Key Feature: In this Hypothesis article, we suggest that omega-3 PUFA dietary supplementation may be beneficial to reduce the risk of coronavirus complications, progressing to serious outcomes like Acute Respiratory Distress Syndrome, with the need for artificial ventilation in intensive care unit
Reference to Original paper: Weill, P., Plissonneau, C., Legrand, P., Rioux, V., & Thibault, R. (2020). May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients? Biochimie. doi:10.1016/j.biochi.2020.09.003
CONCEPTIVE FARMACIA’S REVIEW RESEARCH ABSTRACT: In around 10% of SARS-CoV-2 infected patients, coronavirus disease-2019 (Covid-19) symptoms are complicated with a severe lung damage called Acute Respiratory Distress Syndrome (ARDS), which is often lethal. ARDS is mainly associated with an uncontrolled overproduction of immune cells and cytokines, called “cytokine storm syndrome”; it appears 7e15 days following the onset of symptoms, leading to systemic inflammation and multiple organ failure. Because they are well-known metabolic precursors of specialized pro-resolving lipid mediators (SPMs), omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs) could help improve the resolution of the inflammatory balance, limiting therefore the level and duration of the critical inflammatory period. Omega-3 LC-PUFAs may also interact at different stages of the viral infection, notably on the virus entry and replication. In the absence of demonstrated treatment and while waiting for vaccine possibility, the use of omega-3 LC-PUFAs deserve therefore to be considered, based on previous clinical studies suggesting that omega-3 supplementation could improve clinical outcomes of critically ill patients at the acute phase of ARDS. In this context, it is crucial to remind that the omega-3 PUFA dietary intake levels in Western countries remains largely below the current recommendations, considering both the omega-3 precursor a-linolenic acid (ALA) and long chain derivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). An optimized omega-3 PUFAs status could be helpful to prevent infectious diseases, including Covid-19. CONCEPTIVE FARMACIA’S REVIEW RESEARCH HIGHLIGHTS:
• The viral epidemic caused by the new Coronavirus SARSCoV-2 is responsible for the Coronavirus-2019disease(Covid-Abbreviations: ALA, a-linolenicacid; Arachidonicacid (ARA), arachidonicacid; ARDS, AcuteRespiratoryDistressSyndrome; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid; LC-PUFA, long- chainpolyunsaturated fattyacid; SPM,specializedpro-resolving lipid mediators; SREBP,Sterol RegulatoryElement BindingProtein. 19) • Upon binding via its Spike (S) protein, SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an entry receptor in several cell types, including lung alveolar epithelial cells. This receptor-mediated endocytosis is followed by the activation of the S protein in the viral envelope by the transmembrane serine protease 2 (TMPRSS2), a membrane-bound enzyme localized near the ACE2 receptor [1] • It is crucial to remind that the omega-3 PUFA dietary intake levels in Western countries remain largely below the current recommendations, considering both the omega-3 precursor a-linolenic acid (ALA) and long chain derivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [9,10]. In this Hypothesis article, we suggest that omega-3 PUFA dietary supplementation may be beneficial to reduce the risk of coronavirus complications, progressing to serious outcomes like ARDS, with the need for artificial ventilation in intensive care unit (ICU) • Taking into consideration (i) the role of omega-3 LC-PUFAs in the virus entry, replication and in the resolution phase of inflammation; (ii) the inflammatory processes leading to ARDS; (iii) the large and general deficit in omega-3 LC-PUFAs in the western population, it is possible to raise the hypothesis of a link between omega-3 LC-PUFA consumption deficiency and Covid-19 excessive inflammatory complication (Fig. 1) • It is crucial to remind that the omega-3 PUFA dietary intake levels in Western countries remains largely below the current recommendations, considering both the omega-3 precursor a-linolenic acid (ALA) and long chainderivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [29] • Concerning omega-3 LC-PUFAs, it has been suggested that enteral nutrition enriched with 3.5 g/day EPA and DHA can be administered in Covid-19 patients, not in a bolus [47] CONCEPTIVE FARMACIA’S REVIEW RESEARCH SUMMARY:
