Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients 2023, Glass, Hanson et al

[Sly Saint]

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM.

The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET). Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds.

Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline).

Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.

https://www.mdpi.com/1422-0067/24/4/3685

 

[Mij]

These results may have potential applications as biomarkers.

 

[Kalliope]

tweet from Dr. Maureen Hanson about the study:

 

[Joan Crawford]

This looks really interesting. I hope that they can repeat this in a bigger group of patients and other researchers can do this independently too.

The lack of ability to adapt to an exercise stressor and recovery is such a major symptom so being able to objectively demonstrate an inability to achieve a basic bodily response to activity and exercise could be an important find if it can be replicated.

 

[RedFox]

Fascinating and very unexpected. Levels of many chemicals in healthy controls rose after exercise, but stayed flat in pwME. We often view PEM as an aberrant change in our bodies. But this study hints that in PEM, certain changes that should be happening are not.

 

[Jonathan Edwards]

Is it possible that the changes in controls are due to activities that are normally associated with a pleasurable sense of having done a nice bike ride whereas these do not occur in PWME who are just trying not to feel too awful?

Maybe eating a big dinner?
Having a good long sleep?

 

[Andy]

Is it possible that the changes in controls are due to activities that are normally associated with a pleasurable sense of having done a nice bike ride whereas these do not occur in PWME who are just trying not to feel too awful?

Maybe eating a big dinner?
Having a good long sleep?

Is that likely as the controls were also sedentary, and that the test was "until volitional exhaustion", so the experience was hardly 'a nice bike ride'?

 

[Kitty]

This looks really interesting. I hope that they can repeat this in a bigger group of patients and other researchers can do this independently too.

It is interesting, isn't it? As well as repeating the study with a larger cohort, it would also be good to look at whether full-blown maximal CPET is necessary to reproduce the effect, or whether it can be demonstrated with something safer for PWME.

Is it possible that the changes in controls are due to activities that are normally associated with a pleasurable sense of having done a nice bike ride whereas these do not occur in PWME who are just trying not to feel too awful?

Maybe eating a big dinner?
Having a good long sleep?

Perhaps, but a within-the-bounds-of-normal response is also possible for some people with ME in the first 24 hours. I doubt I'd behave markedly differently to sedentary controls in that period, but on Day Two there probably would be differences, and Day Three I might feel even worse. Obviously I don't know anything about the participants, but if they could do a maximal CPET, they must have been in one of the milder categories (I suspect not many ME patients could even achieve VO2 max, me included).

 

[SNT Gatchaman]

Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.

Haven't yet read paper, but that sounds a lot like —

Under maximum stress, ME/CFS patients are unable to facilitate transcriptomic changes in the cells of their immune system that would allow them to permit recovery. Meanwhile, in response to stress, HCs make several transcriptomic changes related to the integrity and function of their immune cells.

https://www.s4me.info/threads/stres...immune-signatures-2023-van-booven-et-al.31751

 

[Jonathan Edwards]

The findings may be the beginning of something important but I think we should not lose sight of just how different it would be for a patient to go through a research procedure from a healthy control. When I started out on the wards I did a project looking at cortisol levels and they went up high when patients were admitted to the ward. I doubt they would have done for healthy subjects.

This is not an issue of 'psychological overlay'. It is just that the whole scene for a patient making an effort to contribute to a project relevant to there illness is going to be quite different from some odd member of staff or friend of a friend who has agreed to be a normal guinea pig.

Slight shifts in what is in one's mind can change eating, drinking and sleeping patterns. Patients might be better prepared physiologically from having raised their cortisol a bit beforehand - and so on.

 

[Trish]

Would the different psychological effect for patients and controls of taking part in a research study lead to a lack of the metabolites in urine that are present in healthy controls?

I can see that stress related hormone levels might be different, but I don't get the impression that these metabolites are psychological stress related.

 

[bobbler]

The findings may be the beginning of something important but I think we should not lose sight of just how different it would be for a patient to go through a research procedure from a healthy control. When I started out on the wards I did a project looking at cortisol levels and they went up high when patients were admitted to the ward. I doubt they would have done for healthy subjects.

This is not an issue of 'psychological overlay'. It is just that the whole scene for a patient making an effort to contribute to a project relevant to there illness is going to be quite different from some odd member of staff or friend of a friend who has agreed to be a normal guinea pig.

Slight shifts in what is in one's mind can change eating, drinking and sleeping patterns. Patients might be better prepared physiologically from having raised their cortisol a bit beforehand - and so on.

Completely agree.

It is a biggie for PEM/exertion to be mapped better in order that at least with any ME/CFS research it becomes the norm in the method and results section for the 'stage of exertion/PEM' to be a reporting variable. There might even be issues like OI-related and light/noise meaning someone is equivalently to a healthy control in a 'mid-marathon' exertion situation when these tests take place (and that is excluding travel and anything happening around it).

For healthy controls if you had people doing a marathon 2hrs before hand and were strobe lighting them with heavy-metal music whilst you did a test then you'd surely find it 'notable' and report that in the method and assume it could impact results when comparing similar tests done to other healthy controls who had spent the last 2 days in a health spa with their feet up. It would then be interesting to see whether there were differences between those scenarios at least.

