Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis? (2018) Theoharides et al

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J Pharmacol Exp Ther. 2018 Aug 3. pii: jpet.118.250845. doi: 10.1124/jpet.118.250845. [Epub ahead of print]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis?
Hatziagelaki E, Adamaki M, Tsilioni I, Dimitriadis G, Theoharides TC.


Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms. A significant percentage of ME/CFS patients remains undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, mostly with mitochondrial dysfunction, resulting in reduced oxidative metabolism. Mitochondrial dysfunction may be further contributing to the ME/CSF symptomatology by extracellular secretion of mitochondrial DNA, which could create an "innate" inflammatory state in the hypothalamus, thus disrupting normal homeostasis. We propose that stimulation of hypothalamic mast cells activates microglia leading to focal inflammation in the brain and disturbed homeostasis.

KEYWORDS:
cognition; histamine; inflammation; mast cells; obesity
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https://www.ncbi.nlm.nih.gov/pubmed/30076265
http://jpet.aspetjournals.org/content/early/2018/08/03/jpet.118.250845 (full PDF available)
 
I have glanced through the paper. The authors have given a huge list of references to biomedical ME research papers, and written an outline of what they found from reading these papers, so most of their lengthy paper is a literature review.

They then come up with a hypothesis:

We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic, and stress triggers activates microglia leading to focal inflammation in the brain and disturbed homeostasis.
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I gather that the lead researcher on this paper researches mast cells, so not surprisingly the hypothesis proposed gives a central role to mast cell activation. They also make some suggestions of drugs that might help if their hypothesis is correct.

I have insufficient knowledge to judge whether this hypothesis could be helpful. I wonder what our resident experts think - @Jonathan Edwards, @Simon M, @JaimeS ... ?
 
Trish said:
I have glanced through the paper. The authors have given a huge list of references to biomedical ME research papers, and written an outline of what they found from reading these papers, so most of their lengthy paper is a literature review.

They then come up with a hypothesis:



I gather that the lead researcher on this paper researches mast cells, so not surprisingly the hypothesis proposed gives a central role to mast cell activation. They also make some suggestions of drugs that might help if their hypothesis is correct.

I have insufficient knowledge to judge whether this hypothesis could be helpful. I wonder what our resident experts think - @Jonathan Edwards, @Simon M, @JaimeS ... ?
Click to expand...

My first impression:

Like a lot of papers that zoom out like this, I think that they have a great deal valuable to say, but that their final conclusions may be a little hasty.

There's a book along similar lines that I highly recommend called The Stress Response of Critical Illness. It was mind-bendingly intriguing, and a lot of what you see touched on in this paper is further explicated there.

[Edit: uhhhhh NO. Inspirabot is about right. I read it thoroughly and it's pretty crap. Sorry guys.]
 
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Jonathan Edwards said:
Mm...

Seems a bit like inspirobot. Select sexy words at random, connect at random, hypothesis ready.
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Unfortunately, you're probably right.
Despite the fact that they obviously have reviewed much of the important literature, they have some trouble connecting the dots..
E.g., this paragraph appears to be self-contradictory and not much better than some psychobabble we all have seen before..:

Overall, it appears that metabolic disease components show significant correlations with the
fatigue in ME/CFS patients and not with the disease itself. For example, blood pressure, as well as insulin resistance, are probably secondary to fatigue, and most probably reflect the lack of physical activity and prolonged lack of muscle use in ME/CFS patients. This makes sense if one considers that low blood pressure could give rise to fatigue through brain/or muscle hypoperfusion (Newton, et al., 2009), and that insulin sensitivity is highly dependent on the oxidative capacity of the muscle (Canto and Auwerx, 2009).
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I think ME is a disease which will likely be solved by people who dedicate all or most of their time to it, and not by the ones looking at it as a side gig. Theoharides is certainly a very smart guy and I'm glad that he's looking into ME, but I also think this paper reflects the lack of attention to details and nuance. He has a lot on his plate and is printing articles like it's going out of style, so maybe that's why..
 
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