Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids (Germain, Levine, Hanson, 2020)

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Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

by Arnaud Germain 1, Dinesh K. Barupal 2, Susan M. Levine 2 and Maureen R. Hanson 2,*

Metabolites 2020, 10(1), 34; https://doi.org/10.3390/metabo10010034

Received: 20 December 2019 / Revised: 9 January 2020 / Accepted: 12 January 2020 / Published: 14 January 2020

https://www.mdpi.com/2218-1989/10/1/34

Abstract

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways.

Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts.

We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.
 
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Two big findings in here, both of them interesting ones that open up research avenues but will be slow to lead to treatment.

1. Low acyl-cholines. Patients are in blue in these graphs, and lower than controls on all these acyl cholines.

Screen Shot 2020-01-16 at 4.04.13 pm.png


Unfortunately we don't know much about acyl cholines!! They seem to have somethig to do with blood pressure. Maybe. We need some basic research to figure out why they might be screwy and what it means.

Important Finding 2 is that ceramides and sphingolipids are increased. Those with long memories may recall Naviaux raising problems with those same two compounds. I have bad news though. Naviaux found they were decreased! This is a humbling result.

Perhaps metabolomics is bad at tracking ceramides and sphingolipids, perhaps they vary over time, or some othr explanation. This serves as a reminder of the importance of replication, and reminds us just how much more research needs to be done for us to get anywhere.
 
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Unfortunately we don't know much about acyl cholines!! They seem to have something to do with blood pressure
Yes and the abnormalities might explain POTS and similar symptoms. It's a very interesting paper @Murph with a lot for us to consider. As an overview of it I'd say it is the final nail in the coffin for those who STILL believe ME/CFS is a Psychological disorder. Also as the abnormalities identified can be shown to cause most, if not all, of the ME/CFS symptoms then it follows that reversing those abnormalities should lead to a cure. When it comes to treatment the paper mentions the possibility that the abnormalities in 3 types of steroid might be what is causing symptoms. Cant say I agree with that, but there have been cases in which treatment with steroids has been of benefit.
 

percyval577

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It's a very interesting paper
...
Also as the abnormalities identified can be shown to cause most, if not all, of the ME/CFS symptoms then it follows that reversing those abnormalities should lead to a cure.
I completely agree.


They found four major tendencies:

Decreased Acyl Cholines - although still obscure - may be linked to blood pressure (and possibly manifestations), and even to leaky gut and altered gut microbiome (via disrupted hydrochloric acid secretion).

Decreased steroid classes may be linked to hypersensitivity and the HAP axis, and related symptoms of it (energy usage, temperature, immune system, digestion, mood, sexualitiy).

Increased Sphingolipids are at odds with Navioaux who found them decreased in ME - but increased in GWS - and with Nagy-Szakal et al who found some of them decreased in ME without IBS (interstingly, the authors found some of them in ME witout gut symptoms likewise opposed). So, a deregulation may take place. They mention that shingolipids are involved in many cell processes (sitting in the cell membrane), and numerous unrelated pathologies are linked to their imbalance.

Decreased Dipeptides seems to be hardest to interpret, they mention aging, muscle recovery and fatique.


The finding still needs quite a lot interpretation: They looked at about 1750 plasma compounds, in 20 super-pathways, and 113 sub-pathways.
However, we have not unequivocally identified a plasma biomarker or a set of biomarkers, despite the fact that our clinical data indicates our patient cohort had a substantial level of disability.
... the metabolites ... should be considered in light of the metabolic impact even modest changes can have along with the complexity of sources ...
... the changes ... might result from a disturbance occuring in another part of the body ...
 

bertiedog

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Cant say I agree with that, but there have been cases in which treatment with steroids has been of benefit.
I have to take both a glucocorticoid and mineralocorticoid due to Congential Adrenal Hyperplasia which I have only recently found out about and since the latter was added I have been feeling better and have slightly better stamina and ability to be upright for longer periods ...but I still have POTS and PEM if I don't lay down horizontally at regular intervals.

