A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Fluge, Mella et al

[Sly Saint]

Abstract


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established.

We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

https://insight.jci.org/articles/view/149217

 

[Midnattsol]

Oh wow, a lot to dig into here! But no time/energy this week

It looks very exciting, although I'm sceptical of how they "controlled" for the diet of the participants. Looking forward to have a more thorough look at the metabolites included in these analyses!

 

[Rain]

It looks very exciting, although I'm sceptical of how they "controlled" for the diet of the participants.

«Our comprehensive evaluation of possible cofounders such as sex, BMI, age, diet, or medication did not indicate that these were main drivers of the ME/CFS phenotypes, but they may contribute to individual variation »

 

[Midnattsol]

«Our comprehensive evaluation of possible cofounders such as sex, BMI, age, diet, or medication did not indicate that these were main drivers of the ME/CFS phenotypes, but they may contribute to individual variation »

By looking at xenobiotic compounds (written in supplementary material), many of the other metabolites are also influenced by diet.

 

[Hoopoe]

I benefit from carnitine supplementation. Would this be predicted for any metabolic phenotypes described here?

 

[ME/CFS Skeptic]

Summary based on quotes from the text:

Based on metabolites tested, ME/CFS were divided into three groups (M1, M2, M3). There was relatively little overlap between the health controls (HC), ME-M1, and ME-M2 clusters, whereas the ME-M3 subset was positioned as a merger phenotype between the 3 others.

Overall, the patterns that separated the ME/CFS subsets were dominated by lipid and amino acid metabolites.

• The ME-M1 metabotype appears to reflect a lipolytic state with increased utilization of both fatty acids and amino acids as energy substrates, possibly due to ineffective carbohydrate catabolism. The ME-M1 subset presented elevated serum levels of free fatty acids (i.e., NEFA) and ketone bodies, despite normal glucose and insulin. This may resemble a context with physiological correlations to glucose starvation and exercise.
• The ME-M2 metabotype shows indications of disrupted control of lipid metabolism, possibly involving compromised activity of mitochondrial oxidation pathways and consequent effects on lipid trafficking and storage. In the ME-M2 subset, a different metabolic profile was expressed by the elevated serum TAG and insulin mean levels, yet blood glucose was not affected. This may reflect low-grade signs of lipid-induced insulin resistance associated with ectopic peripheral lipid accumulation and inflammatory responses.
• The ME-M3 subset was found to reflect an intermediate state between the 2 other ME/CFS metabotypes, albeit with some more similarity with the ME-M2 phenotype.

Both the ME-M1 and ME-M2 subsets convincingly expressed contexts of underlying energy strain, as further supported by the elevation of metabolic stress hormones such as FGF21 and FABP4.

The following seems to be the main hypothesis:

"The observed metabolic effects may be associated with tissue hypoxia caused by an underlying pathology related to an autoimmune mechanism. An autoantibody-mediated mechanism may influence, indirectly or directly, the fine-tuned autoregulation of blood flow required to meet the metabolic demands of tissues. Endothelial dysfunction has been shown in patients with ME/CFS (65, 66), and this was also supported in substudies linked to the CycloME and RituxME trials. [...] These findings pointing to vascular dysfunction support that exertion-triggered tissue oxygenation may be impaired, and clearly this would contribute to lowered activity tolerance and involve mitochondrial energy metabolism."​

 

[Snow Leopard]

Another key finding buried in the text:

Corticosteroids* did not seem to be involved, since they depended on age and BMI instead of physical function scores (Supplemental Data 3) and we did not find changes in morning cortisol and ACTH in ME/CFS compared with HC.

Which rules out HPA axis related hypotheses.

Also:

It should be kept in mind that none of the patients of our study had a clinical prediabetic or diabetic diagnosis

The 2 most distinct ME/CFS metabotypes, ME-M1 and ME-M2, aligned with well-known phenotypes of chronic diseases with immuno-metabolic projections (34, 37, 38). It should be kept in mind that none of the patients of our study had a clinical prediabetic or diabetic diagnosis. The ME-M1 subset presented elevated serum levels of free fatty acids (i.e., NEFA) and ketone bodies, despite normal glucose and insulin. This may resemble a context with physiological correlations to glucose starvation and exercise (33, 35). In the ME-M2 subset, a different metabolic profile was expressed by the elevated serum TAG and insulin mean levels, yet blood glucose was not affected. This may reflect low-grade signs of lipid-induced insulin resistance associated with ectopic peripheral lipid accumulation and inflammatory responses (56). Both the ME-M1 and ME-M2 subsets convincingly expressed contexts of underlying energy strain, as further supported by the elevation of metabolic stress hormones such as FGF21 and FABP4. Furthermore, we have previously suggested that impaired function of PDH may play a role in ME/CFS (15), which is regarded as a common physiological response under energy strain (57, 58). The third and minor ME/CFS subset (ME-M3) clustered together with HC, albeit with some overlap with the other 2 subsets. The 3 ME/CFS metabotypes likely reflect compatible and functionally connected contexts of compensatory adaptations that may develop in a person-specific manner. Notably, the physical function scores ranked the subsets as ME-M2 < ME-M1 < ME-M3, and there were corresponding trending differences in disease severity. Therefore, it seems possible that these metabolic contexts may influence, or be influenced by, the pattern and severity of symptoms.

