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

Nov 15, 2018 | Research | 0 comments

Published: 13th January, 2018
Authors: James J DiNicolantonio and James H O’Keefe

In Summary:

  • Seed oils are high in omega 6 and can contribute to inflammation
  • Marine omega 3s (fish oil) activate “anti inflammatory mechanisms”
  • Decreasing our omega-6 / omega 3 ratio can reduce inflammation
  • Consuming more Omega 3s and less Omega 6s can “benefit numerous chronic diseases such as rheumatoid arthritis… diabetes, obesity and heart failure.”


“The consumption of seed oils high in the omega-6 polyunsaturated fat (PUFA) linoleic acid (LA) contributes to low-grade inflammation, oxidative stress, endothelial dysfunction and atherosclerosis.

Moreover, dietary LA significantly increases cyclooxygenase-2 (COX-2) expression in the aorta, converting arachidonic acid (AA) to proinflammatory eicosanoids.

This may explain why increasing LA intake can actually lower AA levels due to an increased breakdown into harmful proinflammatory metabolites.

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.

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.

LA also induces an inflammatory environment in endothelial cells that may increase the risk of coronary heart disease (CHD).

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, and lowering dietary LA reduces OXLAMs in the body.

By inhibiting COXs and lipoxygenases (LOXs), marine omega-3s can reduce inflammation caused by the metabolism of AA.

Indeed, compared with high-oleic sunflower oil (3.5 g/day), fish oil (3.5 g/day) reduces acute phase reactants (haptoglobin precursor, haemopexin, alpha-1-antitrypsin precursor and serum amyloid P component).

The authors concluded, ‘The alterations in serum proteins… imply that fish oil activates anti-inflammatory mechanisms believed to impede the early onset of CHD’.

In human atherosclerotic lesions, as the atherosclerotic lesion becomes more advanced, the ratio between oxidised LA and unoxidised LA increases.

Moreover, rats fed LA have a significant increase in tumour necrosis factor (TNF)-alpha (p<0.05) in plasma, and higher levels of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and NF-kB in aortas.

The authors concluded that ‘…our results demonstrated that an excess of LA is more efficient to activate endothelial molecular process than an excess of saturated fatty acids’…

A systematic review of 26 randomised controlled trials (RCTs) concluded, ‘Dietary omega-3 fatty acids are associated with plasma biomarker levels, reflecting lower levels of inflammation and endothelial activation in cardiovascular disease and other chronic and acute diseases, including chronic renal disease, sepsis and acute pancreatitis’.

DHA may be particularly effective for reducing cytokine-induced endothelial leucocyte adhesion molecules due to its ability to incorporate into cellular lipids.15 Moreover, DHA reduces COX-2 expression, which also reduces inflammatory eicosanoid production from AA.”

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.

For example, one study looked at responses in men with metabolic syndrome to an oral fat tolerance test (OFTT) by adjusting the omega-6/3 ratio. Patients ingested two high-saturated fat OFTTs (1 g fat/kg body weight) with either a high omega-6/3 ratio (~18:1) or a low omega-6/3 ratio (~3:1) and a water control in a randomised crossover design.

Reducing the omega-6/3 ratio caused a lower release of the proinflammatory cytokine IL-6 at hours 6 and 8.

Additionally, Nelson and Hickey performed a study showing that an isocaloric replacement of LA with ALA for just 4 days leads to a reduction in soluble IL-6 receptor.

These studies suggest that replacing omega-6 with omega-3 reduces inflammation.


“The reddening and swelling of areas in the body generally occurs because of the release of omega-6 (AA) eicosanoids and cytokines.

This happens when AA is metabolised by cycloxygenases (COX1 and COX2) or LOXs. Aspirin, for example, a well-known pain reliever and fever reducer, inhibits COX1 from breaking down AA, thereby preventing the inflammatory response.

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen inhibit both COX1 and COX2 and are the most popular over-the-counter pain relievers showing just how powerful the proinflammatory metabolites are from AA.

Instead of using NSAIDs to inhibit the formation of omega-6 AA metabolites, eating more EPA/DHA can provide a similar effect. Omega-3s PUFAs act to prevent chronic low-grade inflammation.

Indeed, supplementing with fish oil is known to inhibit inflammatory cytokines such as TNF-alpha and IL-1 beta and proinflammatory/proaggregatory eicosanoids such as thromboxane-2 and prostaglandin E2.

Using long-chain omega-3s to suppress low-grade inflammation may benefit numerous chronic diseases such as rheumatoid arthritis, atherosclerosis, dyslipidaemia, diabetes, obesity and heart failure.

The consumption of omega-6 seed oils may have the opposite effect.”

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