My thyroid antibodies are now normal presumably since being gluten and dairy free over the last year, its the first time in 20 years I have had both antibodies in range.

Pam
 
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On page 11 of the paper it says: "A decrease in long- chained acyl cholines could explain disruption in blood pressure regulation, manifested by dizziness, lightheadedness blurred vision and near synocope when assuming and maintaining an upright position." AND "A decrease in long chained acyl cholines could disrupt hydrochloric acid secretions with consequences that could be as far reaching as leaky gut symptoms and altered gut microbiome populations" The rest of that page is worth a look as it points out that" Long chained acyl cholines have antagonistic activity toward acetylcholine"
 

percyval577

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Long chained acyl cholines have antagonistic activity toward acetylcholine"
I missed that interesting point.

Here also the Sphingolipids may fit in, as Acetylcholine is associated with learning in non-typical situations (I think it´s even this paper mentioning a metaplasticiy), and here Sphingolipids are important for new synapses. So this could be pretty concrete (though difficult in all details, I would think).

(I might even mail them and ask if they may gather informations about the seasons in which all the blood samples (Naviax, Naviaux, Nagy-Szakal) have been taken, though also other circumstances may account for the differences.)
 
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Page 13 of the report says "Finally, five out of the six progestin steroids measured were also lower in patients. This category of steroids is primarily linked to the female reproductive system with known consequences when imbalances occur. eg monthly pain women encounter when this system resets, or during menopause" To my mind this is probably why more women get ME/CFS than men, and why some get better during pregnancy. This paper is a goldmine of useful info.
 

Wishful

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As usual, when I see the testing was done on plasma (or blood, or muscle tissue), I wonder if they're just seeing downstream effects of a neurological disorder. However, it could be part of the feedback loop: reduced lipids making it harder for certain brain cells to work properly.

A simple test would be to (somehow) boost the levels of these lipids in a PWME and see if it has an effect. If there's no effect, it's a result, not a cause.
 
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I strongly encourage everyone interested in the metabolic dysfunction theory of ME/CFS to read this paper twice, then check out the supplemental data provided by the authors (attached). The supplemental data in particular contains a treasure trove of "just barely" significant findings that the authors don't explicitly call out.

This is from Table S4 in the supplemental materials - it shows the high level systems that are dysfunctional, with the p-value and Impact Score.

mecfs-metabolites-s4.png


The interesting thing is lining this list up with supplements that ME/CFS sufferers claim help their condition.
  1. Glutathione Metabolism
    1. Selenium, NAC, and SAMe fall under this umbrella.
  2. Pentose Phosphate Pathway
    1. D-Ribose!!
  3. Valine, leucine, and isoleucine biosynthesis
    1. Lots of threads on amino acids, BCAAs, etc potentially helping
    2. Also pairs with Alanine, aspartate, and glutamate metabolism in this regard.
  4. Steroid hormone biosynthesis
    1. Lots of reports about corticosteroids helping short term

Also some highlights after doing some digging on some of the more statistically significant findings:

Finally, 4‐hydroxyglutamate was found to be twice as high in patients compared to controls (Table 2 and Figure S1a). This latter metabolite is part of the glutamate metabolism, which has substantial implications in brain function [25].
https://en.wikipedia.org/wiki/4-hydroxyglutamate_transaminase
This pathway results in L-Glutamate being metabolized into Arginine and Proline, which Naviaux in 2016 found increased serum Arginine with normal serum L-Glutamate. ME/CFS patients may be over-producing Arginine and Proline for some reason, maybe due to higher metabolic demands on Proline in particular. Proline is used as an energy source in times of metabolic stress or when other nutrients are in short supply (https://cancerres.aacrjournals.org/content/67/9_Supplement/4501). An increased demand for Proline happens when any of the following happen: 1) Glucose is in short supply, 2) mTOR is downregulated, and/or 3) the cell runs out of certain amino acids. This finding seems to reinforce the idea that ME/CFS is a metabolic disorder.

