Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids: Levine,Hanson et al 2020

Sly Saint

Sly Saint

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Article. PDF
Received: 20 December 2019; Accepted: 12 January 2020; Published: 14 January 2020
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 farreaching 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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https://www.google.com/url?sa=t&rct.../10/1/34/pdf&usg=AOvVaw2V_YUpD2lnE2NHCJAMQr0M
 
where did they get the 65 million figure from for the last decade the only figures I have seen where 17-25 million . considering many countries chose not to acknowledge the disease at all I don't think there will ever be an accurate figure for this
 
There was a disappointingly significant difference in the ages of the controls and the women with ME/CFS:
Screen Shot 2020-01-15 at 7.12.57 PM.png

Median of 43 for the controls and 52 for the ME/CFS group.

It's not surprising then that differences in androgenic steroids were found (with the ME/CFS group having lower levels).

Here's a graph of the normal levels of testosterone steroids in women at various ages:
Screen Shot 2020-01-15 at 7.11.31 PM.png
The levels of these steroids should be lower in an older female cohort. I'm surprised there was no mention of the age difference in the two samples in the discussion of this. I wouldn't be surprised if the age difference affected levels of quite a few of the metabolites.

Edited to add - the study found that progestin was lower in the ME/CFS group. Again predictable from the age difference - men, menopausal women and women at certain times in their menstrual cycle have levels that are one-tenth or even one twentieth of the levels that occur in women at other times during their menstrual cycle. Again - I didn't see any discussion of the effect of the age difference in the study.
 
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Re sphingolipids and ceramides - we've seen these come up quite often, so at first that seemed positive.

This study found increases in both, unlike Naviaux who found lower levels.
this study said:
In a similarly sized cohort, Naviaux and colleagues found ceramides and sphingomyelins to be decreased in the patient cohort, regardless of the gender [16]. This result was not reproduced by Nagy‐Szakal and colleagues, where they did not see a consistent decrease in ceramide levels but reported on decreased levels of longer ceramides in patients without IBS [18]. Our dataset instead shows an increase in ceramide levels for our patient cohort compared to controls. When splitting our patient cohort based on their gut symptoms, ceramide levels for patients without gut symptoms tend to be even further increased for CER (18:0), CER (18:1), and CER (20:0).
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So, looks like we forget about those.

this study said:
suggest that changes in sphingolipids are not directly linked to ME/CFS, but are rather a consequence of the disease and the life style that it inflicts on patients such as disturbed diets, lack of physical activity, and medication regimes.
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The authors of this study comment that they were able to process the samples very quickly, unlike their previous study where samples waited maybe 24 hours. They think the processing time accounts for some differences between studies. So it's great that they were able to process these samples so fast.
 
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I don't want to seem negative - I rate the Hanson team highly. They don't hype their results and seem to be working systematically to improve ME/CFS research.

Hopefully there is something in the acyl choline finding:
Most noteworthy is the presence of several lipids belonging to the sub‐pathway of fatty acid metabolism (acyl cholines). Indeed, the means of oleoylcholine, dihomo‐linoleoyl‐choline, linoleoylcholine, stearoylcholine, and palmitoylcholine were more than twice as low in patients compared to controls.

Additionally, Figure 1 shows that the data distribution of all of the seven metabolites belonging to this sub‐pathway is lower in the patient cohort compared to the controls. In fact, it is the same few subjects in the patient cohort that are over the median value of the control cohort. The data imputation is comparable between each cohort and this trend remains the same when missing datapoints are ignored instead of being imputed with the minimum value strategy
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Screen Shot 2020-01-15 at 8.08.41 PM.png
 
I wonder whether it is possible that many metabolites have a temporal aspect which is not taken into consideration. So there may be metabolites that :

-Increase / decrease at specific times of the day
-Increase / decrease momentarily (e.g for 1 hour)

If any of the above takes place then this would be a problem for replication of results. I do not know if the above make sense so it's just a thought.
 
