Philip Calder, PhD, University of Southampton, UK
Previously, Nutri-Facts has reported on Professor Calder’s view on current controversies in omega-3 research (1). This article will examine his long standing research on the effects of omega 3 fatty acids on inflammation, a condition which causes a range of human diseases. The characteristic features of inflammation are heat, redness, swelling pain and loss of function. If acute inflammation is left unresolved, it becomes chronic inflammation and then leads to tissue fibrosis. The omega 3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are known to reduce inflammation and promote resolution (2).
A key step in the inflammatory process is an increased supply of blood to the site of the inflammation and an increased permeability of the vascular wall which allows plasma and large molecules to cross the epithelium. Leukocytes, attracted by chemo-attractants at the site of inflammation, migrate from the bloodstream into the tissue surrounding the damage site. The leucocytes then release a series of lipid-derived mediators (e.g., prostaglandins, leukotrienes, endocannabinoids), platelet activating factor, peptide mediators (e.g., cytokines), amino acid derivatives and various enzymes. This cocktail of metabolites is largely responsible for the characteristic visible signs of inflammation. Ongoing, unresolved inflammation can cause serious disease such as rheumatoid arthritis, inflammatory bowel disease and asthma (4).
The phospholipids of the membranes of cells involved in the inflammatory process are rich in omega 6 fatty acids. Yaqoob et al (8) demonstrated that the membrane lipids of peripheral blood mononuclear cells (PBMC) typically contained around 10% linoleic acid (C18:2) and 20% arachidonic acid (ARA C20:4), but only 0.5% EPA and 2% DHA. However, the composition was radically changed when the patients were supplemented with 2.1g EPA and 1.g DHA per day for 12 weeks resulting in a 20% reduction in ARA levels and consequent replacement with EPA/DHA.
ARA is a precursor of the eicosanoids intimately involved in inflammation. In response to inflammatory antagonists, it is released from its bound phospholipid state in the membrane to the free fatty acid into the cell cytoplasm. The free ARA is then converted into inflammatory eicosanoid mediators via the cyclo-oxygenase (COX), lipo-oxygenase (LOX) and CYTP450. In addition, activated membrane ARA phospholipids initiate the production of pro-inflammatory endocannabinoids. These mechanisms are the targets of many pharmacological interventions.
Higher intakes of omega 3 fatty acids lead to increased incorporation into blood lipids, cells and tissue pools. EPA and DHA modify the structure of cell membranes and thus modify the function of membrane bound proteins which are used for receptors, transporters, signaling and as enzymes. The marine omega 3 fatty acids, DHA, EPA and DPA are pro-resolving mediators able to resolve the inflammation and return the tissue to a homeostatic status (2). These fatty acids work in part by antagonizing the production and actions of arachidonic acid (ARA)-derived eicosanoids and in part by eicosanoid-independent mechanisms (4). We can identify 4 key anti-inflammatory mechanisms of EPA/DHA:
1. They will partially replace ARA in the cell membrane phospholipids reducing the pool of ARA available for eicosanoid production.
2. They also reduce eicosanoid production by attenuating the efficiency of the LOX and COX pathways.
3. Membrane bound EPA is metabolized to 3 series Prostaglandins and 5 series Thromboxanes, which are much more weakly inflammatory than the eicosanoids produced by ARA.
4. EPA is metabolized to pro-resolving E series resolvins, whilst DHA is metabolized to pro-resolving D series resolvins and protectins.
Whilst many nutrients have some anti-inflammatory and anti-oxidant effects, EPA and DHA appear to have very specific effects. A cross sectional population study by Ng et al. (8) which carefully took account of the dietary components including micronutrients demonstrated a specific anti-inflammatory for marine oils on lung function which was protective against chronic airway narrowing and maintained interstitial lung structure and function.
Inflammatory antagonists (including some bacterial polysaccharides and saturated fats) exert their effect on the cell membrane by binding with Toll-like receptor 4 (TLR4). The binding results in formation of NFκB (nuclear factor κB), which makes it way to the nucleus. DHA has been shown to help prevent the binding of the antagonist. This may be due to a direct effect on the NFκB pathway, but it more likely due its ability to bind with the membrane G coupled protein 120 (GPR120). This specific DHA protein receptor then produces PPARγ (peroxisome proliferator activated receptor) which appears to prevent the transit of NFκB to the nucleus (3,6,9). Interestingly, some individuals have a genetically dysfunctional variant of GPR120 known as R270H (7). The variant does not produce the normal anti-inflammatory metabolites and hence is thought to cause insulin resistance and obesity.
To date, whist animal studies have demonstrated benefits of marine omega 3 fatty acids to such chronic inflammatory conditions as rheumatoid arthritis, inflammatory bowel disease (IBD) and asthma, robust clinical evidence only exists for rheumatoid arthritis in humans. The evidence of benefit in IBD and asthma is promising but inconsistent and needs much further work (4).
In summary, Professor Calder has been able to explain how marine omega 3 fatty acids are able to resolve the effects of inflammation. Some clinical benefits such as in the field of arthritis are already clear, whilst other conditions require further clinical trials.