Findings that might still be interesting need to be defined carefully as such because otherwise there will be replicability issues but also what exactly is being described. How someone with moderate ME/CFS is health-wise when they are well-rested and pottering vs having done a full time week of long hours at work as it was 'peak time' are utterly different things and there are shorter-term factors too.

Then add in the weird reversals and envelopes each PwME has and how it affects 'how they are'/stress (by which I mean physiological) on the body at that time and how exerted they are - which might relate approx to severity but be more individual than that.

It doesn't seem impossible with things that are more cyclical and systemic for more longitudinal measures and methods to be sought to be understood in this context, other than that the 'crude' snapshot stuff that perhaps people are having to do in order to get funding for the more expensive next stages are in themselves open to misleading the literature by not having the info done on all this for them to be contextualised appropriately etc.

 

[Hoopoe]

There are some neurological diseases that result from an inability to properly repair damage to the muscle due to a defect in some extracellular matrix protein. It makes me wonder if there is a kind of ME/CFS where something similar occurs, but maybe not specifically in the muscle.

Having read a bit on the topic of muscle repair after exercise, the immune system (neutrophils) and growth factors play an important role in the more delayed repair responses to exercise, which appear with a delay of about two days and can last days or weeks. Sounds familiar, right?

Maybe our problem is more in the immune responses and growth factors. Judging from the data presented here it seems that nothing much is happening. Some signal is dead.

 

[voner]

@Jonathan Edwards, what do you think of this comment from the researchers?

Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.

here is the portion of the paper that describes the Cardiopulmonary Exercise Testing:

///////
4.2. Cardiopulmonary Exercise Testing and Urine Sample Collection

The CPET was performed on a stationary cycle ergometer, with the following proto- col: 3 min of rest followed by continuous cycling in which the incremental workload in- creases 15 watts per minute of exercise until volitional exhaustion (approx. 8–10 min). The respiratory exchange ratio (RER), which is the rate of carbon dioxide production divided by the rate of oxygen consumption, was measured to ensure that participants were per- forming the test with sufficient effort (RER > 1.1 indicates maximal effort).

All urine samples were collected in the morning: (1) 15–20 min prior to the CPET and (2) 24 h later. Urine was collected mid-stream in sterile urine collectors, aliquoted, centri- fuged at 10,000 g for 10 min to remove cell debris, and stored at −80 °C. Urine samples underwent one freeze/thaw cycle for further aliquoting and the aliquots were shipped overnight to Metabolon® on dry ice.
///////

 

[Jonathan Edwards]

@Jonathan Edwards, what do you think of this comment from the researchers?

It is a puzzling finding but without knowing how the levels found normally relate to exertion or other 'stress' it is hard to know what to make of it.

Hanson is an intelligent investigator and I think this is a useful comment. Unexpected findings are often the most important.

 

[Arnie Pye]

Would a potential biomarker have to "work" for males as well as females before it would be considered as a reliable biomarker? Does science/medicine allow for biomarkers for disease that only apply to one gender?

 

[SNT Gatchaman]

On potential links to endothelial dysfunction —

Four compounds in the urea cycle; arginine and proline metabolism subpathway are changing differently after exercise in the ME/CFS patients and controls: carboxy-methylarginine, proline, symmetric dimethylarginine (SDMA), and dimethylarginine (ADMA). Proline is a building block of collagen and is therefore a key component of connective tissues. SDMA and ADMA are both regulators and competitive inhibitors of nitric oxide (NO) production. NO aids in vascular maintenance in healthy individuals, and decreased NO production is associated with endothelial dysfunction and cardiovascular disease.

ADMA can be removed through urinary excretion or it can be degraded in the liver. The increased excretion of SDMA and ADMA in controls but not in patients after exercise implies that controls may be removing excess NO synthase inhibitors in order to maintain vascular homeostasis and that this beneficial adaptation to exertion may not be occurring in patients. The relationship of NO and ME/CFS is unclear; plasma from ME/CFS subjects at baseline was found to induce less NO production by endothelial cells in vitro, but it is unknown whether or not that was due to higher levels of ADMA or SDMA in ME/CFS plasma, as they were not measured in that study and NO regulation is complex.

ETA: I've posted the referenced paper at Elevated levels of plasma [SDMA] and increased arginase activity as potential indicators of cardiovascular comorbidity in [RA] (2018)

 

[Mithriel]

Australian researchers did a study of metabolites in the urine of people with ME many years ago. Over the years. researchers have kept starting things but there was never money to follow anything up.

 

[Sean]

There are some neurological diseases that result from an inability to properly repair damage to the muscle due to a defect in some extracellular matrix protein.

I have long thought that the ECM is a prime candidate for the answer to our problems.

 

[RedFox]

Would a potential biomarker have to "work" for males as well as females before it would be considered as a reliable biomarker? Does science/medicine allow for biomarkers for disease that only apply to one gender?

As someone who's not a woman, if they invented a biomarker that only worked for women, so be it. Better some people than none. Besides, such a technique could likely be adapted to be gender neutral in time.