evidence exists for a positive effect of omega-3 fatty acids on cognitive performance in healthy children. A final trial using a higher dose and sufficiently long duration would be needed to conclude whether omega-3 fatty acid supplementation improves mental development at school age.

This review aims to provide a comprehensive evaluation of the role of omega-3, omega-6, and omega-9 fatty acids in the prevention and management of cardiovascular diseases (CVDs). Specifically, the objective is to analyze the underlying mechanisms of action and critically evaluate the available clinical evidence, addressing current controversies regarding efficacy and safety, particularly concerning different formulations and dosages. Materials and methods: This review is based on an extensive analysis of current scientific literature, including epidemiological studies and randomized controlled trials (RCTs). Key large-scale contemporary trials such as REDUCE-IT, STRENGTH, OMEMI, VITAL, and ASCEND were critically analyzed to assess the impact of marine omega-3 polyunsaturated fatty acids (PUFAs), particularly Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA), on cardiovascular outcomes. The scope also encompassed the chemical characterization, natural sources, and metabolic pathways of these lipids. Results: Omega-3 PUFAs exert multifaceted effects, most consistently reducing serum triglyceride levels through inhibition of hepatic lipogenesis6. EPA and DHA possess potent anti-inflammatory properties, acting as precursors to specialized pro-resolving mediators (SPMs), and exhibit antithrombotic and hypotensive effects. Clinical efficacy is highly dose- and formulation-dependent8. High-dose purified EPA (4 g/day) demonstrated significant risk reduction in major cardiovascular events in statin-treated high-risk patients (secondary prevention). Conversely, mixed EPA/DHA formulations often yielded inconsistent results. A significant safety signal emerged, linking high-dose omega-3 supplementation (doses >1 g/day) to a dose-dependent increased risk of incident atrial fibrillation (AF). Conclusion: Omega-3 fatty acids remain a cornerstone in managing severe hypertriglyceridemia and reducing residual CVD risk in specific high-risk patients with atherogenic dyslipidemia. For the general population, a "food-first" approach is recommended13. High-dose purified EPA represents a distinct and effective pharmacological intervention in secondary prevention, acting beyond simple lipid lowering through plaque stabilization and anti-inflammatory pathways14. Further research is required to fully elucidate the pathophysiological mechanism linking high-dose omega-3s to AF and to establish optimal dosing strategies based on the "Omega-3 Index".

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93–0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OREPA 0.92; 95% CI 0.88–0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. ‘Leave-one-out’ analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power.

Long-chain omega-3 fatty acids belong to a family of polyunsaturated fatty acids that are known to have important beneficial effects on metabolism and inflammation. Such effects may confer a benefit in specific chronic noncommunicable diseases that are becoming very prevalent in Westernized societies [e.g., nonalcoholic fatty liver disease (NAFLD)]. Typically, with a Westernized diet, long-chain omega-6 fatty acid consumption is markedly greater than omega-3 fatty acid consumption. The potential consequences of an alteration in the ratio of omega-6 to omega-3 fatty acid consumption are increased production of proinflammatory arachidonic acid-derived eicosanoids and impaired regulation of hepatic and adipose function, predisposing to NAFLD. NAFLD represents a spectrum of liver fat-related conditions that originates with ectopic fat accumulation in liver (hepatic steatosis) and progresses, with the development of hepatic inflammation and fibrosis, to nonalcoholic steatohepatitis (NASH). If the adipose tissue is inflamed with widespread macrophage infiltration, the production of adipokines may act to exacerbate liver inflammation and NASH. Omega-3 fatty acid treatment may have beneficial effects in regulating hepatic lipid metabolism, adipose tissue function, and inflammation. Recent studies testing the effects of omega-3 fatty acids in NAFLD are showing promise and suggesting that these fatty acids may be useful in the treatment of NAFLD. To date, further research is needed in NAFLD to (a) establish the dose of long-chain omega-3 fatty acids as a treatment, (b) determine the duration of therapy, and (c) test whether there is benefit on the different component features of NAFLD (hepatic fat, inflammation, and fibrosis).

Elevated ratio of arachidonic acid to long-chain omega-3 fatty acids predicts depression development following interferon-alpha treatment: relationship with interleukin-6.

Paola Bozzatello et al. [1] have done a comprehensive qualitative review of the potential use of long-chain polyunsaturated fatty acids in the prevention and treatment of mental disorders.[...].

Omega-3 fatty acids are a family of polyunsaturated fatty acids (PUFAs) with beneficial health effects to humans if consumed in required amounts. Fatty fish species are known to be rich in marine-based omega-3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, C22:6n-3) and docosapentaenoic acid (DPA, C22:5n-3). Sardines (Rastrineobola argentea) from Lake Victoria are a good source of health promoting omega-3 fatty acids. Open sun drying is a common and traditional sardine processing and preservation method. Due to their chemical instability omega-3 fatty acids in sun dried sardines are prone to lipid oxidation during processing and subsequent storage. This study investigated the use of clove (Syzygium aromaticum) water extracts as natural antioxidants to protect omega-3 fatty acids against oxidative damage during storage of sun dried sardines. Lipid oxidation was assessed by peroxide value, volatile secondary oxidation products and fatty acid profiles. The antioxidant capacity of extracts was evaluated by total phenolic content, 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and iron (Fe2+) chelating ability. Clove extracts resulted into significantly higher retention of total PUFAs, DHA, EPA and DPA at the end of 30 days storage period and lower concentrations of secondary lipid oxidation products. This is an evidence of their enhanced oxidative stability in the real food system due to presence of natural clove antioxidants.

Lipid mediators in the regulation of innate and adaptive immunity.

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Since the original American Heart Association (AHA) Science Advisory was published in 1996,1 important new findings have been reported about the benefits of omega-3 fatty acids on cardiovascular disease (CVD). Omega-3 fatty acids are obtained from two dietary sources: seafood and certain nut and plant oils. Fish and fish oils contain the 20-carbon eicosapentaenoic acid (EPA) and the 22-carbon docosahexaenoic acid (DHA), whereas canola, walnut, soybean, and flaxseed oils contain the 18-carbon α-linolenic acid (ALA). ALA appears to be less potent than EPA and DHA. The evidence supporting the clinical benefits of omega-3 fatty acids derive from population studies and randomized, controlled trials, and new information has emerged regarding the mechanisms of action of these nutrients. These are outlined in a recent Scientific Statement, “Fish Consumption, Fish Oil, Omega-3 Fatty Acids and Cardiovascular Disease.”2 See page e20 Large-scale epidemiologic studies suggest that people at risk for coronary heart disease (CHD) benefit from consuming omega-3 fatty acids from plants and marine sources. Although the ideal amount to take is not firmly established, evidence from prospective secondary prevention studies suggests that intakes of EPA+DHA ranging from 0.5 …

Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study