A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID

Apr 27, 2026Frontiers in medicine

A possible link between taste problems from faulty energy signaling and fatigue in chronic fatigue syndrome, based on lessons from long COVID

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Abstract

Evidence suggests that taste dysfunction may be a critical underrecognized feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Alterations in taste perception mediated by Type II taste receptor cells could be associated with ME/CFS symptoms.
There are clinicopathological similarities between long-COVID and ME/CFS, indicating potential shared mechanisms.
Dysregulation of ATP signaling through specific receptors may underlie both gustatory impairment and core symptoms of ME/CFS.
Chemosensory dysfunction might serve as a potential indicator of the progression or severity of post-exertional malaise (PEM).
Standardized taste testing is proposed as a non-invasive screening tool to complement molecular biomarkers for ME/CFS.
Limitations and confounding factors, such as medications and deficiencies, may independently affect taste-related symptoms in ME/CFS.

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Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a neuroimmune disease characterized by debilitating post-exertional malaise (PEM), brain-fog/cognitive problems, and dysregulation of the autonomic nervous system. Currently, there are no objective biomarkers for ME/CFS despite decades of research. Here, we compile evidence from literature that supports taste dysfunction, particularly alterations of taste perception mediated by Type II taste receptor cells, may be a critical underrecognized feature of ME/CFS. The impetus is drawn from the emerging evidence of clinicopathological similarities between long-COVID and ME/CFS. We discuss in parallel the mechanisms of cellular metabolism, inflammation, vascular dysfunction, and autonomic dysregulation in ME/CFS and long-COVID pathophysiology. We postulate that mechanistically, dysregulation of ATP signaling through P2X2/P2X3 purinergic receptors underlies both gustatory impairment and core ME/CFS symptoms. Adopting information from the NIH-RECOVER shared resources, we present evidence that suggests chemosensory dysfunction as a potential indicator of progression/severity of PEM. We discuss standardized taste testing as a non-invasive screening tool complementary to molecular biomarkers for ME/CFS. Notwithstanding, we acknowledge the limitations, confounding and contributing factors such as medications and deficiencies that may exacerbate or independently cause taste-related symptoms in ME/CFS. In conclusion, we present a compelling case for the multi-factorial role of taste dysfunction in ME/CFS and suggest specific research priorities for investigating the relationship between chemosensory function and post-viral chronic illness.