Omega-3s have a reputation for being anti-inflammatory, but how do they work in the body, and especially when it comes to the immune system? This blog will discuss how omega-3s work in the context of immune function, as well as what data exist on the connection between infection and the Omega-3 Index.
How Omega-3s Work When the Body is Challenged
Omega-3s are generally anti-inflammatory, but inflammation is only the first step in a highly complex, overall immune response to viral infections. Below is a diagram of the immune system (see Figure 1). From a timing point of view, the first level of protection is on the far-right side where barriers like “skin” are obvious obstacles to micro-organisms.
Moving left, we see the next level of protection. If bugs — bacteria, viruses, fungi, etc. — get past the first level, cells in the blood take up the fight. These are white blood cells like “macrophages” that, like Pac-Man, gobble up bacteria that get in and digest them. To help these “eating/killing” cells be more specific, the “acquired” immune system creates antibodies (protein molecules that specifically identify new bacteria or viruses) that help direct the eating cells to more quickly find and kill the invading bugs. It’s a highly regulated and integrated dance of molecules and cells that, together, keep us healthy.
With that brief introduction, let’s turn to omega-3 fatty acids. What role do they play in this system? The cartoon below (see Figure 2) summarizes how omega-3 EPA and DHA can influence the inflammatory response, which is the first phase of the overall immune response. Like Figure 1, we will not attempt to explain this diagram in detail, but everywhere that you see this symbol: “—|” it means that EPA+DHA blocks that pathway, most of which are “activations.” It’s not important that you understand exactly WHAT is activated, but suffice it to say that the net effect is a blunting of pro-inflammatory pathways. This does not mean that EPA+DHA completely shuts down these pathways — that would be fatal! — only that they are slowed down.
In the context of COVID-19, we hear a lot about “flattening the curve”, and that’s in a sense what EPA and DHA do within your body as it responds to infections. The infection does not cause an over-stimulation of the inflammatory response — it allows for what some call a “Goldilocks” response: not too much and not too little, but just right.
The mechanistic data clearly shows that omega-3s in cell membranes play an important role in taming the more toxic aspects of the immune response. Taken together, both Figure 1 and Figure 2 show just how complicated the system is.
Omega-3 Metabolites Are ‘Healers’ After the Immune System Attacks
As the immune system can use toxic measures to destroy unwanted organisms (the innate piece), this has to be a targeted response (the adaptive piece) and there must be a healing from the collateral damage done by this powerful response. That healing is an active process itself called “resolution.” The resolution of the acute inflammatory response is mediated by metabolites of omega-3 fatty acids called “specialized pro-resolving mediators” (SPMs).
The discovery of the SPMs has been an exciting area of research lead by Dr. Charles Serhan over the last 20 years. SPMs are released over the hours and days following an inflammatory response as seen in Figure 3 below. They are an essential part of the healing process.
When there are lower levels of omega-3s in the body, there is less starting material for SPMs to be made from, and thus, a less effective healing process and lingering inflammation and damage. A study by Norris and Skulas-Ray found that people taking a high dose of EPA+DHA (900-3400 mg/d) and then tested with an inflammatory challenge produced significantly higher levels of SPMs for 24 hours after the challenge compared to the controls. Not only do omega-3s play a role in mollifying the initial inflammatory response but they also help after the attack is over.
Does Having a High Omega-3 Index Make You More Susceptible to Infection?
A review by Fenton et al. shows how the cell membrane composition of omega-3s can affect the immune system (and all bodily systems) if it is either too high or too low (see Figure 4 below). The definition of “too low” is likely an Omega-3 Index <4%, which is more typical in adults living in Western populations than very high levels (>12%). With regard to the immune system, an omega-3 deficiency could result in excessive and damaging inflammation while an excessive omega-3 blood level could result in a lack-luster inflammatory response to an infection.
Having an Omega-3 Index >12%, on the other hand, is relatively rare and not well studied, and thus there is not enough data to know what level is too high and what that looks like, which is why testing is important. Our recommendation would be to consume enough EPA and DHA to reach and maintain an Omega-3 Index of between 8-12%.
A 2001 paper authored Theis and colleagues studied the effects of DHA and fish oil (containing EPA and DHA) on “natural killer” (NK) cell activity. (See Figure 1 above, the left arm of the “Innate” immune system, under “Phagocytes” – the 5th cell type). In this study, researchers gave healthy people either 720 mg DHA or 1 g EPA+DHA (720 mg EPA + 280 mg DHA for 12 weeks and tested the in vitro (i.e., in a test tube) effect on NK cell activity. They concluded that since NK cell activity was reduced in the EPA+DHA group but not the DHA group that EPA inhibited NK cell activity. Therefore, EPA “might have adverse immunologic effects.”
Two points need to be made here: 1) testing the effect of omega-3 supplementation on only ONE component of the immune system does not tell you what its effects are on the immune system as a whole; and 2) testing the effects in a test tube, not “in vivo” (in the whole body) is very artificial and may be misleading.
A 1993 paper published in the Journal of Clinical Investigation reported on the effects of fish feeding (high fat vs low fat fish) on “immune responses”. This diet provided 1.23 grams per day of EPA+DHA and was fed for 24 weeks.
The researchers concluded: “Our data are consistent with the concept that the NCEP (National Cholesterol Education Panel) Step 2 diet that is high in fish significantly decreases various parameters of the immune response in contrast to this diet when it is low in fish. Such alterations may be beneficial for the prevention and treatment of atherosclerotic and inflammatory diseases but may be detrimental with regard to host defense against invading pathogens.”
So these two reports raise the possibility — but certainly do not prove — that omega-3s might make it tougher to ward off infections. What we need is a large study where thousands of people were given omega-3 (or placebo) and the effects on infections and respiratory diseases was tracked. Thankfully, we have a study like this that studied the effects of 4 grams of EPA on the occurrence of diseases over five years. The study was called REDUCE-IT and the reported effects of EPA (vs placebo) on several infection-related diseases from the Supplementary Data section is shown below in Table 1.
|Percent of patients|
|Upper Respiratory Infection||7.6||7.8|
What these data show is that there was no effect whatsoever of EPA treatment on any of these conditions, which offers strong evidence that EPA does NOT, in real life (as opposed to a test tube), increase risk for infection. But likewise there is no reason to believe from this study that high dose EPA will decrease risk for respiratory infections either.
What Omega-3 Index Level is Best for Immune Support?
In short, we do not have a definitive answer for this question but staying within the desirable range of 8-12% is a good place to start. To date, the precise definition of an omega-3 blood level that is too high is relatively unknown. We set our desirable range at 8-12%, which has been confirmed to be clinically important for cardiovascular disease risk, and it appears as though many of the other health benefits are achieved within this range. Higher blood levels of omega-3s have been associated with lower risk of dying from any cause, although most of that data was collected in a time with vaccines for most known infectious diseases.
The link between Omega-3 Index levels and the severity of COVID-19 symptoms (or lethality) is a question we are hopefully going to start researching very soon. Until we know more, keep eating a healthy diet including omega-3s, wash your hands and don’t touch your face!