Powerful Immune Influencers: Omega-3 Fats and Specialized Pro-Resolving Mediators (SPMs)

by Michael Stanclift, ND

Many of us have been using omega-3 fats, such as fish oil, for managing inflammatory conditions. Interestingly, fish oil and special molecules made from them called specialized pro-resolving mediators (SPMs) have big impacts on our immune system and play an important role in the activity of immune cells.

The key lies in how fats such as the ones found in fish oil influence the behavior of the white blood cells (WBCs) of our immune system. Our body uses these special fats, like EPA and DHA, to send chemical instructions to our immune cells, and these instructions determine how our immune cells behave. If we have an imbalance from other fats such as omega-6s, often found in processed foods, our immune cells will get different instructions that can weaken how we respond to infections and cause more damage from inflammation. How do omega-3 fats fit into this? Our bodies store some of the fats we eat in our cell membranes, and those fats are used to create powerful chemical instructions to our immune cells. Let’s get into some of that biochemistry, and then we’ll talk about what it means clinically.

Omega-3 and omega-6 fats: chemical instructions to immune cells

Omega-3 and omega-6 fats can be made into classes of molecules called eicosanoids (“eye-cosa-noids”) and SPMs.¹ Research into SPMs is intensifying in recent years, and we’ll discuss this important class of molecules in a bit.

Eicosanoids, made from omega-3 and omega-6 fats, tell our immune cells to behave with more or less inflammation.¹ In general, the eicosanoids made from omega-6 fats are more inflammatory, and the ones made from omega-3s are less inflammatory.¹ When it comes to infections, we know that inflammation is a necessary “second line” defense process, but we want to keep the response contained so it doesn’t cause more damage than it’s preventing.²

Overreactive immune and inflammatory states

We see the effects of the chemical signals from omega-3 fats on our immune system very early on in our lives. By age 3 children who don’t get enough omega-3 fats in their diet are more likely to develop asthma and allergic conditions, like eczema.³ These conditions are examples of what happens when our immune system overreacts—immune cells recognize a substance (like a food or dust) that they would normally tolerate, but instead they treat the substance like something they need to get out of our body.

With infections such as COVID-19 we see an overexuberant inflammatory response from the immune system that can result in a cytokine storm, causing dangerous blood clots.^4,5 During severe COVID infections, this cytokine storm can also cause immune cells to flood into the lungs, causing intense damage to the lung tissue.⁶ At these stages, the immune-mediating effects from omega-3 fatty acids may not be enough. A randomized placebo-controlled trial in severely ill (acute lung injury) mechanically ventilated patients showed that high dosage IV fish oil did not improve an inflammatory marker or organ failure score, reduce ICU/ventilator usage, or improve 60-day mortality.⁷ Likely by the time patients had reached this point, they have passed the potential therapeutic opportunity window.

Under high levels of inflammation, omega-3 fats can be susceptible to damage from oxidation.⁵ Sustained high levels of oxidative stress in the body can lead to chronic immune activation and mitochondrial dysfunction, which in turn leads to more oxidative stress.⁵ In an example of sustained immune dysfunction and inflammation, stable human immunodeficiency virus (HIV) patients were given 1.6 g/day of fish oil or placebo.⁸ In this study fish oil did not improve immune function or inflammation, suggesting this level of intervention was not enough.⁸ So how might omega-3 fats help our bodies improve their immune response? To help answer that, let’s look downstream at a class of compounds with emerging research, SPMs.

SPM production from omega-3 and omega-6 fats

As we mentioned, omega-3 fats can help our bodies produce less inflammatory eicosanoids, but another way these fats help us is through the production of their powerful metabolites, SPMs. In fact, even the omega-6 fats can be used to create protective SPMs, and the proinflammatory signal from omega-6 eicosanoids amplifies SPM production (see figure below).

SPMs are the signaling molecules our body uses to tell the immune cells to clean up the mess of inflammation and repair any damaged tissue.⁹ But the pathway from omega-3 fats to SPMs is one prone to interference and roadblocks as they must go through numerous “bottleneck” enzymes competing with omega-6 compounds and drugs that inhibit the activity of these enzymes (see figure above).

Many of the classical anti-inflammatory drugs can alter our body’s ability to produce protective SPMs, either directly or indirectly.^10,11 Common chronic inflammatory conditions such as obesity, arthritis, and cardiovascular disease are also associated with SPM deficits.^12-18 This has led prominent researchers to suggest supplementing SPMs directly to intervene with severe inflammatory conditions associated with infections.^4,19

Omega-3s, SPMs, and clinical effects on immune behaviors

Even in some of the most inflammatory of conditions, supplementing omega-3s can reduce inflammation while at the same time increasing immune defenses.²⁰ As an example, a systematic review and meta-analysis looked at studies of cancer patients undergoing surgery (a highly inflammatory condition, with weakened immune defenses).²⁰ The researchers discovered supplementing omega-3s 5-7 days before surgery and in the postoperative period significantly reduced the inflammatory responses and reduced infections.²⁰ Omega-3s reduced inflammatory markers like IL-2, IL-6, and TNF-α and increased levels of helpful immune cells such as CD3⁺, CD4⁺, CD8⁺ and Th1.²⁰  This can be described as an immunomodulatory effect; it reduced a potentially harmful response and raised a helpful one. Supplementing omega-3 fats in recently diagnosed breast cancer patients had similar immune-modulating effects, benefiting the protective benefits while dampening the destructive ones.²¹

