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

My bold:

I just hope that somebody at least tries to replicate it. Not infrequently these pilot studies seem to turn up interesting results that nobody even tries to replicate, for whatever reasons.

I’ve not read the paper and I’m completely out of my depth so I apologise if this question doesn’t make sense but, if the results prove to be reliable, is it possible that the problem is with the excretion of the metabolites, rather than their production?

Another thing I’m wondering is whether there might be any value in doing a similar type of metabolomic analysis following alcohol consumption? Although it’s not a requirement for diagnosis, my understanding is that alcohol intolerance is a very common symptom in ME/CFS and that this is very unusually in other chronic illnesses. It has always felt to me like it must be a clue, and yet it doesn’t seem to be something that many researchers have taken much interest in investigating.

When I first became unwell in 1992, one of the ways I described my symptoms (as a 19 year old who knew nothing about ME/CFS and had never heard of PEM) was that it felt like I couldn’t get rid of the waste products that were being generated through aerobic activity. And it was the same feeling on the rare occasions that I felt well enough to try drinking alcohol.

 

It looks very interesting.

I don't know enough about the measures they are looking at vs how long it would take for things to show in urine, but am intrigued by the method going for 'before' and '24hr after'.

Does that mean that they can tell (by these timings) whether these increases in healthy controls would have only occured after?

and that the PwME figure is actually 'no change' and not just that some of these things might have been depleted at some point yet only restores to where it was etc, even theoretically switching on early in the 'during' just to get through etc? Or that it is a matter of 'timing difference' etc. Although admittedly the graph post-exercise for ME/CFS does look dramatically flat and uneventful, I can't currently try and get my head around what is in those graphs re: calculations of 'differences' etc. but can see log function has been used (which would make 'much smaller change' look 'flat' ?)

There is always the potential that whilst CPET is a maximal stressor for HCs from what wasn't probably a situation where they were maximally stressed before, that situation/change isn't the case for anyone with ME/CFS whose task of just turning up on time to that first urine sample (if taken not at home several days prior) could mean they were say 90% there already at some point prior to what is deemed 'baseline'.

I'd be intrigued if there was potential to compare HC 'post-exercise' with ME/CFS 'baseline' perhaps for that reason even though it would be imperfect of course (timing of when it 'hits' and what people have been doing before etc). My point is that this could be showing - if I'm reading right that the graphs are plotting change rather than absolutes - potentially more the 'envelope situation', or being beyond that more constantly (like a vehicle with a tiny engine having to drive at its max on the side roads before it even gets to the motorway) over the entire period vs the 'hit' applied to HCs of turn up for a CPET.

It is still interesting though and I can see the likelihood that the answers to these questions makes 'averaging' PwME graphs as a result less useful - ie 24hrs sort of makes sense, then individual differences potentially across those with ME could happen more? And the issue with urine being that timings and aspects which are individual start layering on each other too.

I guess with urine using '24hr urine' ie all urine output over the 24hrs collected into one, (or different time chunks) could provide some 'pros' in answering some questions too (checking nothing happened in that xhrs period) vice versa.

I don't know whether there is equivalent research studying these measures in 'healthy controls' (noting they are sedentary too, and their BMI median being 33.3 vs 24 for ME/CFS group) or any other health conditions.

 

I find the alcohol one fascinating too - you almost feel there might be some paper-based clues from it too. The thing is .. I initially jumped to the 'being a lightweight' type issue too (tho that always seemed to point to something for me, as it has happened with v small amounts of certain 'normal' alcohol types and the drunkness was v fast so wondered if that was a metabolism/pathway-related remark based on that) - then realised that runs into all sorts of arguments and issues based on other things that relate to tolerance like ...building one up by drinking, would you be able to get controls who were similar on all of these who would be prepared to drink for the test too?

 

I look forward to hearing Maureen Hanson's comments about this study and hear which of these findings she thinks are significant. As @Hutan stated, the paper is clearly written.

 

I'd like to know if similar findings also happen in similarly related conditions.

 

What kind of problem could be causing such drastic changes in a wide range of metabolites?

Is there a body wide "rest, repair and recover" signal that is broken in ME/CFS?

It seems to make sense that people so affected would have to rest a lot because they are gaining much less recovery from it.

I know about growth hormone and its role in recovering from exertion. What else is there?

