DHA may be more effective at reducing inflammation chronic than EPA also in COVID-19

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The omega-3 fatty acids EPA and DHA work differently against chronic inflammation, according to the results of a small randomized study, suggesting each has its own important role to play in regulating the immune system.

The 34-week trial, led by researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (HNRCA), compared the effects of the two omega-3s in a small group of older adults with obesity and chronic low-grade inflammation.

The participants were randomly assigned to receive either EPA or DHA supplements twice a day. The results are published today in Atherosclerosis.

EPA and DHA, plentiful in fish and shellfish, have, in some studies, been linked to lower risk of heart disease and are believed to work by reducing inflammation. The results showed that DHA had a stronger anti-inflammatory effect than EPA:

DHA lowered the genetic expression of four types of pro-inflammatory proteins, whereas EPA lowered only one type.

DHA lowered white blood cell secretion of three types of pro-inflammatory proteins, whereas EPA lowered only one type.

DHA also reduced levels of an anti-inflammatory protein, whereas EPA did not.
However, EPA improved the balance between pro- and anti-inflammatory proteins:

After being metabolized, EPA produced by-products that were associated with immune function regulation and worked differently from those derived from DHA.

“The jury has been out, so to speak, on how the two major components of fish oil work – and whether one might be better than the other. These results suggest that DHA is the more powerful of the two on markers of inflammation in the body, but that’s not the end of the story,” said Stefania Lamon-Fava, a scientist on the Cardiovascular Nutrition Team at the HNRCA.

Lamon-Fava is also chair of the Division of Biochemical & Molecular Nutrition and an associate professor at the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts.

“In our bodies, there is always this balance between pro-inflammatory and anti-inflammatory proteins, and we found EPA was better than DHA at enhancing that balance.

For the prevention of cardiovascular disease, previous research tells us that balance is very important,” explained first author Jisun So, who did this work as part of her dissertation at the Friedman School, working on the Cardiovascular Nutrition Team at the HNRCA.

According to the 2015-2020 Dietary Guidelines for Americans, adults should consume at least two servings of seafood (4 ounces per serving) weekly. Salmon, cod, sardines, trout and light, canned tuna are good sources of EPA and DHA.

“Our study gives us a snapshot of how EPA and DHA may work to reduce chronic inflammation, and how each has distinct effects. Our results provide insight for future research to explore why that is the case and who would benefit from one or both of these healthy fats,” Lamon-Fava said.

Methodology

The study was a double-blind trial, meaning neither the participants nor the laboratory workers or scientists knew which supplement each individual received.

The 21 participants received EPA or DHA supplements in a sequence that included supplement-free periods to create a blank slate from which to measure the impact of each supplement. During a lead-in phase, participants took supplements containing only high-oleic sunflower oil (similar to olive oil and not containing omega-3 fatty acids), to create a basis for comparison.


n the recent COVID-19 (caused by SARS-Cov-2 virus) pandemic a subgroup of patient death is attributed to the so-called “cytokine storm” phenomenon (also called cytokine release syndrome or macrophage overactivation syndrome) (Mehta et al., 2020).

To date, the molecular events that precipitate a “cytokine storm” or the applicable therapeutic strategies to prevent and manage this process is not elucidated because of the complex nature of this problem (Tisoncik et al., 2012). Recent articles suggest that specific nutrients such as vitamin B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper may play a key role in the management of cytokine storm (Calder et al., 2020; Grant et al., 2020; Muscogiuri et al., 2020).

Among these micronutrients LC-PUFAs (long chain polyunsaturated fatty acids) such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are noteworthy because of their direct influence in the immunological response to viral infections (Calder et al., 2020; Messina et al., 2020).

In this paper, we would like to draw the attention to the possible beneficial effect of EPA and DHA supplementation in SARS-CoV-2 infection and urge the medical community for further investigations and conduction of clinical trials.

Evidence suggests that n-3 LC-PUFAs can modulate the immune response and function in many ways (Calder, 2007, 2013; Zivkovic et al., 2011; Maskrey et al., 2013; Tao, 2015; Allam-Ndoul et al., 2017). Among these complex immunomodulatory effects, interleukin-6 (IL-6) and interleukin-1ß (IL-1β)—because of the suspected central regulatory role in the “cytokine storm”—should be highlighted. These cytokines can be affected by dietary EPA and DHA intake (Figure 1).