Hutan said:
I don't want to seem negative
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The paper is a bit difficult to comprehend (might have to read it again), but I also got the impression that the study showed mostly null results. The authors write:
One striking observation is that no broad difference is observed when comparing the control cohort to the patient cohort. This is, by itself, a result worth noting that we will discuss later. [...] We are reporting on the largest number of metabolites in the ME/CFS field to date, about 1750 plasma compounds, encompassing 20 super‐pathways and 113 sub‐pathways. However, we have not unequivocally identified a plasma biomarker or set of biomarkers with abundances drastically different between controls and ME/CFS patients, despite the fact that our clinical data indicates our patient cohort had a substantial level of disability
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mariovitali said:
I wonder whether it is possible that many metabolites have a temporal aspect which is not taken into consideration. So there may be metabolites that :

-Increase / decrease at specific times of the day
-Increase / decrease momentarily (e.g for 1 hour)

If any of the above takes place then this would be a problem for replication of results. I do not know if the above make sense so it's just a thought.
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I wonder this too, aside from individuel differences there might be differences due to areas, seasons, and daytime. It could also point simply to an exaggeration.

My personal impression is that it is pretty unlikely that the findings in metabolism and the immune system give a direct cause. They might reflect a disturbed homeostasis, or are downstream effects.


Michiel Tack said:
The paper is a bit difficult to comprehend (might have to read it again), but I also got the impression that the study showed mostly null results. The authors write:
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I would say, an interesting result, that in itself doesn´t tell much, instead is asking for interpretations, and technically for more details.

They say as well:
Nevertheless, the metabolites ... should be considered in light of the metabolic impact even modest changes can have along with the complexitiy of sources ...
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... the changes observed might result from a disturbance occuring in another part of the body ...
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(from the conclusions)


The main tendencies - if I am allowed to put like so - are:
  • decreased Acyl Cholines (which are still obscure although providing already a variety of links to ME symptoms)
  • decreased Dipedtides (which are not well understood)
  • increased Sphingolipids (at odds with Naviaux [who found them decreased in ME, though increased in GWS], and with Nagy-Szakal et al [who found only some of them decreased in ME without IBS].)
  • decreased Steroids, three classes of them (referring to de Vega et al with guessing hypersensitivity and reduced HPA-axis, which is not fully understood).
 
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@Hutan

Thank you for the analysis you provided. I was not able to read very closely the paper but i wanted to ask regarding the following reference to cholate (=cholic acid) on page 5:


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 absorption because of its detergent properties [23].
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which was not found elsewhere in the text. Why this is so?
 
Yes, interesting point @mariovitali.
There is Figure 3 later in the document.
Extending the quote you gave a bit further - the authors note that all of the other metabolites in the same pathway were also considerably lower.
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 absorption because of its detergent properties [23]. All the other metabolites classified in that sub‐pathway were also lower in the patient cohort compared to the control cohort at a 1.3 to 1.6‐fold (Table S2).
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You can see the dot for the 'Primary Bile Acid Metabolism' pathway with 9 metabolites. So, it looks like something to keep an eye on.

Screen Shot 2020-01-18 at 12.37.24 PM.png
 
Checking that the mean age difference between the control and ME/CFS sample might explain the bile acid differences, specifically cholic acid, I thought this 2016 paper was an interesting read.
Age-Related Changes of Plasma Bile Acid Concentrations in Healthy Adults—Results from the Cross-Sectional KarMeN Study

They did find differences in bile acid concentrations in plasma with age and with sex, but those differences probably don't explain the differences found in the ME/CFS study. Concentrations didn't vary between pre- and post-menopausal women and, if anything, concentrations slightly increased with age in women.

It looks as though there is a lot of variability in levels between individuals though and diet does affect levels. I didn't find any mention of the ME/CFS study requiring participants to fast, so the differences found perhaps can be explained by different diets and perhaps time since last eating.

Maybe there should be some standardisation of food intake prior to blood collection in these studies e.g. participants should be required to eat specified meals the day before, and fast before a morning collection.
 
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