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

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent or recurring symptoms including fatigue, post-exertional malaise (PEM), myalgia, joint pain, sleep disturbances, and cognitive dysfunction (1, 2). Proposed triggers include new or reactivation of latent viral infections, physiological or psychological stressors, and genetic susceptibility (3). Significantly, as the long-term effects of the recent severe acute respiratory syndrome (SARS) coronavirus-2 (CoV2) pandemic unfold, emerging data suggest that post-acute SARS-CoV2 symptom complex (PASC) shares many features of ME/CFS symptoms, including debilitating fatigue, PEM, cognitive issues, and sleep disturbances (3–5). Data from NIH’s RECOVER initiative reveal that new ME/CFS cases are 15 times more frequent than before pandemic and that the increased risk is independent of severity of CoV2 infection or reinfection status (5, 6). Indeed, PEM is recommended as an outcome measure for PASC or long-COVID clinical trials (7).

Yet, an interesting discrepancy is the frequent occurrence of dysgeusia in long-COVID and its paucity in ME/CFS reports (3, 4). Persistent taste dysfunction extending for periods longer than one-year post-CoV2 infection has been consistently reported as a component of PASC (8, 9). Isolated dysgeusia, independent of smell loss, occurred in 5–10% of long-COVID cases (10). Furthermore, longitudinal electronic health records of PASC showed that even in children and adolescents CoV2 reinfection increased the risk of chemosensory dysfunction with an odds ratio of 2.83 (1.41–5.67) (11). Interestingly, an observational study reported that dysgeusia occurred in 19% of cases of long-COVID patients diagnosed with ME/CFS (12). Yet, in general, taste dysfunction has not been recognized amongst the symptom clusters of ME/CFS. This could be due to under-recognition, rather than true absence. Indeed the 2021 guidelines by the National Institute of Health and Care Excellence includes altered taste and smell sensitivities as associated symptoms of ME/CFS (1). Evidence supporting under-recognition has been overlooked. A large Belgian study of 2,073 CFS patients reported that 38–42.4% of patients meeting Fukuda or Holemes criteria experienced altered taste, smell, or hearing (1). Further, existing data are derived from patient self-report, which underestimates true symptom prevalence. This trajectory parallels the historical pattern of other ME/CFS symptoms that were initially overlooked but subsequently validated through objective measurements.

The ME/CFS patient community has long advocated for objective diagnostic biomarkers to validate illness and improve care. In this perspective, we present a mechanistic model highlighting the critical roles of taste dysfunction in ME/CFS with supporting evidence from long-COVID as a natural experiment. In the following sections we first provide a brief overview of physiology of taste and introduce a framework for understanding the shared biological pathways between ME/CFS and long-COVID. We next review evidence linking taste dysfunction and ME/CFS emphasizing adenosine triphosphate (ATP) dependent mechanisms of bioenergy deficit and inflammation. We then provide evidence from a publicly available long-COVID data set that supports taste dysfunction as biomarker for ME/CFS. In conclusion, we propose an ATP-dysfunction based model that integrates these separate but related fields, namely chemosensory dysfunction, in particular taste dysfunction, and ME/CFS.

Gustation, the sense of taste, is mediated by taste buds located chiefly on the tongue’s papillae. Each taste bud contains 50–100 taste receptor cells (TRCs), classified as Type I supporting cells, Type II cells that detect sweet, bitter, and umami tastes, and Type III cells responsible for sour perception (13). TRCs exhibit a turnover rate of 8–10 days, with loss modulated by apoptosis and extrusion and regeneration mediated by proliferation of stem cells (13). Taste disorders include dysgeusia, hypogeusia, phantogeusia, and ageusia. Age associated increased apoptosis or extrusion of TRCs, genetic variants in bitter TRCs, mutations in ATP-channel proteins, and systemic or local inflammation that impairs TRC regeneration are mechanisms attributed to taste dysfunction (13–15).

Several reports show that patients with long-COVID experience dysgeusia characterized by prolonged metallic or bitter taste in the mouth (e.g., coffee tastes metallic and that chocolate has lost its typical taste) (9, 16). Type-II TRCs that mediate such taste dysfunctions rely on ATP as their primary neurotransmitter. Mechanistically, the tastants bind G protein coupled receptors on type-II TRC’s, activate phospholipase C beta 2 (PLCβ2), generate inositol 1,4,5-trisphosphate (IP3), and release intracellular Ca²⁺, which drives ATP efflux through calcium homeostasis modulator 1 (CALHM1) channels. Subsequently, released ATP activates specific purinergic receptors such as P2X2 and P2X3, on cranial nerves VII, IX, and X, triggering action potentials that are transmitted to central gustatory regions culminating in taste perception (13, 17).

