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Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles

Kyla

ᴀɴɴɪᴇ ɢꜱᴀᴍᴩᴇʟ
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http://www.nature.com/articles/srep34990

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles

Emi Yamano, Masahiro Sugimoto, Akiyoshi Hirayama, Satoshi Kume, Masanori Yamato, Guanghua Jin, Seiki Tajima, Nobuhito Goda, Kazuhiro Iwai, Sanae Fukuda, Kouzi Yamaguti, Hirohiko Kuratsune,Tomoyoshi Soga, Yasuyoshi Watanabe & Yosky Kataoka
  • Scientific Reports 6, Article number: 34990 (2016)
  • doi:10.1038/srep34990
  • Download Citation
Abstract
Chronic fatigue syndrome (CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, lasting at least 6 consecutive months. Its pathogenesis remains incompletely understood. Here, we performed comprehensive metabolomic analyses of 133 plasma samples obtained from CFS patients and healthy controls to establish an objective diagnosis of CFS. CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid (TCA) and urea cycles. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 (95% confidential interval [CI]: 0.711–0.890, P < 0.0001) and 0.750 (95% CI: 0.584–0.916, P = 0.0069) for training (n = 93) and validation (n = 40) datasets, respectively. These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma.
 

Kyla

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Unfortunately uses Fukuda criteria, but it will be interesting to see how this matches up with Navieux , Hansen, other metabolomics research
 

Kyla

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How many people were in the study? A bit too foggy to find it myself. Thanks for posting.
upload_2016-10-11_14-34-46.png
 
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In summary, our study has demonstrated a profile of abnormal energy metabolism resulting from deficiencies in aconitase activity in the TCA cycle and dysregulation in the urea cycle in CFS patients. Two ratios, pyruvate/isocitrate and ornithine/citrulline, the changes of which may reflect inactivity of the two above-mentioned cycles in CFS, could be useful index markers to discriminate CFS patients from healthy controls. Although a further large-scale investigation is needed, the metabolite index markers identified in this study provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of small molecules in plasma.

Do we have any experts who can interpret this ?
 
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Wow, another metabolomic study showing decreased ATP production, ie energy production. Looks promising.

Interesting that they suggest personalized diet or supplements might help.

And suggestions of biomarkers.

My biochemistry knowledge is not sufficient to tell whether it directly confirms Naviaux findings. Any experts here?
 
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RogerBlack

Senior Member
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902
It would be interesting to do the above with a set of patients meeting Oxford criteria, and simply depressed people.
To actually nail down in really simple words that yes CFS/ME is different from depression and anxiety disorders.
Indeed - this is an ideal 'big data' type project - once you have a list of proteins in patients serum, it should be trivial to take this data, and compare it against other datasets got for different conditions.
 

J.G

Senior Member
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162
Admittedly a total layman in this area, but this observation by the authors caught my eye (from the paper):
"The decreased concentrations of organic acids related to the TCA cycle and energy metabolism in the CFS patients suggested that they have deficiencies in adenosine triphosphate (ATP) production secondary to dysregulation of the flow from pyruvate to citrate via acetyl CoA and abnormalities in the conversion of citrate to isocitrate by aconitase."

So the authors identify two aspects to what appears to be underperforming cellular respiration: Krebs Cycle intermediates are abnormal (1), ATP production is impaired (2). Of course these are two sides of the same coin; the former problem leads to the latter, and since ATP is required to make ATP, feeds back on it. However, analytically separating these opens the door to the idea that organic acid abnormalities are a response to a central ATP production obstacle - and that we should look into it.

More broadly, both observations tie in nicely with Armstrong et al's earlier suggestion that ME/CFS energy metabolism leans heavily on glycolysis alone, i.e. the first step in cellular respiration, for ATP production. It's congruent with Shungu's elevated lactate findings. It also fits with Jamie's hypothesis on lipid rafts cutting short mitochondrial function (if I remember, and understood, it correctly).

If further studies confirm aberrant ME/CFS energy metabolism (which seems increasingly likely), I'm excited to find out how the dots will eventually connect to blood volume/circulation problems and potential autoimmunity. That is, if they connect, and are not subsets.

I'm sure there's lots more to this paper that's striking. I eagerly await the comments of someone with expertise. :D
 
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15,786
It would be interesting to do the above with a set of patients meeting Oxford criteria, and simply depressed people.
To actually nail down in really simple words that yes CFS/ME is different from depression and anxiety disorders.
There's already been hundreds of papers showing that ME/CFS is different from mood disorders. We certainly don't need more money wasted on such studies merely because some people aren't willing to read the existing ones.
 

RogerBlack

Senior Member
Messages
902
Every group that has looked at energy production with a metabolomics approach has found problems. Is this correct or am I being misled by false hope?

Not quite.
There was a recent study n=20, looking at some immune cell I've forgotten that found exactly nothing.
https://www.ncbi.nlm.nih.gov/pubmed/27713703
Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study.

Participant ratings of fatigue and other symptoms, as well as blood samples, were obtained at baseline, and five other time-points up to 72 h after 25 min of moderate-intensity cycling exercise. Leucocyte mRNA of 19 metabolite-sensing, adrenergic, immune, and neurotransmission genes was examined using quantitative polymerase chain reaction. Patients with CFS reported substantial fatigue, functional impairment, and poor sleep at baseline (all p < 0.02), and exercise immediately induced worsened patients' fatigue (effect size, ES = 1.17). There were no significant changes in gene expression after exercise and patients did not differ from control participants at any time point. Higher levels of expression of ficolin (FCN1) and a purinergic receptor (P2RX4) in patients with CFS were found when all time points were combined. Patients with CFS did not show significant exercise-induced changes in leucocyte mRNA of 19 metabolite-sensing, adrenergic, immune and neurotransmission genes despite a prominent exacerbation of fatigue.

Hmm - this is a gene expression study, not proteomics. I would be really interested to know what the proteome looked like in these cells at this time.
Perhaps they picked a cell population that is not particularly affected by PEM.

Or perhaps their patient population was poorly chosen.
The patients did report PEM.
 
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Navid

Senior Member
Messages
564
Does this paper allow any of you brainy science ppl to draw any conclusions as to what supplements may be useful in overcoming the deficiencies found in the study. I know grasping at straws again, but that's where life has lead me these days. Thanks to anyone who might have some ideas.

:vomit:
 

FMMM1

Senior Member
Messages
513
Does this paper allow any of you brainy science ppl to draw any conclusions as to what supplements may be useful in overcoming the deficiencies found in the study. I know grasping at straws again, but that's where life has lead me these days. Thanks to anyone who might have some ideas.

:vomit:
Not a brainy science person but listen in to Armstrong's webinar (is that the word) it's available now, he deals with issue of supplements late on in the talk. First things first, you need to know that you have the biochemical abnormality (crebbs cycle - glycolysis - whatever it's called).
Interestingly Armstrong used NMR for his recent work I.e a different technique from the other studies which used Mass Spectrometry. He reckons that his work, Naviau's recent paper, mitochondria proteomics paper from folks in Pisa and this paper are all on the same page. This may be complex but at least there is agreement re problem. Interestingly Armstrong looks at links to sepsis.
Re focus on patient selection criteria; we seem to be looking at a diagnostic blood test and leaving the collection of symptoms behind - good in my view.
We need to get to try to get these blood based diagnostic tests delivered.