 

[Midnattsol]

While none of the patients had a diagnosis of prediabetes, some of them (eight from Figure 3C) have glucose readings above 6.0mmol/L which is the criteria for prediabetes in Norway. The criteria for diabetes is above 7mmol/L, and two patients are above 8mmol/L while another might be above 7mmol/L. I hope that they are not diagnosed mean that they have been checked out for this, but that might not be the case as sometimes people find out they have a marker for disease by taking part of a study (currently in Norway people taking part in the HUNT study, and also I think the Tromsø Health Study, have been told they have previously undiscovered celiac disease).

 

[Milo]

While none of the patients had a diagnosis of prediabetes, some of them (eight from Figure 3C) have glucose readings above 6.0mmol/L which is the criteria for prediabetes in Norway. The criteria for diabetes is above 7mmol/L, and two patients are above 8mmol/L while another might be above 7mmol/L. I hope that they are not diagnosed mean that they have been checked out for this, but that might not be the case as sometimes people find out they have a marker for disease by taking part of a study (currently in Norway people taking part in the HUNT study, and also I think the Tromsø Health Study, have been told they have previously undiscovered celiac disease).

Do you mean A1C? Diabetes is not typically diagnosed from 1 single random glucose. The A1C represents a value that represents the bigger picture and a longer term (last 3 months) of the blood glucose.

 

[Midnattsol]

Do you mean A1C?

No, regular glucose. Since it doesn't say HbA1c in the plot or table of clinical values I assume that's what's been measured. The patients can have normal HbA1c values, but that's not clear from the paper. I'm also making the assumption that the blood was sampled when patients were fasted, as that is a requirement when looking at TAG (it says the blood for the clinical test was done following standard procedure. For the metabolomics blood there was a mix of fasted/non-fasted participants).

 

[Sly Saint]

Article on this research:

https://www.news-medical.net/news/2...sms-involved-in-Chronic-Fatigue-Syndrome.aspx

 

[Grigor]

Hmm, so unlike other researchers. Are these researchers suggesting that this is one condition with different phenotypes?

 

[Milo]

Hmm, so unlike other researchers. Are these researchers suggesting that this is one condition with different phenotypes?

I think it’s inevitable that there will be different phenotypes. I would suggest there are others with different diagnosis.

 

[Campanula]

Hmm, so unlike other researchers. Are these researchers suggesting that this is one condition with different phenotypes?

From what I gather the different phenotypes refer to different strategies of compensating for the energy strain that they describe. So the underlyting energy strain seems to be more fundemental, whereas the compensatory mechanisms the body chooses to use to try to adapt to it, are more diverse. The common mechanism that underlies it all seems to be tissue hypoxia according to their model (according to their previous article in JCI):

"Endothelial dysfunction with inadequate flow regulation to meet the demands of tissues, reduced venous tone and return, and reduced cardiac output on exertion as well as AV shunting with reduced peripheral oxygen extraction would all result in tissue hypoxia, which we believe may be a common pathomechanistic denominator in ME/CFS" (Bolding mine)

 

[tuha]

From what I gather the different phenotypes refer to different strategies of compensating for the energy strain that they describe. So the underlyting energy strain seems to be more fundemental, whereas the compensatory mechanisms the body chooses to use to try to adapt to it, are more diverse. The common mechanism that underlies it all seems to be tissue hypoxia according to their model (according to their previous article in JCI):

"Endothelial dysfunction with inadequate flow regulation to meet the demands of tissues, reduced venous tone and return, and reduced cardiac output on exertion as well as AV shunting with reduced peripheral oxygen extraction would all result in tissue hypoxia, which we believe may be a common pathomechanistic denominator in ME/CFS" (Bolding mine)

I really like this hypothes. How difficult it is to prove that there is that problem with tissue hypoxia and endothel dysfunction?

 

[Campanula]

I really like this hypothes. How difficult it is to prove that there is that problem with tissue hypoxia and endothel dysfunction?

I like it as well. I think blood flow problems are definitely an important aspect of my own illness. Unsure whether autoantibodies are what's behind it though, but I guess we'll see if this pans out in the future?