Much of SPM research has looked at how our immune cells respond to infectious and inflammatory signals. We know when healthy immune cells (macrophages) are exposed to disease causing bacteria such as E. coli or S. aureus, they produce double the variety and 10 times the normal amount of SPMs.²² SPMs can also dampen proinflammatory cytokine production and increase antibody production from B-cells and enhance the antibody response to flu vaccine in an animal model.^23,24 These are mechanisms explaining how SPMs influence innate and adaptive immune responses and may clarify why we see an overlap of conditions associated with SPM deficits and those most affected by severe infections.⁶

Clinical research using SPMs supplements (rather than omega-3 parent compounds) in humans is still in its early stages, and the immune effects appear to be supporting what we’ve seen in preclinical models. Recently researchers published a double-blind placebo-controlled study looking at various doses of an SPM supplement in healthy individuals, then challenged their immune cells to see their responses.²⁵ They found immune cells from participants in the SPM arm responded with a dampened inflammatory response and dramatically enhanced the cell’s ability to contain pathogens compared to placebo.²⁵ Another recent study compared the effects of SPM supplementation in healthy individuals and those with peripheral artery disease (PAD) -a chronic inflammatory condition.²⁶ Similarly, they found SPMs improved inflammatory and immune responses both in healthy volunteers and in the setting of PAD. ²⁶ It is important to note that all human clinical research in SPM supplementation has so far come from a single supplier, and the effects observed may not be representative of all SPM supplements available in the marketplace.

Conclusion

Both omega-3 fats and SPMs are naturally occurring compounds in our bodies but are commonly low due to low dietary intake and potential issues with their endogenous production. While we have mostly focused on the inflammation-dampening effects of omega-3 fats, it’s important to consider that these actions are carried out by the cells of the immune system. SPM research is rapidly expanding and demonstrating how these compounds influence immune cell behavior. Given the rising concern of infectious diseases, and their effects on those with preexisting inflammatory conditions, we may want to consider omega-3 fats and their SPM derivatives in a new clinical light.

Citations

1. Shaikh SR et al. n-3 polyunsaturated fatty acids exert immunomodulatory effects on lymphocytes by targeting plasma membrane molecular organization. Mol Aspects Med. 2012;33(1):46-54.
2. Stone WL et al. Pathology, Inflammation. [Updated 2020 Aug 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534820/
3. Lee-Sarwar K et al. Dietary and plasma polyunsaturated fatty acids are inversely associated with asthma and atopy in early childhood. J Allergy Clin Immunol Pract. 2019;7(2):529-538.e8.
4. Regidor PA et al. Pro resolving inflammatory effects of the lipid mediators of omega 3 fatty acids and its implication in SARS COVID-19. Med Hypotheses. 2020;145:110340.
5. Rogero MM et al. Potential benefits and risks of omega-3 fatty acids supplementation to patients with COVID-19. Free Radic Biol Med. 2020;156:190-199.
6. Pal A et al. Obesity-driven deficiencies of specialized pro-resolving mediators may drive adverse outcomes during SARS-CoV-2 infection. Front Immunol. 2020;11:1997.
7. Stapleton RD et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.Crit Care Med. 2011;39(7):1655-1662.
8. Swanson B et al. Effects of fish oil on HIV-related inflammation and markers of immunosenescence: a randomized clinical trial. J Altern Complement Med. 2018;24(7):709-716.
9. Dalli J et al. Pro-resolving mediators in regulating and conferring macrophage function. Front Immunol. 2017;8:1400.
10. Barden A et al. Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids. 2018;139:31-39.
11. Krishnamoorthy N et al. Specialized proresolving mediators in innate and adaptive immune responses in airway diseases. Physiol Rev. 2018;98(3):1335-1370.
12. López-Vicario C et al. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 2019;33(6):7072-7083.
13. Titos E et al. Signaling and immunoresolving actions of resolvin D1 in inflamed human visceral adipose tissue. J Immunol. 2016;197(8):3360-3370.
14. Barden AE et al. Specialised pro-resolving mediators of inflammation in inflammatory arthritis. Prostaglandins Leukot Essent Fatty Acids. 2016;107:24-29.
15. Arnardottir HH et al. Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation. J Immunol. 2016;197(6):2362-2368.
16. Fredman G et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016;7:12859.
17. Elajami TK et al. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J. 2016;30(8):2792-2801.
18. Bazan HA et al. Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease. Prostaglandins Leukot Essent Fatty Acids. 2017;125:43-47.
19. Panigrahy D et al. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Metastasis Rev. 2020;39(2):337-340.
20. Yu J et al. Effects of omega-3 fatty acids on patients undergoing surgery for gastrointestinal malignancy: a systematic review and meta-analysis. BMC Cancer. 2017;17(1):271.
21. Paixão EMDS et al. The effects of EPA and DHA enriched fish oil on nutritional and immunological markers of treatment naïve breast cancer patients: a randomized double-blind controlled trial. Nutr J. 2017;16(1):71.
22. Werz O et al. Human macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity. Nat Commun. 2018;9(1):59.
23. Ramon S et al. Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. J Immunol. 2012;189(2):1036-1042.
24. Ramon S et al. The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: A new class of adjuvant? J Immunol. 2014;193(12):6031-6040.
25. Souza PR et al. Enriched marine oil supplements increase peripheral blood specialized pro-resolving mediators concentrations and reprogram host immune responses: a randomized double-blind placebo-controlled study. Circulation Research. 2020;126(1):75-90.
26. Schaller MS et al. Treatment with a marine oil supplement alters lipid mediators and leukocyte phenotype in healthy patients and those with peripheral artery disease. J Am Heart Assoc. 2020;9(15):e016113.

Michael Stanclift, ND graduated from Bastyr University’s school of naturopathic medicine and practiced in Edinburgh, Scotland, and Southern California. He enjoys educating other healthcare providers and impacting the lives of their many patients. When he’s not working, he spends his hours with his wife and two children.