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