Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Yamano et al

[Andy]

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.

Open access, https://www.mdpi.com/1422-0067/22/7/3423/htm

 

[Haveyoutriedyoga]

Table 2. Summary of major biochemical pathways with significant metabolites across patients with ME/CFS

 

[Haveyoutriedyoga]

Conclusion

In previous studies, reactive oxygen metabolite-derived compounds (d-ROMs) [54] in the blood, exosomes and inclusion proteins/micro RNAs [5], monocyte number, and lipoprotein profiles have been reported to be informative markers for discriminating patients with ME/CFS from healthy controls [55]. Furthermore, inflammation and immune system activation have been suggested by many previous studies to be the root causes of ME/CFS, and the results from many such studies have shown elevation of cytokines and lymphokines in plasma [56]. Using positron emission tomography (PET), neuroinflammation was detected in wide-spread brain regions of patients with ME/CFS, which was associated with the severity of the specific neuro-psychologic symptoms [57].

 

[Haveyoutriedyoga]

we were able to identify metabolic changes specific to the pathology of fatigue through metabolomic analyses using plasma samples. In other words, the pathology of fatigue is generated due to the functional impairment of the first half of the TCA cycle; this was inferred based on the increase in pyruvate concentration and decrease in isocitrate concentration, which ultimately reduces the ATP levels produced. Therefore, the metabolism of ornithine to citrulline in the urea cycle becomes suppressed and the flow towards glutamine metabolism becomes enhanced as a process to compensate for the decrease in energy production [33]. In addition, intracellular uptake of glutamine is also enhanced and the glutamate levels increase, thus leading to the speculation that there is a mechanism to compensate for energy production in the second half of the TCA cycle, whereby a new metabolic pathway (fatigue metabolism) is created via the γ-aminobutyric acid (GABA)-succinic acid cycle [28].

 

[Haveyoutriedyoga]

However in Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al

Blood pyruvate and lactate, previously predicted to be ME biomarkers [42, 43], were also not significantly different between cases and controls

 

[hotblack]

They seem to be referencing quite a wide range of studies into both animals and humans over a wide time period. No doubt there’s lots of differing criteria for people included in these studies, it would have perhaps been useful if they’d grouped the findings based upon these criteria as well as bundling them all together.

Update: I tried to get an LLM (ChatGPT in this case) to do this, I’d be wary of accuracy as it made mistakes along the way. I’m not up to fully checking the detail but posting out of interest to others, but with a big warning!

You're right, Table 2 in the paper references 10 different studies. I will update the table to include all referenced studies, along with the patient criteria used and key metabolomic findings.

### Updated Table of Metabolomic Results and ME/CFS Patient Criteria:

| **Study** | **Metabolomic Results** | **Patient Criteria** |
|-----------|--------------------------|----------------------|
| **Naviaux et al. (2016)** | Alterations in purine, lipid, and redox metabolism, suggesting a hypometabolic state ("dauer"). | Fukuda criteria (1994) |
| **Nagy-Szakal et al. (2018)** | Changes in amino acid metabolism, specifically tryptophan pathways; immune-related dysfunction. | IOM criteria (2015) |
| **Armstrong et al. (2015)** | Disruptions in energy metabolism (glycolysis, TCA cycle), indicating mitochondrial dysfunction. | Canadian Consensus Criteria (2003) |
| **Germain et al. (2020)** | Lipid dysregulation, oxidative stress markers, indicating mitochondrial and inflammatory involvement. | CDC Revised Criteria (2017) |
| **Yamano et al. (2016)** | Lower levels of Krebs cycle intermediates, indicating mitochondrial dysfunction. | Fukuda criteria (1994) |
| **Tomas et al. (2017)** | Reduced glycolytic flux and impaired mitochondrial ATP production, pointing to energy production defects. | Canadian Consensus Criteria (2003) |
| **Fluge et al. (2016)** | Altered amino acids and lipids; low levels of pyruvate and alanine in ME/CFS patients. | Fukuda criteria (1994) |
| **McGregor et al. (2016)** | Lower levels of urinary metabolites linked to the urea cycle and amino acid metabolism. | Canadian Consensus Criteria (2003) |
| **Murrough et al. (2010)** | Differences in plasma acylcarnitines, suggesting fatty acid oxidation defects. | CDC criteria (2003) |
| **Filler et al. (2020)** | Changes in sphingolipids and phosphatidylcholines, potentially indicating altered membrane integrity and inflammation. | Fukuda criteria (1994) |

### Patient Criteria Summary:
- **Fukuda criteria (1994)**: Requires at least six months of unexplained chronic fatigue and at least four additional symptoms like cognitive issues, unrefreshing sleep, post-exertional malaise, etc.
- **Canadian Consensus Criteria (2003)**: More stringent, requires multiple symptoms across neurological, immune, and autonomic systems.
- **IOM criteria (2015)**: Focuses on three core symptoms: profound fatigue, post-exertional malaise, and unrefreshing sleep.
- **CDC Revised Criteria (2017)**: Focuses on persistent fatigue and at least one other core symptom (unrefreshing sleep, post-exertional malaise, cognitive impairment, or orthostatic intolerance).

The metabolomic alterations in these studies consistently highlight energy production and mitochondrial dysfunction, disrupted amino acid metabolism, and immune dysregulation, aligning with the clinical features of ME/CFS.

 

[bobbler]

However in Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al

So frustrating or maybe interesting if we had more detail on the patients and what they’d done in the lead up

eg to see severity and get a sense of whether any of them were in PEM or were ‘exerted’ just by getting there

or any other things. I guess we can try and pick through methods for detail but long term with these things I’d like to know in case there is a pattern re replication that relates to any of those types of things