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

Intriguing study.

[My bold] So they want to expand their pilot study but don't currently have the funding to do it? Or am I misreading between the lines? Someone, anyone, please give this team a big pot of money!

There's one thing that's tying my brain into knots with studies like this one which point towards a failure of ME cells to mount an appropriate response to exertion. Why don't these studies show any difference at rest/baseline? We're most categorically ill all of the time, albeit more severely with PEM - so surely something must be measurably different already at baseline. Why does this not show up in the metobolomics?

Other studies have led to hypotheses that ME cells are stuck in a cell danger response or that they're exhausted (immune cells) or that they're running at full capacity and with all compensatory mechanisms switched on already at rest, or all of the above, and that the cells therefore are unable to respond to further demand. Which would fit the findings here that ME cells simply do nothing in response to exercise. But I would expect all of the hypotheses to impact metabolism at baseline as well as after exertion. So why do our baseline metabolomes look so seemingly normal? What are we missing? Something the tests aren't measuring? Yet they do throw up all manner of unidentified compounds. Or are the sort of pwME who participate in CPET studies so mild they're actually as well as the general population between episodes of PEM? That sounds unlikely to me.

On a different note, I find the sheer number of unknown compounds detected in these metabolomic studies staggering. There is so much still to be discovered about our basic biochemistry. Not sure if I find this more encouraging or more discouraging.

 

How much do charities pay towards research? Can patients laise with charities to request the kind of studies we would like more funding to go towards?

 

A failure to excrete toxic metabolic byproducts generated during exertion would fit with the poisoned feeling that many patients can relate to.

The assay used in this study doesn't detect small molecules. So there could be an accumulation that's not visible in the analysis.

(it's also showing what is being excreted, not what is potentially accumulating)

 

So which organs are responsible to excrete toxic metabolic products (ie detoxification?)? That's right, the main organ is the Liver.

 

The liver being the hub of metabolism in the body does seem interesting in this context of a lack of response to exercise in many metabolic pathways.

 

Ultimately we have to know what has been working and what not. In an email sent to Professor Hanson on April 24th 2018 , I explained to her about the possibility that what we are dealing with is some kind of liver dysfunction, along with proposed mechanisms in a document that discussed detoxification, urea cycle , bile acid metabolism etc etc . Professor Hanson did in fact replied saying that "this information is quite interesting" and asked me what where the input data used in order to support the findings of the AI framework (which of course makes sense).

Here is my answer to her :



I will also post this on Twitter, the next things we should be looking at are the role of flavoproteins and sulfation and of course detoxification. I sure hope this does not take another 5 years to find.

 

The other organ that seems like it could be relevant here would be the kidneys.

 

While I agree that particular end organs might be of greater importance than others in ME/CFS, I think we should think more in terms of specific organelles in specific cell types, rather than whole organs.

All (?) significant irregularities found in various metabollc studies can potentially be understood as mitochondrial and/or perixosomal dysfunction.

 

Of course. I do this with my donations to OMF and they acknowledge my requests.

 

True, however we now have Prusty (a virologist) and Karl Morten suggesting "there may be something going on with the liver".

In the last papers of Hanson there are mentions on Liver disease and liver function.

Yes, it could be the kidneys but the major metabolic organ is the Liver. That is a fact. We fall into the trap believing that normal liver enzymes mean that there is no problem with the Liver. This is wrong.

 

Acyl glycine fatty acid metabolites were the only compounds that stood out in ME/CFS patients.

Acyl glycines are altered specifically in disorders of branched-chain amino acid metabolism and fatty acid β-oxidation. The mitochondrial acyltransferase, glycine N-acylase, is expressed in liver and kidney.

I'm a carrier of MCAD deficiency. Maybe this acts as predisposing factor.

 

Thank you for sharing this regarding MCAD. Of course, it could all be a coincidence or even confirmation bias from my side (regarding the Liver) but i found the following :

https://www.mayoclinic.org/diseases-conditions/mcad-deficiency/symptoms-causes/syc-20353745

 

Just searched the paper for "24334" and noticed that it's related to "fatty acid metabolism"*. I think I recall Chris Armstrong highlighted differences re fatty acids - correct?

"Out of those four metabolites, only X-24334 is also changing significantly differently over time between controls and ME/CFS patients in the LMM and is increased after exercise in the control group."
Makes X-24334 even more interesting?

I wonder if GWAS will help to understand these findings? E.g. selecting using X-24334, and then doing GWAS, may provide clues re what the cause of the difference. Also, whole genome sequences may provide evidence of rare mutations i.e. indicating the (general) cause of this.