 

I get the impression that this is a major problem in ME/CFS research. The number of un-validated studies must be running into the hundreds if not thousands by now. Many researchers are not interested in other researchers work as it's not their speciality or they don't have the same equipment which is fair enough but I can't help getting the impression that the main reason is that it's not "their" baby. Why bother validating somebody else's work, what's in it for "me", proving somebody else right?

We need an overall authority in charge of ME/CFS research with a wider view of what is needed deciding which studies need replicating, which new avenues of research need looking into and offering funding to researchers to carry out these studies. Now we have the opposite, researchers carrying out the research that they want to not what is needed.

 

@Jonathan Edwards Is this something that’s been discussed in the DHSC research group that Javid initiated?

Is there a thread on that group anywhere or are discussions confidential at this stage? Sorry, I’ve been out of the loop for a while and have lost track of developments.

 

Good to see that this is considered in the paper as you quote above.

Is it possible that excretion of metabolites could be affected by endothelial dysfunction?

 

@John Mac Amen

 

Mauren Hanson on Twitter, "The lead author of our recent urine metabolomics paper, Dr. Katie Glass, has provided a brief video abstract."

https://www.youtube.com/watch?v=UTD4GSiDClo

The volume seems to be very quiet on the video.

 

in this 2023 paper, the authors state that this group of patients were in the same subject group on their previous metabolomics paper in March 2022. Here’s the quote from the current paper. That paper had similar BMI for controls and subjects.

Our group previously published plasma metabolomics data from these same subjects [25]. These subjects underwent the complete two-day CPET protocol and along with urine collection, blood was drawn from each subject at four time points: baseline (P1), 15–30 min after the CPET (P2), 24 h after the CPET (P3), and 15–30 min after the second CPET (P4) which was performed 24 h after the first CPET (Figure 1A in [25]).

this previous paper is discussed here:

https://www.s4me.info/threads/plasm...ud-germain-maureen-r-hanson-et-al-2022.25196/

and the title and abstract:

Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/ chronic fatigue syndrome, Germain, et al, March 31, 2022.


Post-exertional malaise (PEM) is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We monitored the evolution of 1157 plasma metabolites in 60 ME/ CFS (45 female, 15 male) and 45 matched healthy control participants (30 female, 15 male) before and after 2 maximal cardiopulmonary exercise test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four time points allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of participants with ME/ CFS compared with the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.


here is a quote from the March 2022 paper about the symptom levels of the patients:

Nevertheless, the selected ME/CFS population was capable of traveling to the testing sites and performing 2 CPETs and would therefore be considered to have less severe symptoms compared with patients who are bedbound. However, the scores on the Bell scale and 36-Item Short-Form Health Survey (SF-36) indicate that very few patients could be considered to have mild disease.

 

I remember the very valid point made by @Jonathan Edwards that a big 'link in the chain' that is missing for ME/CFS is proper medical clinics and suspect this is a major hurdle.

Recruitment of those who are definitively with ME/CFS but the right level of illness for a particular study and able to participate due to location must be made all the harder vs this being one 'source' for most/many (?) other conditions - and indeed all the trust issues (including 'will it affect my health' given how precarious the situation for most with ME/CFS is, with little responsibility currently taken by anyone for 'remedying if they put them through treatment that harmed them' etc).

From a research point of view it is where people get their feet wet and become interested in other theories - we are missing the 'hands on' vs desk-based only experience being prevalent to create some oomph etc?

 

Actually we do have this in the UK. It is the MRC. To be fair they did just this. Eleanor Riley was charged with asking experts what research was considered worth pursuing and what new avenues were worth looking in to. They identified a genome-wide study and offered funding.

The chief reason why researchers do not replicate ME studies is that they don't think there is a strong likelihood of anything coming out of it with a significant impact. There are some preliminary metabolic findings that are probably worth checking but in general in research the team putting out such preliminary data is expected to take it far enough to look reasonably convincing before others invest time in replicating.

The one thing that has been identified by the DHSC group where there is a general agreement that further studies would be welcome is in re-purposing of drugs. So far the only clear candidate is naltrexone but it could be used as a test model for methodology that could be rolled out for other drugs.

 

Hanson is the MVP in ME/CFS research, imo. Her work is very well structured and concise, very consistently so, in everything she does. It is actually fun to read most of her papers. We can be really glad to have her in our corner.