• The viral epidemic caused by the new Coronavirus SARSCoV-2 is responsible for the Coronavirus-2019disease(Covid-19). • The authors review the data obtained in animal experiments, human clinical trials and epidemiologicalstudiessupportinganinterestingroleofomega-3 PUFA supplementation against viral infection-associated inflammation. • An optimal resolution of acute inflammation, as well as the control of chronic low-grade inflammation [28], is based on the cellular availability of these omega-3 fatty acids exclusively provided by the diet and in particular on the dietary intake level of ALA, EPA and DHA. • Taking into consideration (i) the role of omega-3 LC-PUFAs in the virus entry, replication and in the resolution phase of inflammation; (ii) the inflammatory processes leading to ARDS; (iii) the large and general deficit in omega-3 LC-PUFAs in the western population, it is possible to raise the hypothesis of a link between omega-3 LC-PUFA consumption deficiency and Covid-19 excessive inflammatory complication (Fig. 1). • Rats fed semi-synthetic diets supplemented with 1% total lipids of EPA, DPA and DHA in ethyl esters form from weaning to 6 weeks clearly increased the omega-3 LC-PUFA level in all studied tissues, including the lung [36]. • It is crucial to remind that the omega-3 PUFA dietary intake levels in Western countries remains largely below the current recommendations, considering both the omega-3 precursor a-linolenic acid (ALA) and long chainderivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [29]. • It is interesting to underline that the beneficial effect exists whatever the type of omega-3 LC-PUFA supplementation (ALA, EPA or DHA diets). • Omega-3 PUFA, in the form of fish oil, mostly rich in EPA and DHA, have been used as a treatment in several clinical trials in enteral and parenteral nutrition with ARDS patients. • In addition to EPA and DHA, recent epidemiological and mechanistic data suggest a specific role for omega-3 DPA in lung tissue [27,36,48]. • The authors can raise the hypothesis that increasing the level of omega-3 LC-PUFAs in the diet or as a pharmaco nutrient in addition to artificial nutrition, could reduce the impact of inflammation caused by viral infectious diseases, such as the Covid-19. • The biochemical mechanisms described here, reinforced by clinical, animal and epidemiological data suggest that the effect of nutritional supplementation could accelerate recovery, reduce hospitalization, duration of stay in ICU and reduce mortality due to the new Coronavirus SARS-Cov-2. • Concerning omega-3 LC-PUFAs, it has been suggested that enteral nutrition enriched with 3.5 g/day EPA and DHA can be administered in Covid-19 patients, not in a bolus [47]. • Two clinical trials are on their way in Covid-19 patients and in older people with the aims to evaluate whether omega-3 PUFA diet enrichment could protect patients against severe forms of Covid-19, and to increase the awareness of the scientific community towards the beneficial role of good nutrition as a “barrier diet” against future pandemic. CONCLUSION: Although scientific research on drug treatment are progressing, the ARDS experts recommend now, not only for Covid-19 derived ARDS, to give more attention on prevention in addition to treatment [49]. In this context, we can raise the hypothesis that increasing the level of omega-3 LC-PUFAs in the diet or as a pharmaco nutrient in addition to artificial nutrition, could reduce the impact of inflammation caused by viral infectious diseases, such as the Covid-19. The biochemical mechanisms described here, reinforced by clinical, animal and epidemiological data suggest that the effect of nutritional supplementation could accelerate recovery, reduce hospitalization, duration of stay in ICU and finally reduce mortality due to the new Coronavirus SARS-Cov-2. Omega-3 LCPUFAs could play a central role in prevention of the cytokine storm (Fig. 1), at least maybe by decreasing the intensity of inflammation and risk of mortality for patients with Covid-19. CONCEPTIVE FARMACIA’S REVIEW RESEARCH FIGURES:
Figure 1: e Expected mechanisms of the anti-inflammatory effect of omega-3 long chain polyunsaturated fatty acids(omega-3 LC-PUFAs) and cytokine storm prevention during the Coronavirus disease-2019. General population has deficiency in Omega-3 LC-PUFAs that increases proportion of arachidonic acid (ARA) from Omega-6 PUFA family in phospholipid membranes of the cells. ARA is liberated from its sn-2 position by the phospholipase A2 (PLA2) and become a substrate for cyclooxygenase enzymes (COX1 and COX2). Prostaglandins E2 (PGE2) is synthesized from ARA and is pro-inflammatory by activating NF-kB and lead to systemic chronic low-grade inflammation and a higher response to severe acute inflammation. A nutritional supplementation in omega-3 fatty acids may decrease or even remove the deficiency in population. This supplementation will increase eicosapentaenoic acid (EPA), omega3 DPAand docosahexaenoic acid (DHA) proportion in phospholipid membranes of the cells. EPA, DPA and DHA are, like ARA, liberated by PLA2. It is a limiting step for the synthesis of lipid mediators from PUFAs. EPA is a substrate for COX enzymes and also lipoxygenases (LOX). PGE3 and E-series resolvins are produced from EPA and have anti-inflammatory properties. DHA is a substrate for LOX and produces D-series resolvins, protectins and maresins that have anti-inflammatory properties. These specialized pro-resolving mediators from EPA and DHA, in a case of acute inflammation by activation of NF-kB, will activate peroxisome proliferator-activated receptor (PPAR)-g. PPAR-g inhibits NF-kB. Consequently, the production of pro-inflammatory cytokines is reduced and may prevent cytokine storm