DHA Effects in Brain Development and Function

The brain has a unique fatty acid composition, and DHA is quantitatively the most important omega-3 fatty acid in the brain.  The DHA fatty acid has consistently been shown to have unique and indispensable roles in the neuronal membrane.

Nutrition plays an important role in brain development and cognitive function.  Intake of EPA and DHA is considered particularly important for neuronal development during early infancy where a substantial amount of DHA is accumulated in the brain.  This accumulation of DHA continues throughout childhood, especially in the frontal cortex, which is involved in cognitive and socioemotional functions, which continue to develop until early adulthood.  Worldwide oily fish are currently the primary dietary source of EPA and DHA.  A number of randomised clinical trials of oily fish intake have demonstrated benefits for cognition, learning and/or mental health in pre-school children, in primary school children, and in adolescents. Two important points:

• All of these studies were conducted in Scandinavian countries where baseline levels of omega-3 PUFAs are higher than the worldwide average – benefits were still seen where levels were further increased.
• The improvements in cognition and mental health were most marked in those with the best adherence to the study diet – i.e. in those children whose oily fish intake actually increased, and in whom blood levels of DHA increased.

Inflammation in the brain is beneficial to maintain organ homeostasis in response to infection.  Brain inflammation involves microglial cells, the resident macrophages of the central nervous system.  When activated, these cells produce pro- and anti-inflammatory cytokines.  However, when the production of proinflammatory cytokines is sustained, these molecules become neurotoxic, leading to neuronal damage involved in many brain pathologies.  Hence, limiting inflammation is of great importance.  A large number of studies support the hypothesis that long chain omega 3 fatty acids or their products are candidates for limiting neuroinflammation.

Many studies evaluating the relationships between long-chain omega-3 fatty acids intake and risk of dementia or Alzheimers disease suggest that there was may be a potential protective effect of long-chain omega-3 fatty acids on incidence of dementia and Alzheimers disease.

In the last 20 years, epidemiologic studies have linked dietary PUFAs in the pathophysiology of mood disorders.  In particular, dietary intake of food rich in n-3 LC-PUFAs is associated with reduced prevalence of major depression, postpartum depression, or bipolar disorder.

The cardiovascular benefits of diets rich in omega 3 fatty acids were first observed in studies in Greenland Eskimo, where low rates of coronary heart disease and low mortality from ischaemic heart disease were observed.  Fish, rich in omega 3 fatty acids, was an important component of the diet.

The concept of cardiovascular protection offered by omega 3 fatty acids has been proven beyond doubt.  Compelling evidence is provided from pooled data analysis and meta-analysis.  The Lancet published systematic review of dietary risks (Global Burden of Disease Study) indicates that mortality risk decreases by 10-30% with each 100 mg increment in dietary EPA and DHA intake.  In a recently completed Framingham study, each 1% increment in the omega-3 index (EPA+DHA as % of total fatty acids in red blood cell membrane) was associated with a 15% reduction in cardiovascular events and a 10% reduction in total mortality.

Lee et al. (2008) considered 3 studies of 32,000 participants randomized to receive omega-3 fatty acid supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or to act as controls.  These trials showed reductions in cardiovascular events of 19% to 45% in treated groups.  Harris et al. (2007) considered 25 studies and concluded that the long-chain omega 3 fatty acids, especially DHA, were consistently and significantly reduced in patients experiencing coronary heart disease events.  Mozaffarian and Wu (2011) concluded that the current data provide strong evidence that omega 3 fatty acids are bioactive compounds that reduce risk of cardiac death.  They specifically mentioned that guidelines have converged on consistent recommendations for the general population to consume at least 250 mg/day of long-chain n-3 PUFA.  More recently Mozaffarian et al (2013) found that circulating omega 3 fatty acid levels are linked to lower total mortality among generally healthy adults later in life, with potentially greatest associations with cardiovascular events and especially arrhythmic cardiac death.

The beneficial effects of EPA and DHA in humans are believed to result from their presence in cell membranes.  From this location, they influence many molecular pathways including membrane structure, ion channel properties, genetic regulation, fatty acid metabolism (in hepatocytes), eicosanoid and inflammatory mediator synthesis.  It appears likely that some of the beneficial effects of omega-3 PUFAs on cardiovascular health are mediated through downstream effects on blood pressure and heart rhythm.

