Candida hyphae and healthspan: Hypothesis

Candida is traditionally considered an opportunistic pathogen. However, recent research, accelerated by COVID-19, has raised thought-provoking questions about the limitations of this view. Dietary carbohydrates and ethanol have been shown to enable its pathogenic transition. Its hyphae express epitopes that may initiate celiac and Crohn’s diseases. Hyphal mannan is potentially linked to Gq-coupled G-protein coupled receptors. Antibodies to these receptors include chemotactic cytokine receptors, which may mediate the escape of latent Epstein–Barr virus. Candida hyphae induce mast cells to release histamine and tryptase, which are associated with paroxysmal orthostatic tachycardia syndrome, mast cell activation syndrome, and hypermobility spectrum disorder—conditions frequently observed in long COVID (LC). Hyphae are also implicated in periodontitis, a condition linked to and potentially serving as a sentinel risk indicator for cancer, dementia, autoimmune disease, atherosclerotic cardiovascular disease, and chronic diseases in general. Candida yeast and hyphae can produce their own indoleamine dioxygenase (IDO), which antagonizes host IDO, impacting tryptophan metabolism. Altered tryptophan metabolism is observed in cancer, dementia, autoimmune diseases, and LC. Candida overgrowth (CO) also releases candidalysin, a toxin that suppresses competing intestinal bacteria, triggers inflammasomes, and causes hypercitrullination, a process associated with several autoimmune diseases and cancers. In addition, CO produces aspartyl protease, leading to the release of zonulin from intestinal epithelial cells, which increase intestinal and endothelial permeability – hallmarks of autoimmune diseases. Candida-induced acetaldehyde amplifies the harmful effects of a genetic variant, highly prevalent in Americans, linked to cancer, dementia, and autoimmune diseases. The gut microbiome is increasingly recognized as critical to overall health, and hyphae may play a major role in determining its composition. In this review, the roles of cholecalciferol, tryptophan, and magnesium in counteracting the yeast-to-hyphae transition and invasion are explored. The approach presented here is conceptual rather than empirical.