In addition, poly(ADP-ribose) polymerase enzymes that have anti-inflammatory properties, translatable to human COVID-19 infection were shown to improve tissue levels of DHA and EPA, as well as the downstream anti-inflammatory metabolites of EPA and DHA (Kiss et al., 2015; Curtin et al., 2020) further underscoring the applicability of DHA and EPA in COVID-19.

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Figure 1
Main pathways for the metabolism of DHA and EPA yielding anti-inflammatory metabolites. The two most important n-3 LCPUFAs, DHA and EPA, can be either released from the membrane of cells by PLA2 or dietary DHA and EPA can be utilized for enzymatic conversion by LOX and COX enzymes that generate bioactive, anti-inflammatory downstream metabolites. These metabolites bind to their respective receptors and elicit anti-inflammatory changes in cells mainly through rearranging the transcriptome. These pleiotropic effects altogether lead to decreases in IL-6, IL-1, or TNFα, key cytokines provoking cytokine storm. PLA2, phospholipase A2; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; LOX, Lipoxygenase; PGs, Prostaglandins; PGE3, Prostaglandin E3; RvE1,2, Resolvin E1 and E2; LTB5, Leukotriene B5; RvD1-6, D-series resolvins; PD1, Protectin D1; MaR, Maresin. The sketch of the membrane is a stock image from shutterstock.com (No. 1106910629).

IL-6 blockade using Tocilizumab monoclonal antibody has been identified as a feasible therapeutic target in SARS-CoV-infections (Liu et al., 2020), nevertheless, reducing the expression of additional proinflammatory cytokines (e.g., IL-1ß, IL-38) may have beneficial effects (Conti et al., 2020).

Both EPA and DHA can decrease the secretion of inflammatory cytokines in vitro and animal studies (Gutierrez et al., 2019). Pre-supplementation with DHA (400 mM) significantly decreased the release of IL-6 and IP-10 by Calu-3 cells infected with Rhinovirus RV-43 and RV-1B (Saedisomeolia et al., 2009).

Based on the results of a randomized, controlled study published in 2018, high-dose (1.5 g/day EPA and 1.0 g/day DHA) n-3 supplementation can reduce plasma levels of both IL-6 and IL-1ß (Tan et al., 2018). The anti-inflammatory effect of EPA and DHA supplementation seems consistent with most of the previous clinical findings (Fritsche, 2006; Vedin et al., 2008; Kiecolt-Glaser et al., 2012; Muldoon et al., 2016; Calder et al., 2020) (Table 1).

Table 1

The effects of DHA and EPA supplementation on cytokine production.

ReferencesTypeSupplementationSubjectsEffects
Ramon et al. (2012)in vitroa50 nM 17-hDHA
b100 nM 17-hDHA
CD19+ B cellsIL-6 ↓44%a
IL-10 ↓49 %a; 54%b
TNF-α
Allam-Ndoul et al. (2017)in vitroa10 μM DHA
b50 μM DHA
c75 μM DHA
d10 μM EPA
e50 μM EPA
f75 μM EPA
THP-1 acute monocytic leukemia cell lineIL-6 ↓ 12%a; 19%b; 30%c; 6%d; 13%e; 24%f
TNF ↓ 6%a; 12%b; 15%c; 18%f
Saedisomeolia et al. (2009)in vitroa200 μM DHA
b400 μM DHA
c200 μM EPA
d400 μM EPA
Airway epithelial cells (Calu-3) with RV-43IL-6 ↓ 16%b
IL-8
IP-10 ↓ 28%b
Airway epithelial cells (Calu-3) with RV-1BIL-6 ↓ 13%a; 29%b
IL-8
IP-10 ↓ 24%b
Tan et al. (2018)RCTa1.5 g/day DHA 4th weeks
b1.5 g/day DHA 8th weeks
Plasma of patients with chronic venous leg ulcersIL-6 ↓ 12%a; 22%b
IL-1ß ↓ 29%a; 44%b
TNF-α ↓ 12%a; 23%b
Vedin et al. (2008)RCT1.7 g/day DHA
and
0.6 g/day EPA
Blood mononuclear leukocytes of Alzheimer disease patientsIL-6 ↓ 43%
IL-1ß ↓ 35%
TNF-α
Kiecolt-Glaser et al. (2012)RCTa2.5 g/day n-3 PUFAs
b1.25 g/day n-3 PUFAs
Serum of healthy adultsIL-6 ↓a, b
TNF-α ↓a, b
Zhou et al. (2019)RCTa3.6 g/day EPA + DHA
b1.8 g/day EPA + DHA
Peripheral blood mononuclear cells (PBMCs) in Hypercholesterol-emic AdultsTG ↓ 20%a; 13 %b
IL-6 ↓ 37%a;
TNF -α
Muldoon et al. (2016)RCT0.4 g/day DHA
and
1.0 g/day EPA
Serum of healthy adultsIL-6
% change in the expression of cytokines upon DHA and/or EPA supplementation were either calculated from original data or reproduced from given publications, where available. A ↓ notation stands for a statistically significant decrease in the measured levels of the examined cytokines. Identical superscripts both in the “Supplementation” and “Effects” columns (a, b, c, d, e, f) denote the published effect(s) of the given supplementation group/dose.

