Can essential fatty acids (EFAs) prevent and ameliorate post-COVID-19 long haul manifestations?

Abstract

It is hypothesized that COVID-19, post-COVID and post-mRNA COVID-19 (and other related) vaccine manifestations including "long haul syndrome" are due to deficiency of essential fatty acids (EFAs) and dysregulation of their metabolism. This proposal is based on the observation that EFAs and their metabolites can modulate the swift immunostimulatory response of SARS-CoV-2 and similar enveloped viruses, suppress inappropriate cytokine release, possess cytoprotective action, modulate serotonin and bradykinin production and other neurotransmitters, inhibit NF-kB activation, regulate cGAS-STING pathway, modulate gut microbiota, inhibit platelet activation, regulate macrophage and leukocyte function, enhance wound healing and facilitate tissue regeneration and restore homeostasis. This implies that administration of EFAs could be of benefit in the prevention and management of COVID-19 and its associated complications.

Keywords: COVID-19; Eicosanoids; Essential fatty acids; Inflammation; Lipoxin A4; Maresins; Polyunsaturated fatty acids; Protectins; Resolvins; SARS-CoV-2.

Fig. 1

Scheme showing potential interaction between EFAs and their metabolites and serotonin. Legend to Figure 1. Indoles are synthesized from tryptophan by gut microbiota that express tryptophanase (TP). Indoles are cytoprotective molecules. Indolepropionic acid (IPA) synthesized by gut microbiota is a neuroprotective substance and binds to the pregnane X receptor (PXR) in intestinal cells, to facilitate mucosal homeostasis. IPA absorbed from the gut is transferred to the brain to prevent β-amyloid fibril formation. Tryptophan is metabolized to indole-3-aldehyde (I3A) by gut microbiota that acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells. Gut microbiota have the ability to alter the expression of serotonin-related genes and thus, alters its (serotonin) biosynthesis. Gut microbiota (i) directly act on enterochromaffin (EC) cells to increase colonic tryptophan hydroxylase 1 (Tph1) expression and promote serotonin synthesis; (ii) alter host by direct action or through their metabolites, short chain fatty acids (SCFAs), tryptophan, tryptamine, and secondary bile acids; (iii) SCFAs stimulate serotonin synthesis and release by their action on enterochromaffin cells; (iv) influence serotonin metabolism; and (v) promote Tph1 expression and stimulate serotonin synthesis (90, see Fig. 3) (tryptamine is a ligand for the 5-HT₄ receptor (5-HT₄R) and secondary bile acids, formed by the gut microbiota). Gut microbiota survival, proliferation and metabolism are influenced by EFAs. Dietary EFAs are converted to their long-chain metabolites by desaturases and elongases. EFAs and their metabolites are necessary for the integrity and function of enterochromaffin cells and gut function. By their action on enterochromaffin cells, EFAs can influence serotonin metabolism. EFAs and their metabolites can minimize TLR3 expression. Similarly, EFAs and their metabolites suppress cGAS-STING pathway and inhibit the production of pro-inflammatory cytokines and thus, inhibit their production. The coagulation by aggressive platelets aggregation can also be suppressed by EFAs and their anti-inflammatory metabolites and thus, prevent thrombotic episodes. EFAs and their metabolites stimulate vagus nerve and thus enhance the production of acetylcholine that has anti-inflammatory actions. EFAs and acetylcholine enhance the production of LXA4, a potent anti-inflammatory bioactive lipid (derived from AA). Thus, EFAs and their metabolites have a plethora of actions that explain their role in post-COVID long haul syndrome. The red arrows indicate pro-inflammatory pathways. The blue arrows indicate the pathways stimulated by cytokines that are pro-inflammatory in naure. The green arrows indicate the metabolism of dietary EFAs to their long-chain metabolites and action on enterocytes and their beneficial actions

Fig. 2

Metabolism of essential fatty acids (EFAs), their role in inflammation and factors that influence desaturases. SARS-CoV-2 activates PLA2 (phospholipase A2) and induces the release of GLA, DGLA, AA, EPA, and DHA from the cell membrane lipid pool. SARS-CoV-2 inhibits the activities of desaturases and thus, decreases the formation of GLA, DGLA and AA from LA and EPA and DHA from ALA. SARS-CoV-2 activates both COX and LOX enzymes resulting in increased formation of PGs (prostaglandins), LTs (leukotrienes) that have pro-inflammatory action and. enhanced formation of LXA4, resolvins, protectins and maresins that may induce hypotension

Fig. 3

Scheme showing tryptophan metabolism and its interaction with gut microbiota and EFAs. Legend to Figure 3. Indoles are synthesized from tryptophan by gut microbiota that express tryptophanase. Indolepropionic acid (IPA) synthesized by gut microbiota is a neuroprotective substance that binds to several receptors, including the pregnane X receptor (PXR) in intestinal cells, to facilitate mucosal homeostasis. IPA is absorbed from the gut and transferred to the brain, where it prevents β-amyloid fibril formation. Tryptophan is metabolized to indole-3-aldehyde (I3A) by gut microbiota acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells. Gut microbiota act (i) directly on enterochromaffin (EC) cells to increase colonic tryptophan hydroxylase 1 (Tph1) expression and promote serotonin synthesis; (ii) alter host by virtue of their metabolites, including short chain fatty acids, tryptophan, tryptamine, and secondary bile acids; (iii) short chain fatty acids (SCFAs) stimulate serotonin synthesis and release by acting on enterochromaffin cells; (iv) tryptophan metabolism is regulated by the gut microbiota and thus, the gut microbiota influences serotonin metabolism; and (v) tryptamine is a ligand for the 5-HT₄ receptor (5-HT₄R) and secondary bile acids, formed by the gut microbiota promote Tph1 expression and stimulate serotonin synthesis [88].

Fig. 4

A Mechanisms by which EFAs and their beneficial metabolites prevent complement = coagulation and endothelial cell damage and useful in the prevention of long-haul syndrome due to COVID-19. Figure 4 B EFAs and their metabolites prevent complement activation, platelet-monocyte aggregation formation and tissue injury by virtue of their ability to maintain endothelial integrity, preventing platelet and monocyte activation, cytoprotective actions and virus inactivation. Figure 4A and B are modified from references [114, 115]