The clinical overlap between ME/CFS and long-COVID has become increasingly apparent as the long-term effects of SARS-CoV-2 infection continue to unfold (4, 5). Similarly, emerging data show that multiple interconnected biological pathways implicated in the ME/CFS pathology are also observed in long-COVID pathology (3, 4). Building on these shared mechanisms, we discuss how dysgeusia, specifically the most frequently reported bitter taste dysfunction, could connect to ME/CFS through energy-dependent mechanisms (Figure 1).

Researching COVID to enhance recovery (RECOVER) is a NIH initiated program to understand, diagnose, prevent, and treat long-COVID. Data from this initiative showed that 4.5% of post-COVID-19 participants met ME/CFS diagnostic criteria, compared to 0.6% of uninfected participants (35). As of January 2026, this dataset curated for adult COVID included 84,172 and 58,320 entries from SARS-CoV2 infected and uninfected participants, respectively. We queried the data set of infected participants for the following symptoms over a period of 2–4 years post-index date; (Q1) loss of or change in smell or taste, (Q2) How much does your post-exertional malaise bother you? and (Q3) How much do your problems thinking or concentrating (“brain fog”) bother you?. The percentage of participants reporting “yes, I still have it” for Q1 exhibited an increasing trend, from 9% at 24 months to 17% at 48th month post-index period. Similarly, the percentage of participants responding “very much” for Q2 and Q3 increased with time from 24 to 48 months, consistent with previous reports (Figure 2A). Interestingly, the number of people reporting chemosensory disturbance and PEM increased from 1% in 24 months to 4% in 48 months (Figures 2B, C). Furthermore, the number of people reporting chemosensory disturbance and brain fog doubled from 6% in 24 months to 13% in 48 months. Collectively, these observations suggest that chemosensory dysfunction could represent a biomarker for increased PEM and brain fog, characteristic features of ME/CFS (Figure 2B). However, correlational occurrences are interpreted with caution. The data set does not allow tracking of individual responses, and the combined symptoms could potentially indicate new onset of either symptom. Infrequent reports of taste dysfunction in pre-COVID era in ME/CFS further adds to the cautious interpretation.

Yet, considering that millions of people were exposed to SARS-CoV2, and the increasing trajectory of new ME/CFS, the value of a non-invasive, easily measurable clinical marker such as quantitative taste-testing is very high, even if it is restricted for a subset of ME/CFS patients. Pertinently, ME/CFS therapeutic strategies under development such as P2X3 receptor antagonists and interventions aimed at boosting cellular energy are closely connected to taste perception (18, 19). Yet, with respect to long-COVID data the following limitations are acknowledged: (1) combined documentation of taste and smell changes in the NIH shared data resource and (2) inherent neurotropism of SARS-CoV2 that contributes to the increased chemosensory dysfunction in long-COVID, as opposed to other ME/CFS associated viruses.

Available literature presents substantial indirect and supportive evidence for taste dysfunction as a biomarker or indicator of disease progression or severity of ME/CFS. Future longitudinal studies that systematically track the onset, severity, and fluctuation of taste dysfunction alongside other symptoms in a well-characterized cohort of ME/CFS patients (e.g., Canadian Consensus Criteria or the Institute of Medicine criteria) will determine the significance of dysgeusia, if any, in ME/CFS. As opposed to the emerging screening platforms such as 3D genomics or transcriptomics that need specialized infrastructure, taste testing provides a rapid, inexpensive, non-invasive option that can be repeated frequently in clinical or home settings (36). Quantifying taste preference and thresholds for the five basic tastes and serial assessments can potentially anticipate PEM episodes, offer an objective index of disease progression, and identify individuals needing confirmatory molecular testing. The metabolic-neurotransmitter hypothesis could be addressed by quantifying ATP levels and mitochondrial function in TRCs and using advanced brain imaging to investigate the integrity of gustatory brain regions.

We acknowledge Dr. Randy Levinson for careful review and suggestions for improving our manuscript.

The author(s) declared that financial support was received for this work and/or its publication. This research was funded by support from “Delta Dental Research Program” to MS: Award # 44-762-54. This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U. S. Department of Health and Human Services.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

MS: Conceptualization, Formal analysis, Funding acquisition, Resources, Visualization, Writing – original draft, Writing – review & editing. PJ: Funding acquisition, Conceptualization, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing.

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors MS and PJ were declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

This article has been corrected with minor changes. These changes do not impact the scientific content of the article.

The author(s) declared that Generative AI was not used in the creation of this manuscript.

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