key: cord-0810281-xf9o4doc authors: Das, Undurti N title: Essential fatty acids and their metabolites in the pathobiology of COVID-19 date: 2020-11-11 journal: Nutrition DOI: 10.1016/j.nut.2020.111052 sha: 63a98d53f32f122e35a0645f21732405d2a9a773 doc_id: 810281 cord_uid: xf9o4doc nan correlated with aberrant extrafollicular TNF-α accumulation in the spleen and lymph nodes 2 . Thus high TNF-α levels seen in severe COVID-19 not only causes 'cytokine storm' but also suppresses immune response 3, 4 . In this context, the proposals made by Torrinhas et al 5 and Sukkar and Bassetti 6 suggesting the potential beneficial action of parenteral fish oil and induction of ketosis respectively in COVID-19 are rather interesting. Dietary EFAs cis-linoleic acid (LA, 18:2 n-6) and α-linolenic acid ( Most of these PGs, TXs and LTs are pro-inflammatory in nature except that 2 series PGs, TXs and 4 series LTs are more potent compared to 3 series PGs, TXs and 5 series LTs with regard to their pro-inflammatory action. Thus, PGE2 is more potent compared to PGE3 in inducing inflammatory events 7 . AA is also the precursor of lipoxin A4 (LXA4), a potent anti-inflammatory compound, whereas anti-inflammatory resolvins of E series are derived from EPA and resolvins of D series, protectins and maresins from DHA. LXA4 inhibits the production of PGE2 and LTs. GLA, DGLA, AA, EPA, DHA, PGE1, PGE2, LXA4, resolvins, protectins and maresins inhibit the production of IL-6 and TNF-α 7 . PGE2 has both a pro-and antiinflammatory actions. Adequate formation of PGE2 is necessary for optimal amount of inflammation to occur that, in turn, initiates anti-inflammatory events by augmenting LXA4 formation 8, 9 . Thus, AA metabolism is crucial to the inflammatory process. PGE2 and LTs facilitate generation of M1 macrophages (which are pro-inflammatory in nature) whereas GLA, DGLA, AA, EPA, DHA, PGE1, LXA, resolvins, protectins and maresins favor generation of M2 macrophages 10, 11 (which are anti-inflammatory in nature). The keto diet is a high-fat, moderate-protein, low-carbohydrate regimen. Keto diet results in production of ketones, which are used as fuel by the body. Keto diet results in faster metabolism, decreased hunger, and more efficient weight loss. Initially, keto diet was recommended for children with intractable epilepsy though why it is effective is not clear. Ketogenic diet is beneficial for those with type 2 diabetes mellitus, hypertension, and obesity. Sukkar and Bassetti 6 proposed that keto diet inhibits M1 macrophages, activates M2 macrophages, enhance type 1 IFN production that is mediated by augmented lactate production and thus, suppresses 'cytokine storm' seen in COVID-19. PGE3 and LTs of 5 series formed from EPA are less pro-inflammatory compared to PGE2 and LTs of 4 series formed from AA implying that PGE3 and LTs of 5 series do not trigger inflammation of sufficient degree to initiate inflammation resolution process. Hence, resolvins, protectins and maresins may be inadequate to trigger efficient inflammation resolution process even though they are anti-inflammatory compounds. It is noteworthy that LXA4 generation is enhanced by resolvins 12, 13 . This implies that resolvins, protectins and maresins may enhance the formation of LXA4 to resolve inflammation. This is supported by our studies which showed that LXA4 is more potent than resolvins and protectins in preventing the cytotoxic action of benzo(a)pyrene, streptozotocin and doxorubicin [14] [15] [16] . AA and LXA4 have potent anti-inflammatory actions by suppressing IL-6 and TNF-α, and expression of NF-κB [14] [15] [16] , whereas AA enhances LXA4 formation to bring about its anti-inflammatory action. resolution AA supplementation to animals and humans enhanced its tissue content with no change in PGE2 levels but increased LXA4 formation [17] [18] [19] . PGE2 suppresses IL-6 and TNF-α production and alters macrophage polarization induced by mesenchymal stem cells (MSCs) 20, 21 . At low concentrations, PGE2 binds to EP4, a high affinity receptor, and enhances the production of IL-23, whereas high PGE2 amounts bind to EP2 receptor to inhibit IL-23 production 22 . Furthermore, PGE2 triggers the production of LXA4 and inhibits LTB4 synthesis by modulating the expression of 5-and 15lipoxygenases and thus, induces resolution of inflammation 23, 24 . A delicate balance is maintained between T H 1 (IL-2, IFN-γ) and T H 2 cytokines Resolvin E1 has actions similar to LXA4 and suppresses IL-23 and IL-17 production in addition to its ability to inhibit IL-6 and TNF-α. Resolvin E1 promotes LXA4 production 13, 25 suggesting that a crosstalk occurs between n-3 and n-6 fatty acids' metabolism. The proposal by Torrinhas et al 5 is interesting but fails to consider the critical role of AA and its products PGE2 and LXA4 in inflammation and its resolution. Resolvins, protectins and maresins are certainly important in the resolution of inflammation [11] [12] [13] [14] [15] [16] . But the resolution of inflammation would not occur without optimal inflammation in the first place. This is so since PGE2 triggers the production of LXA4 and inhibits LTB4 synthesis by modulating the expression of 5-and 15-lipoxygenases to induce resolution of inflammation 23-25 . Furthermore, resolvins enhance the synthesis of LXA4 12, 13 . Inhibition of 15-PGDH-(15-prostaglandin dehydrogenase, a prostaglandin degrading enzyme) not only enhances PGE2 levels but also increases hematopoietic capacity 26 . Hence, administration of AA, the precursor of PGE2, is expected to augment hematopoiesis in those with COVID-19 who are known to have lymphopenia 27 . This implies that administration of appropriate amounts of AA/PGE2/LXA4 in a timely fashion could be of significant benefit in COVID-19. Human cells exposed to SARS-Co-V-2 and/or human coronavirus 229E (HCoV-229E), release significant amounts of AA and LA which inactivate the viruses 28, 29. These results support of our previous proposal 30 It is known that calorie restriction enhances the activity of desaturases especially delta-6-desaturase and thus, increases the formation of GLA, DGLA, AA, EPA and DHA that may lead to increased formation of LXA4, resolvins, protectins and maresins 35 . But whether such a change occurs with keto diet needs to be confirmed. One of the concerns about employing keto diet in those with COVID-19 is whether there is enough time to see the potential benefits of this diet (since COVID-19 progresses within 10-14 Page 6 of 11 days from mild to severe form) and induction of ketosis that may have some unintended adverse consequences. 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