Bioactive omega-3 fatty acids are associated with reduced risk and severity of SARS-CoV-2 infection (2025)

In this issue of the American Journal of Clinical Nutrition, Harris etal. [1] report that a higher status of the bioactive omega-3 fatty acid docosahexaenoic acid (DHA) is associated with a lower risk of testing positive for SARS-CoV-2 and of being hospitalized with the disease it causes, COVID-19. DHA and its precursor eicosapentaenoic acid (EPA) are obtained from the diet, with the richest source being seafood, especially fatty fish, and are also found in “fish oil” supplements. Circulating levels of EPA and DHA are higher in those who consume fatty fish regularly and in those who use “fish oil” supplements. Harris etal. [1] used data from the UK BioBank, a prospective, population-based cohort of approximately 500,000 individuals recruited between 2007 and 2010 at assessment centers across England, Wales, and Scotland [2, 3]. Baseline data derived from questionnaires, biological samples, and physical measurements were collected on all participating individuals, with longitudinal monitoring occurring via a mix of in-person and electronic medical record data. From the entire UK BioBank population, a random subset of nonfasting baseline plasma samples from 118,466 individuals had been analyzed using high-throughput nuclear magnetic resonance spectroscopy. Harris etal. [1] used data on 110,584 of these individuals to assess the association between DHA status and hospitalization with or mortality from COVID-19. Furthermore, they used data on 26,594 individuals for whom information was available on the outcome of a test for infection with SARS-CoV-2 to assess the association with DHA status. These outcomes were assessed between January 1, 2020 and March 23, 2021. Included participants had mean age of 68 y, were mainly White and were roughly evenly distributed between the sexes. A positive test for SARS-CoV-2 infection was reported for 15% of those tested, whereas less than 1% of the participants were hospitalized with COVD-19; of these, 20% died. Mean plasma DHA was 2% of total fatty acids; Harris etal. [1] used an existing algorithm to calculate a mean omega-3 index (EPA plus DHA in red blood cells) of 5.6%.

Harris etal. [1] report an inverse association for a positive test for SARS-CoV-2 infection and for hospitalization with COVID-19 across quintiles of plasma DHA. In unadjusted analysis, the hazard ratio for testing positive for SARS-CoV-2 in the highest compared with the lowest quintile of plasma DHA was 0.60 [95% confidence interval (CI): 0.55, 0.67; P < 0.001], whereas for hospitalization with COVID-19, it was 0.48 (95% CI: 0.38, 0.60; P < 0.001). Data were adjusted with 3 models that included age at the start of the pandemic, sex, and race; age at the start of the pandemic, sex, race, and waist circumference; and age at the start of the pandemic, sex, race, waist circumference, Townsend Deprivation Index, time since enrolment, smoking status, education, self-reported health, blood pressure, slow walking pace, and intake of fresh fruit, dried fruit, fresh vegetables, cooked vegetables, and grain fiber. The protective association of DHA toward both outcomes was maintained with these adjustments. In the most fully adjusted analysis, the hazard ratio for testing positive for SARS-CoV-2 in the highest compared with the lowest quintile of plasma DHA was 0.79 (95% CI: 0.71, 0.89; P < 0.001), whereas for hospitalization with COVID-19, it was 0.74 (95% CI: 0.55, 0.94; P < 0.05). Both outcomes showed a significant inverse linear trend across quintiles for unadjusted and all adjusted analyses (P < 0.001 in all cases). Findings for mortality from COVID-19 were slightly different: the hazard ratio in the second highest compared with the lowest quintile of plasma DHA was 0.42 (95% CI: 0.27, 0.66; P < 0.001) in the unadjusted analysis and 0.61 (95% CI: 0.39, 0.98; P < 0.05) in the fully adjusted analysis. However, the hazard ratio was not different between the highest and lowest quintiles of plasma DHA; this suggests a U-shaped association between DHA status and mortality from COVID-19.

Harris etal. [1] are not the first to report inverse associations been long-chain omega-3 fatty acids and SARS-CoV-2-related outcomes [[4], [5], [6], [7], [8], [9], [10]]. Using the same UK BioBank dataset as Harris etal. [1], Julkenen etal. [4] reported that higher plasma DHA was associated with lower risk of being hospitalized with COVID-19 in an age- and sex-adjusted model; unlike Harris etal. [1], they did not adjust for any other covariates or report on the effect of DHA on test positivity or mortality. Using UK BioBank data, Sun etal. [5] reported that plasma DHA was inversely associated with testing positive for SARS-CoV-2 (odds ratio: 0.91; 95% CI: 0.87, 0.94) and hospitalization with COVID-19 (odds ratio: 0.78; 95% CI: 0.72, 0.85) after adjustment for age, sex, ethnicity, body mass index, Townsend deprivation index, and assessment center. Fish oil use was recorded in the UK BioBank, and from 110,440 participants, 26.6% reported habitual use of fish oil supplements. Ma etal. [6] reported that habitual fish oil use was associated with lower risk of hospital admission with COVID-19 (hazard ratio: 0.79; 95% CI: 0.69, 0.83) and mortality from COVID-19 (hazard ratio: 0.69; 95% CI: 0.58, 0.83) after adjustment for age and sex, and this remained significant after further adjustment for age, sex, and multiple other covariates. Beyond UK BioBank, a study based upon self-reporting through a mobile phone application identified that among 372,720 UK participants who had a test for infection with SARS-CoV-2 (6.3% tested positive), users of fish oil supplements had a 12% lower risk of testing positive for SARS-CoV-2 than nonusers, after adjusting for age, sex, body mass index, sign-up health status, and multiple testing [7]. Similar lower risk for testing positive in fish oil supplement users was observed among smaller numbers of participants from the United States (n = 45,757) and Sweden (n = 27,377) [7]. Omega-3 index was measured in 100 patients hospitalized with COVID-19 in the United States (59% men, mean age 72.5 y), 14 of whom died [8]. After adjusting for age and sex, the odds ratio for death in patients with an omega-3 index in quartile 4 compared with those with an omega-3 index in quartiles 1 to 3 was 0.25 (95% CI: 0.03, 1.11; P = 0.07). In a case-control design study from Chile, hospitalized patients with severe SARS-CoV-2 infection (n = 73) had a lower omega-3 index than a group of ambulatory patients with mild SARS-CoV-2 infection (controls, n = 71) [9]. Among the patients with severe COVID-19, there was an inverse association between omega-3 index and need for mechanical ventilation (odds ratio: 0.46; 95% CI: 0.21, 0.99) and death (odds ratio: 0.28; 95% CI: 0.08, 0.985), even after adjusting for sex, age, body mass index, comorbidities, and tobacco use [10].

