Abstract
The pandemic has supercharged growing awareness of the gut microbiome as a critical determinant of human health. Long haulers share microbiomes similar to those seen in myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia, all frequently associated with Candida overgrowth (CO). Candida has a unique relationship with indoleamine dioxygenase (IDO) and altered tryptophan metabolism (ATM), mediated by IFN-γ. Zonulin, a circulating protein that increases intestinal and endothelial permeability, has emerged as a central player. This protein can be activated by proteases secreted by Candida and mast cells, enabling myriad autoimmune and other chronic diseases. Many of these are seen in long Covid (LC).
Candida hyphal walls express proteins analogous to gliadin/gluten, e.g., celiac disease (CeD), and mannans, e.g., Crohn’s disease (CrD), that may trigger antigliadin and possibly anti-GPCR auto-antibodies linked to their lectin binding domain respectively. These latter may include the GPCR auto-antibodies seen in LC and POTS. Both autoantibody producing pathways activate zonulin. IFN-γ, a marker for LC, can activate not only IDO but also zonulin. Candida can synthesize IDO and the mannan immune epitopes on its hyphae reveal remarkable spatial and phylogenetic diversity.
The spike protein S on SARS CoV2 can attach to both the ACE2 receptor (required for tryptophan absorption) and Toll-like receptor4 (TLR4) bearing endothelial cells and enterocytes. Spike protein S is persistent in most with LC and, as a ligand for TLR4, can also activate zonulin. S can also activate the NLRP3 inflammasome, as can candidalysin. This inflammasome is directly connected to dementia, cancer, autoimmunity and obesity. A hypothetical pathophysiologic model is proposed implicating pre-existing CO, aggravated by Covid-19, in not only the genesis of LC but also that of autoimmune disease, dementia, cancer, many chronic diseases, and aging. Candida may accomplish this directly or through IFN-γ induced upregulation of both IDO and zonulin. Candida can even synthesize IDO.