When it comes to endothelial dysfunction, there's already been three studies that have discussed this, as far as I know, but I haven't looked into them in detail. Here they are, for anybody interested:

1. Blausteiner et al.
2. Scherbakov et al.
3. Sørland et al.

 

[Sly Saint]

Myalgic encephalomyelitis associated with cellular energy strain

by University of Bergen

Professor Karl Johan Tronstad at the University of Bergen has supervised a study which found biochemical changes in the blood of ME patients. The results support the hypothesis that the disease involves impaired cellular energy metabolism.

ME (Myalgic Encephalomyelitis), also known as Chronic Fatigue Syndrome (CFS), can be a debilitating disease. It frequently presents after an infection, and key features are long-lasting fatigue and worsening of symptoms after exertion. Symptoms include flu-like malaise, muscle and joint pains, headaches, and cognitive problems.

One hypothesis suggests that ME is caused by an irregularity in the patients' immune system. This assumption was supported by the observations of oncologists Olav Mella and Øystein Fluge at Haukeland University Hospital, who found that some cancer patients who also suffered from ME, experienced an improvement in ME symptoms when they were given immunosuppressive cancer treatment.

This gave Tronstad's group at the Department of biomedicine a basis to explore the mechanistic connections in more detail, in close collaboration with the clinical research group. At first, they found evidence suggesting reduced function of a central enzyme in the cell's energy metabolism called pyruvate dehydrogenase (PDH). They have now performed a comprehensive study of the biochemical composition of the blood.

"We compared blood samples from 83 patients and 35 healthy controls, and measured over 1700 different compounds", says the professor. "We found significant differences in the levels of over 300 different substances, many of which were related to amino acid and lipid metabolism."

A defect in cellular energy supply

A common trait of the ME patients' blood samples was changes in energy metabolites (molecules associated with cellular energy metabolism) which would typically occur when the body is subjected to exertion or a limited energy supply. Furthermore, the levels of certain metabolites varied between subgroups of ME patients:"Changes that are common within the patient group may be associated with a common disease mechanism. We also identified metabolic signatures that point to different kinds of metabolic adaptations among the patients, some of which appeared to relate to the severity of the disease. Part of our work consisted of grouping the patients based on the metabolic differences to explore associations with clinical patient data", says Tronstad.

The findings by Tronstad and colleagues support a theory that ME is associated with a persistent disturbance in the cells' ability to satisfy energy needs.

According to Tronstad, some changes are expressed differently in different patients because the body has distinct ways of dealing with threatening situations. By ways of example, he mentions the body's response to fasting: When you fast, you limit the normal supply of nutrition to the cells, and the body will respond by supplying the cells with alternative sources of energy via the blood. Such metabolic compensatory mechanisms can be triggered by illness and may vary from individual to individual.

"Among the ME patients, we found characteristic features of two types of metabolic adaptations, one of which was associated with a more severe symptomatology. Possible contributing factors include diets, drugs, genetics, and lack of physical activity", says Tronstad

https://medicalxpress.com/news/2021-08-myalgic-encephalopathy-cellular-energy-strain.html

 

[Tia]

Myalgic encephalomyelitis associated with cellular energy strain

by University of Bergen


https://medicalxpress.com/news/2021-08-myalgic-encephalopathy-cellular-energy-strain.html

A hypothesis that makes sense to a non scientist like me and resonates with my own experiences. Any idea what the 'lack of physical activity' bit in the last line of the article above means? Does it mean that it could be the lack of physical activity in severe patients which could provoke the body to make the metabolic adaptation rather than the other way around? I don't understand.

 

[FMMM1]

I benefit from carnitine supplementation. Would this be predicted for any metabolic phenotypes described here?

Weird my wife takes carnitine (post antibiotic) and my daughter has disabling fatigue.

Carnitine "transports long-chain fatty acids into mitochondria to be oxidized for energy production" [Wiki] so I'm guessing that if you increasing your dependence on fatty acids [for energy], i.e. due to ME/CFS, and didn't have enough carnitine then yes carnitine supplementation might help - I'm a lay person by the way.

The GWAS study might help to understand this study (and indeed others) @Simon M
These studies are telling us outcome but not the underlying cause [I think!] ---- GWAS might help by providing clues to genes which protect and increase risk of developing ME/CFS.

The references to "endothelial and microcirculatory dysfunction effects on vascular endothelium" made me think of @Snow Leopard

 

[FMMM1]

A hypothesis that makes sense to a non scientist like me and resonates with my own experiences. Any idea what the 'lack of physical activity' bit in the last line of the article above means? Does it mean that it could be the lack of physical activity in severe patients which could provoke the body to make the metabolic adaptation rather than the other way around? I don't understand.

Yea that's a common concern i.e. how do you get adequate controls to assess the affect of sedentary behaviour?