Importance of maintaining a low omega–6/omega–3 ratio for reducing inflammation

• Published in: Open heart Vol. 5; no. 2; p. e000946
• Main Authors: DiNicolantonio, James J, O’Keefe, James H
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.11.2018; BMJ Publishing Group
• Subjects: Atherosclerosis; Biomarkers; Blood; Cardiovascular disease; Cell adhesion & migration; Chemokines; Chronic illnesses; Cytokines; Fatty acids; Fish oils; Gene expression; Inflammation; Metabolism; Metabolites; Oils & fats; Proteins; Systematic review; Tumor necrosis factor-TNF; Vegetable oils; linoleic acid; omega-6; omega-3; INFLAMMATION; fish oil
• ISSN: 2053-3624; 2398-595X; 2053-3624
• DOI: 10.1136/openhrt-2018-000946

Additionally, there is an AA-independent pathway of inflammation promoted by the intake of omega-6 seed oils such as increased production of oxidised linoleic acid metabolites (OXLAMs) and proinflammatory LA CYP-eicosanoids.3–5 OXLAMs formed from LA activate NF-kB and increase proinflammatory cytokines, endothelial adhesion molecules, as well as chemokines, all of which are paramount in the formation of atherosclerosis.5–8 LA also induces an inflammatory environment in endothelial cells that may increase the risk of coronary heart disease (CHD).8 OXLAMs are found at a 50-fold higher concentration in plasma than AA metabolites, suggesting that they are more consequential in CHD and other chronic diseases,2 3 9 and lowering dietary LA reduces OXLAMs in the body.3 By inhibiting COXs and lipoxygenases (LOXs), marine omega-3s can reduce inflammation caused by the metabolism of AA. The authors concluded, ‘Compared with placebo, icosapent ethyl 4 g/day significantly decreased oxidized-low density lipoprotein (Ox-LDL) (13%, p<0.001, ANCHOR), Lp-PLA2 (14%, p<0.001, MARINE; 19%, p<0.001, ANCHOR), and high-sensitivity c-reactive protein (hsCRP) levels (36%, p<0.01, MARINE; 22%, p<0.001, ANCHOR)’.12 The benefits regarding a reduction in ox-LDL was not found with 2 g of Vascepa/day, suggesting that 4 g of Vascepa (3.4 g of eicosapentaenoic acid (EPA) as ethyl esters) may be ideal for reducing ox-LDL.12 Furthermore, DHA alone (at 3 g/day) has been found to reduce inflammation (interleukin (IL)-6, hsCRP and granulocyte monocyte-colony stimulating factor) in men with hypertriglyceridaemia after 3 months of use and to increase the anti-inflammatory matrix-metalloproteinase-2.13 Thus, it appears that both EPA and docosahexaenoic acid (DHA) have anti-inflammatory benefits. Omega-3 PUFAs also reduces adhesion molecules (VCAM-1 and ICAM-1), chemokines (MCP-1), matrix metalloproteinases and inflammatory cytokines.17 Another meta-analysis of 18 RCTs found that supplementing with omega-3 PUFAs significantly reduces soluble intercellular adhesion molecule-1, suggesting that marine omega-3s inhibit atherosclerosis formation, whereas LA can activate vascular endothelial cells, which is a critical event in inducing atherosclerosis.18 19 In a cross-sectional study, the omega-3 index (omega-3 PUFA content of red blood cells) was inversely related to inflammation (C reactive protein (CRP) and IL-6) in patients with peripheral arterial disease (PAD).20 Those with a mean omega-3 index of 6.8% had the lowest log-CRP values (0.6 mg/L) compared with those with omega-3 indexes of 4.5% and 3.7% (1.4 mg/L for both). [...]LA in red blood cells and in plasma does not correlate well with intake, whereas DHA, especially in red blood cells but also in plasma, had good correlation (EPA also had fairly good correlation with intake as well but only with red blood cell levels).21 The omega-3 index is an independent risk factor for CHD mortality22 and is inversely related with inflammation (CRP and IL-6) in patients with stable CAD.23 One study found that omega-3s (around 25 oz. of fatty fish weekly plus 15 mL (one tablespoonful) of sardine oil daily) in those over 60 years of age reduces inflammation (CRP and IL-6) and improves insulin sensitivity, which may partially be due to its ability to reduce free fatty acids release by catecholamines.24 Compared with 15 mL/day of safflower oil (rich in LA) consuming 15 mL of flaxseed oil (around 7 g of alpha linolenic acid (ALA)/day) for 3 months decreases CRP (38%), serum amyloid A (23.1%) and IL-6 (10.5%).25 Moreover, compared with margarine rich in LA, margarine rich in ALA (total ALA intake around 6–8 g/day) significantly reduced CRP after 1 and 2 years (−0.53 mg/L and −0.56 mg/L, respectively).26 Thirty grams of flaxseed flour (5 g of ALA/day) has been found to significantly reduce CRP, serum amyloid A, white cell count and fibronectin, suggesting that flaxseed may be beneficial for suppressing chronic low-grade inflammation in obesity.27 Decreasing the omega-6/3 ratio decreases inflammation Decreasing the omega-6/3 ratio seems to reduce the inflammatory response to a high-fat meal.