A DHA metabolite (17-hDHA) can reduce IL-6 secretion in human B cells (Ramon et al., 2012).

The triglyceride-lowering effect of n-3 LC-PUFA supplementation is well-known (Yanai et al., 2018; Zhou et al., 2019; Abdelhamid et al., 2020). Lower levels of triglyceride present a lower risk of developing a “cytokine storm” based on the score from the available sHLH score system (Mehta et al., 2020). This approach represents another standpoint for the promotion of n-3 LC-PUFA supplementation in COVID-19 disease.

In addition, evidence suggests that in non-viral infected critically ill patients n-3 LC-PUFA supplementation can be helpful but data are highly limited (Rangel-Huerta et al., 2012). A recent meta-analysis reported the effects of omega-3 fatty acids and/or antioxidants in adults with acute respiratory distress syndrome in which the authors concluded that any beneficial effect in the duration of ventilator days and ICU length of stay or oxygenation at day 4 seems uncertain because of the very low quality of evidence (Dushianthan et al., 2019). To date there is no direct evidence of any beneficial or deleterious effect of immunonutrition with EPA and DHA in COVID-19 patients.

EPA and DHA supplementation can alter many biological pathways which may have direct influence in the outcome of COVID-19 (Fenton et al., 2013; Duvall and Levy, 2016; Curtin et al., 2020).

The safety of EPA and DHA supplementation should be also highlighted. Although, the US Department of

Health & Human Services National Institutes of Health Office of Dietary Supplements (ODS) concluded that a daily intake of EPA+DHA of up to 3.0 g/d is safe (Usdhhs N. I. O. H. and Office of Dietary Supplements, 2019), the European Food Safety Authority (EFSA) stated that the long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe for the general public (EFSA, 2012).

In addition some evidence suggest that long-term supplementation of EPA and DHA may have side effects such as increasing risk of certain types of cancers, but the results are conflicting (Gerber, 2012; Alexander, 2013; Serini and Calviello, 2018). It should be also noticed that the usage of algae- or plant-based sources of EPA and DHA seems more preferable than marine or animal-based sources (Doughman et al., 2007; Lane et al., 2014; Harwood, 2019).

Summary: Based on the available data, the supplementation of EPA and DHA in COVID-19 patients appears to have potential beneficial effect in managing the “cytokine storm.” Therefore, the use of EPA and DHA supplementation should be considered as both a supportive therapy and a prevention strategy in SARS-Cov-2 infection.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318894/


Authors and funding

Additional authors on the study are Dayong Wu, Alice H. Lichtenstein, and Nirupa R. Matthan at the HNRCA; Albert K. Tai at Tufts University School of Medicine; and Krishna Rao Maddipati at Wayne State University.

Funding: This work was supported by the U.S. Department of Agriculture’s National Institute of Food and Agriculture through an Agriculture and Food Research Initiative grant and by The Drs. Joan and Peter Cohn Research Fund. Any opinions expressed in this paper are those of the authors and not the funders. None of the authors disclosed conflicts of interest.

Source:Tufts University

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