The brain and eye are highly enriched with omega-3 fatty acids, which accumulate in these tissues during late fetal and early neonatal life.  Very high levels of the omega-3 fatty acid docosahexaenoic acid (DHA) are present in the retina, and specific parts of the retina.  And interestingly DHA appears to be maintained at a certain level in the retina despite reductions in dietary intake of omega-3 fatty acids.  The high DHA content and its specific and consistent tissue distribution suggest that DHA has an important function in the retina (Rodriguez de Turco et al., 1991).

Birch et al. (1992) conducted a study with very low birth weight (premature) infants.  The infants were randomized to one of three diet groups: corn oil, which provided solely linoleic acid; soy oil, which provided linoleic and a-linolenic acids; or soy/marine oil; which was similar to the soy oil formula but also provided preformed long chain omega 3 fatty acids.  Only the soy/marine oil group had acuities comparable to the “gold standards” of VLBW infants fed human milk and closer-to-term (ie larger) infants.  The results suggest that dietary omega 3 fatty acid supply may play an important role in early human visual development.

Omega 3 fatty acids play an important role in eye health.  Previous studies have shown that Retinitis Pigmentosa patients have significantly reduced plasma DHA levels, suggesting an association between DHA deficiency and higher risk of RP (Gong et al., 1992; Schaefer et al., 1995).  Treatment with omega 3 fatty acids has also been associated with improvement in some of the clinical outcomes in patients with RP (Hodge et al., 2006).  Meta-analysis of pooled data from nine studies showed that high dietary intake of omega 3 fatty acids was associated with 38% reduction in the risk of late age-related macular degeneration (AMD) (Chong et al., 2008).  Fish intake at least twice per week was associated with reduced risk of both early and late AMD.  The incidence of dry eye syndrome was less common among women who consumed higher amounts of omega 3 fatty acids (Miljanovic et al., 2005).

The omega 3 fatty acids EPA and DHA support an effective immune system and optimal immune function, including by helping to resolve inflammation and the inflammatory response, and therefore reduce the risk and consequences of infections.

The immune system is comprised of the innate (fast, non-antigen specific) and adaptive (slower, antigen-specific) responses.

The innate immune system is the fast, “general”, response and is comprised of physical barriers, such as the skin, that help to prevent the pathogen gaining entry.  It also includes some cells such as neutrophils and macrophages that recognise pathogens are present.  The innate system acts quickly to recognize and destroy pathogens, typically via inflammatory processes.  Then the inflammation is resolved, and any damage is repaired.

Subsequent to the innate response, the adaptive response is engaged.  It is a more “specific” response.  So although slower to respond, it can generate a “memory”, such that a repeat infection with the same pathogen will generate a vigorous, fast antigen-specific response.

Inflammation is therefore a key component of the (innate) immune response.  Pro-inflammatory mediators are produced by many different types of cell, and “inflammation” results in the influx of fluid, immune cells, and other mediators that function to eliminate the infection.  Typically, Inflammation resolves quickly at the end of the immune response, due to activation

of specific negative-feedback mechanisms.  Among these, EPA and DHA present at the site of inflammation are converted to specialised pro-resolving mediators (SPMs).  These, and some other molecules, work together to end the inflammation and to support healing, including in the respiratory tract.  Nutritional deficiencies in EPA and DHA can result in delayed or suboptimal resolution of inflammation.  This could be very important in the context of severe COVID-19 which manifests as uncontrolled inflammation, often referred to as the ‘cytokine storm’, linked with acute respiratory distress syndrome (ARDS).  In animal models, some of the SPMs formed from EPA and DHA have been shown to protect against, and resolve, acute lung injury and ARDS.

An adequate intake of EPA and DHA supports the resolution of inflammation via the production of anti-inflammatory metabolites of these fatty acids, including in the respiratory tract.  An intake of 250 mg EPA + DHA per day is recommended.

Adapted from: Calder, P.C., Carr, A.C., Gombart, A.F., Eggersdorfer, M. 2020. Oprimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients 12(4): 1181