Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2019, Fisher et al.

[Andy]

Now published, see https://www.s4me.info/threads/prepr...fisher-et-al-now-published.10412/#post-190278

Preprint.

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work.

Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems.

Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Open access at https://www.preprints.org/manuscript/201907.0196/v1

 

[Hoopoe]

Fisher is that Aussie mitochondria expert, right? He seemed to really know what he was talking about.

 

[Hutan]

This looks to have been written primarily by Daniel Missailidis, who I think was the impressive young researcher at the Emerge conference.

Author Contributions: D.M., writing – original draft preparation and editing; S.J.A & P.R.F., writing– review and editing.

I think it's a useful review, clearly setting out the situation of sparse and conflicting results that is ME/CFS biological research right now. There's a reasonable level of scepticism e.g. about NK cells it is written

Overall inconsistent evidence – role mostly unknown

And about biomarker discoveries:

Consequently, the discovery of a reliable diagnostic biomarker is perhaps the most common recurring theme in modern ME/CFS research. Despite myriad relevant study outcomes [5-16], no such discovery has yet been widely validated or implemented as a suitable diagnostic biomarker of ME/CFS.

The authors clearly understand key historical problems in ME/CFS research e.g.

Case definitions such as the commonly termed Oxford [1] or Fukuda [2] criteria are most often utilized throughout the UK and USA respectively, yet may fail to discriminate between generalized chronic fatigue and ME/CFS which specifically also involves PEM, which aids in characterizing this disorder as a discrete clinical entity.

I'm probably more sceptical than the authors about the hypocortolism finding that's reported - it looks less solid to me. Maybe they needed to look at more studies in more detail. (although they use an odd wording of 'previously suggested' which might indicate some lack of uncertainty about its current validity)

Further, the linkage of cortisol-driven stress responses to the gut through the hypothalamic-pituitary- adrenal (HPA) axis [168] could be dysfunctional in ME/CFS due to the hypocortisolism previously suggested to play a role in the condition [169,170].

This seems to be the main point of the paper:

Based on current biomedical literature, perturbations to the various systems listed in Table 1 are implicated in the underlying pathological mechanisms in ME/CFS. These phenomena are correlated clinically in that they appear in people with the disorder. However, the causal links between them are unknown and cannot be discerned purely on the basis of clinical correlation. There are many scenarios where more than one of the affected systems may exert pathological effects on another and vice versa.

This complex and often reciprocal regulatory cross-talk between systems makes it difficult to distinguish cause from effect, so there is great need for the potential causal relationships to be addressed directly using appropriate experimental models.

That is, despite the probably heterogeneous cohorts used in past research, there seems to be evidence of things that are wrong with the biochemistry of people with ME/CFS. But finding these things that are wrong might not be enough to unravel the cause, as there are all sorts of complicated feedback loops and interactions.

So Daniel and the Fisher team seem to be suggesting that experimental models are required. I'm not sure what they have in mind, but more power to them. I hope they manage to get a good share of the Australian funding for ME/CFS.

 

[Milo]

So Daniel and the Fisher team seem to be suggesting that experimental models are required. I'm not sure what they have in mind, but more power to them

Animal model? Artificial Intelligence?

Moderator note: Posts discussing animal models have been moved to this thread:
Animal studies: why are we not doing them?

 

[Mithriel]

When we are cold we can't heat up and when we re hot we can't cool down. I wonder if the same thing happens with lots of our body systems.

If it does, the amount of any particular chemical will be different in everyone so nothing significant will be found. So it is not a homeostatic shift so much as a slowing of the homeostatic process.

 

[wigglethemouse]

So Daniel and the Fisher team seem to be suggesting that experimental models are required. I'm not sure what they have in mind, but more power to them. I hope they manage to get a good share of the Australian funding for ME/CFS.

Saw this write up on Paul Fisher on Health Rising

Emerging Insights #II: “The Cellular Equivalent of Chronic Fatigue” Found in ME/CFS
https://www.healthrising.org/blog/2019/07/18/cellular-equivalent-chronic-fatigue-mitochondria-found/

The "model" he used here was a sample of a patients lymphocytes that he grew in culture, and continued to grow. That way he could perform experiment after experiment on the same set of lympocytes and so remove a big variable.

The write up also made me wonder if Karl Morten and Paul Fischer are in touch. Sure would be good if the two could build a relationship to bounce ideas off. Both are very senior mitochondrial experts who want to help us.

 

[Milo]

Mod note: The part of this post discussing animal studies has been moved to the other thread.

The "model" he used here was a sample of a patients lymphocytes that he grew in culture, and continued to grow. That way he could perform experiment after experiment on the same set of lympocytes and so remove a big variable

Yes, cell cultures are being used in isolation, as opposed to understanding the multi-systemic ramifications of our pathology(ies). I am not sure we can understand brain inflammation, hormonal disruptions and gut issues by only studying one type of lymphocytes of the peripheral blood in a cross-sectional setting.

 

[Trish]

The published version of this paper is now available:
Pathological Mechanisms Underlying Myalgic Encephalomyelitis /Chronic Fatigue Syndrome
Daniel Missailidis,Sarah J. Annesley and Paul R. Fisher

Abstract:
The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise.

ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work.

Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances.

It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift.

Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition.

Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Sorry I don't have the energy to check if it's the same as the preprint.