A number of association studies, including those using the large UK BioBank dataset, indicate that higher DHA status is associated with lower risk of testing positive for SARS-CoV-2, being hospitalized with COVID-19, and severe outcome from COVID-19. Even with the multiple adjustments for covariates used in most of those studies, they remain observational, and cause and effect cannot be inferred. This requires controlled trials. So far there are few such trials. Doaei etal. [11] randomized critically ill patients with COVID-19 to a high protein enteral formula providing 400 mg EPA and 200 mg DHA daily for 14 d (n = 42) or to a control group that received the formula without added omega-3 fatty acids (n = 86). The omega-3 group had better indicators of some, but not all, physiological functions at day 14 and had better survival at 1 mo (21% compared with 3%, P = 0.003).

Understanding possible mechanisms of action of the protective effect of omega-3 fatty acids, and DHA in particular, would add plausibility to the associations described. In this respect, the lower risks of testing positive for SARS-CoV-2 and of COVID-19 being more severe, requiring hospitalization, and leading to mortality need to be considered separately. Testing positive for SARS-CoV-2 obviously requires exposure to the virus. This is why strategies such as hand washing, wearing face masks, social distancing, and isolation are effective in reducing infection risk. It is possible that those with higher DHA status, which would most likely result from eating fatty fish or using omega-3 supplements, show greater compliance with health behaviors that limit exposure to SARS-CoV-2 and therefore are less likely to test positive. However, it is also possible that DHA has effects that restrict viral entry to host cells, limit viral replication, or promote virus elimination so that post-SARS-CoV-2 exposure, evidence of infection is absent. One example of such an effect is that DHA, and also EPA, may hold the spike glycoprotein of SARS-CoV-2 in a closed configuration that is unable to bind to the ACE2 receptor on host cells [12], thereby preventing viral entry. EPA is also able to inhibit the activity of key proteases that cleave spike proteins to enable viral entry [13]; DHA seems not to have been tested in this regard. Coronaviruses are known to use the sterol regulatory element binding protein dependent pathway for replication; omega-3 fatty acids are inhibitors of gene transcription and protein maturation of sterol regulatory element binding proteins [14], which may act to suppress viral replication. Hence, there are several possible sites of action for long-chain omega-3 fatty acids to inhibit SARS-CoV-2 entry into host cells and replication, effects that would result in lower risk of testing positive. Of course, such effects would also be important in an infected individual and would act to restrict an increase in viral load, thereby contributing to a better prognosis and less likelihood of progression to more severe disease requiring hospitalization and resulting in death. However, other actions of DHA are likely to be important in this regard also. A heightened inflammatory response is linked to more severe COVID-19 and poor outcome [[15], [16], [17]]. Omega-3 fatty acids including DHA have multiple anti-inflammatory actions [18] that might limit harmful exaggerated inflammation, thereby decreasing the risk of progression to more severe disease. DHA is also a precursor for specialized proresolution mediators (SPMs), several of which are beneficial in rodent models of respiratory disease and infection [19]. Higher plasma DHA would link with higher levels of SPMs [20], in turn helping to control exaggerated inflammation and decreasing risk of more severe COVID-19.

The research of Harris etal. [1] extends the earlier studies based on the UK BioBank dataset [[4], [5], [6]] and offers a more complex analysis of these data. The research of Harris etal. [1] has strengths and weaknesses. Strengths include the large sample size and the statistical adjustments made to the data. One limitation of the findings is that vaccination was introduced in the UK during the follow-up period, and participants’ vaccination status is not known.

In summary, using the large UK BioBank dataset, Harris etal. [1] report that higher DHA status is associated with lower risk of testing positive for infection with SARS-CoV-2 and of being hospitalized with COVID-19. There is also an indication that higher DHA status is associated with reduced risk of mortality for COVID-19, although this effect was attenuated at the very highest status level. These findings suggest that consuming more long-chain omega-3 fatty acids (EPA and DHA) should be encouraged as a strategy to reduce the impact of the ongoing SARS-CoV-2 pandemic and of future respiratory virus infection outbreaks. Increased intake of EPA and DHA can be achieved through consumption of fatty fish or use of supplements containing EPA and DHA.