The Supplemental Materials show that tryptophan metabolism is slightly impaired compared to controls. Indolelactate is a metabolite expressed primarily in human gut bacteria that was moderately reduced compared to controls. Lactobacillus and Clostridium express this enzyme. This is yet another point that ME/CFS gut bacteria are disturbed, and give some guidance as to which species in particular are messed up.
 

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pattismith

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. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort.
.
I am currently menopausal, and started to suffer hot flashes and nocturnal sweating a few months ago.
It's a long time since my progesterone decreased, but I still had some estrogen until recently. When it went low, the hot flashes appeared...
So after one year without any mense I started Tibolone three weeks ago, a drug that has some progesterone + estrogen + androgen activity, depending of tissu metabolism. His effect on muscle and brain sounded interesting to me.
This drug quickly made the difference for me, pain has mostly resolved, brain fog and headache are gone, mood is much better, energy is back. It's hard to believe that such a miracle is going to last, but I wish it will!
 
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It's a long time since my progesterone decreased, but I still had some estrogen until recently. When it went low, the hot flashes appeared...
I used progesterone cream (half the daily recommended dose)..for about...12-15 years...it reduced hot flashes and night sweats to rarely. so I started around age 53. That cream also stopped the pre-menopausal heavy periods i was starting to get...that were yucky... (not what I was used to dealing with)...thats when i started...

funny- the hot flash happens the moment I would lie down.

I stopped...finally- (why am I still doing this I was wondering)...hot flashes extremely rare now.
 

pattismith

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I used progesterone cream (half the daily recommended dose)..for about...12-15 years...it reduced hot flashes and night sweats to rarely. so I started around age 53. That cream also stopped the pre-menopausal heavy periods i was starting to get...that were yucky... (not what I was used to dealing with)...thats when i started...

funny- the hot flash happens the moment I would lie down.

I stopped...finally- (why am I still doing this I was wondering)...hot flashes extremely rare now.
I think I am lacking progesterone for decades, but had no hot flashes before my estrogen completely dropped.
The strange thing is that I never improved with DHEA nor with progesterone cream. I was also given some oral progestagen and couldn't tolerate it!
Tibolone is the first drug that ever helps me since I struggle with my female hormons as a teen. Note that it's only three weeks since I started, so I am still suspicious whether it will keep working.
Last 7 days, I was able to travel 48 hours and visit a foreign town, push my husband wheelchair and help him walking, and back to work on Monday I was able to cope with a new software at work, working up to ten hours a day….And got no payback, no PEM from all that. I'm still waiting for a bad backlash and can't see it happening.
I though I would need cortisone to cope with this difficult week, but I took none.:woot:
 
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The interesting thing is lining this list up with supplements that ME/CFS sufferers claim help their condition
Yes it's an interesting finding, particularly that of BCAA disturbance.
Keep in mind it was only female patients included in the study. Seems like all the metabolomics papers so far that has included both sexes have found slightly different changes.
In view of the findings of abnormalities in female hormones perhaps future research will separate the sexes as it is at least probable that some aspects of the illness are influenced by gender.
Tibolone is the first drug that ever helps me since I struggle with my female hormons as a teen
Last 7 days, I was able to travel 48 hours and visit a foreign town, push my husband wheelchair and help him walking, and back to work on Monday I was able to cope with a new software at work, working up to ten hours a day….And got no payback, no PEM from all that
Sounds very positive . Have you considered starting a thread about your improvement?
 
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On page 5 of the paper it says "The other lipid reduced by over three-fold in the patient cohort is Cholate, a major primary bile acid produced in the liver and known to facilitate fat absorbtion...." This substance is used in medicine in the form of Sodium Cholate for bile acid disorders. Wondering if anyone here has ever taken it.
 

SlamDancin

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On page 5 of the paper it says "The other lipid reduced by over three-fold in the patient cohort is Cholate, a major primary bile acid produced in the liver and known to facilitate fat absorbtion...." This substance is used in medicine in the form of Sodium Cholate for bile acid disorders. Wondering if anyone here has ever taken it.
@mariovitali