Hypothesis A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in [ME/CFS]: lessons learned from long-COVID,2026, Srinivasan et al

[forestglip]

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

Srinivasan, Mythily; Joseph, Paule Valery

Abstract
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.

Web | DOI | PDF | Frontiers in Medicine | Open Access

 

[Peter T]

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.

To me this is a big improvement on the usual opening sentences, at least it avoids ‘complex multi system’ and drops any mention of ‘fatigue’. Although does ‘dysregulation of the autonomic nervous system’ still go beyond what we can currently demonstrate?

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.

Although the disruption of a sense of smell is common in Covid 19 and to a lesser extent in Long Covid, and sensory hypersensitivity to smell is frequent in ME/CFS, I am not aware of people commonly reporting taste dysfunction. Personally. over the 30 years of my ME, I am not aware of any significant changes in my sensations relation to taste other than related to normal aging. Is this something others experience?

 

[ChronicallyOverIt]

No, taste differences for me. Thought wasn’t there a lot of talk of olfactory gene hits a while back? Any link to this paper?

 

[Jonathan Edwards]

As far as I can see type II taste receptors are true taste buds - mediating salt an umami etc. In Covid I understood that the problem was with olfactory receptors. Most loss of taste called 'dysgeusia' is based on olfactory problems. I cannot see it likely that type II receptors are a problem in ME/CFS and probably not olfactory either. If anything olfactory sensitivity is a problem.

 

[Evergreen]

The real problem with the paper is that they don't present any convincing evidence that dysgeusia is commonly reported in ME/CFS without COVID.

I do not recall reading accounts of dysgeusia in ME/CFS over the decades before the pandemic, but those accounts would be mostly from those with mild, moderate and severe ME/CFS. Maybe people with very severe ME/CFS frequently report this?

I'm severe and I've had minor changes to taste e.g. rosemary now tastes like toothpaste to me, but nothing like what people reported after COVID. The vast majority of food tastes normal to me. When I had a bout of not being able to eat enough, it had nothing to do with taste.

Here's how the Cleveland Clinic describes dysgeusia:

Dysgeusia affects people in different ways. In general, food just doesn’t taste the same as you remember. Some common symptoms are:

• All foods taste metallic or bitter.
• Foods that are characteristically sweet or salty no longer taste sweet or salty.
• Foods that used to taste good now taste bad, and sometimes rotten.
• There’s a nasty taste in your mouth even though you haven’t eaten anything.

I don't find this too convincing:

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.

Here are the two mentions of taste in the NICE guidline:

p.14 Be aware that the following symptoms may also be associated with, but are not exclusive to, ME/CFS:
...heightened sensory sensitivities, including to light, sound, touch, taste and smell...

p.50 Monitor people with severe or very severe ME/CFS who are at risk of malnutrition or unintentional weight loss because of:
•restrictive diets
•poor appetite, for example linked with altered taste, smell and texture
...

Back to the paper:

A central feature of ME/CFS is a profound disturbance in cellular energy metabolism due to mitochondrial abnormalities, resulting in low ATP levels...Alternatively, ME/CFS represents a “cell danger response” driven largely by extracellular ATP acting on purinergic (P2X) receptors (20).

The bioenergy deficits and extracellular ATP dynamics shared between CFS, and long-COVID offer a biologically coherent explanation for why taste dysfunction may both mirror and contribute to ME/CFS pathophysiology. Low ATP levels in ME/CFS could directly impair TRC function by interfering with signal transduction, and neurotransmitter synthesis, thereby disrupting the flow of taste information. Altered purinergic receptor activation patterns could further disrupt taste signaling (17, 24).

Hm.

Some limitations are noted:

3.5.4 Potential confounding factors for taste dysfunction as a symptom of ME/CFS​

The unique gustatory and olfactory neural tropism of SARS-CoV2 with potential central and/or peripheral effects could contribute to the altered taste perception in long-COVID. Hence, dysgeusia as contributing factor could be restricted to the ME/CFS cohort secondary to CoV2 infection (21, 32). Several additional factors can be etiologically related to gustatory disorders. These include multiple classes of drugs, such as anti-infectives, anti-inflammatory anti-pyretic, antihistamines, antihypertensives, sympathomimetics, anti-diabetics and psychopharmacologic agents (33). Furthermore, oral health issues such as candidiasis and xerostomia (dry mouth) secondary to medications can distort taste sensations. Systemic co-morbidities such as fibromyalgia and Sjogren’s syndrome associated with ME/CFS can also contribute to the taste dysfunction independently or due to medications (14, 34).