*Extract from paper:
"2.5. Acyl Glycines Have Lower Concentrations in the Urine of ME/CFS Patients Compared to Controls 24 Hours Post-Exercise The four metabolites found at significantly lower concentrations in ME/CFS vs. control subjects at the post-exercise time point in the univariate LMM analyses (q < 0.1) were 3-hydroxyoctanoylglycine, hexanoylglycine (C6), 2-octenoylglycine, and unknown X– 24334. The three known compounds are all in the Metabolon® subpathway acyl glycine fatty acid metabolism. The heatmap in Figure 5A shows the osmolality-normalized concentration post-exercise for these metabolites for every subject. Using agglomerative hierarchical clustering, the subjects clustered into three groups: (1) six control subjects, (2) two control subjects and one ME/CFS subject, and (3) the remaining nine ME/CFS subjects. The cluster of control subjects predominantly shows higher concentrations for all four metabolites while the cluster of ME/CFS subjects shows lower concentrations for all four metabolites. The small cluster with subjects from both groups shows intermediate values. The boxplots in Figure 5B demonstrate the minimal amount of overlap between the ME/CFS and control groups for these metabolites. Out of those four metabolites, only X-24334 is also changing significantly differently over time between controls and ME/CFS patients in the LMM and is increased after exercise in the control group."

 

About a year before I considered myself an ME sufferer, or had even heard of it, I started noticing that sport didn't seem to do anything for me any more (I had always done a lot of sport, enjoyed it and felt great afterwards). No more healthy glow after a day's cycling or a workout in the fitness studio. This was before ME affected my day-to-day life, it was just something I noticed with sport. I cycled with my two oldest boys from our house in Germany to my parents in England, 17 days, 1,500 km. I was really looking forward to getting and feeling fit that summer. But when we got there, nothing, I just felt like a tired old man. On one day of the trip I was suddenly and unaccountably more tired than I had ever been in my life, and just wanted to lie down in the road and have someone throw a blanket over me, but I kept going and it passed.

That autumn I was in the fitness studio for my regular workout when I felt a stabbing pain in my kidneys, just about managed to crawl home, and lay on the sofa for a few days. So began my ME journey about 10 years ago.

So I was a non-ME sufferer who stopped feeling the same after sport. I wasn't going through a research procedure or even aware that I had an illness or was part of an experiment.

 

If this turns out to have potential even only in some areas it is pretty exciting - tho it takes my mind trying to bend thinking about what could or couldn't work just from this one defined study as an example re: the possibilities, and what could or couldn't be answered, or done methodologically - it feels something like this could fill some interesting knowledge and method/measure gaps.

One thing that is key about this 'politically' is, I suppose, that they have begun comparing 'equal absolute exercise-based exertion' in an acute sense (if you were a layperson reading this literally as the only exertion being the CPET both groups are both doing). So that we don't have any cart before horse 'less metabolites = maybe if they did more exertion to have these all would be great' stuff. And the fact the controls were sedentary with regards this issue.

It is interesting when you think of the methods and how everything needs to be done 'comparatively' (whether a change or a difference between groups), plus of course the broader timescales vs e.g. measuring HR or Vo2, and from a funding vs 'all the things you could do' and how you approach demonstrating it being worthy of further funding with a small pot to do one demonstration first up which angle you/one/I might have picked.

This to me doesn't seem like a bad starting point when you imagine the conundrum of all that might be involved with choosing one's 'project'. And yes then come in the whys, hows, and details and so on if more funding follows. Which mightn't have happened if you didn't pick well with that first one

Defining what 'rest' means and 'rested' is hard nevermind achieving it across an ME sample with heterogenous triggers, sensitivities, severities, cycles and so on when you've got PEM involved is perhaps a heck of a task. Whole thread there probably (hope it gets there one day).

I hope I'm not being naive in thinking that the urine aspect of this might be a positive because of the potential for this to be more 'in situ' long-term, allowing for at-home but also - if we can ever find a way for people to accept the 'same isn't equal' issue of ME/CFS re: methods - for instructions/process to be based on 'fit into your normal routine and take at the point when [e.g. you have just had a 'mega-rest' and feel at most rested, and then another measure after taking a shower]. And sort of combine with the 'heart rate in the home' type idea. It feels like the only chance of catching 'rest' as we'd get close to defining it (even using the broadbrush 'what most people think is a restful activity is actually an exertion even for milder PwME')?

BUT of course I don't know from these results whether we'll all be thrown by the absence of whatever being the finding. Or whether it is delay and so on. I like the fact that perhaps 24/4/6hr total urine collection (and could that potentially be done for e.g. a week follow-up) could be used to not add in unnatural exertion for PwME by prescribing precise timings whilst also not risking missing something due to a snapshot.

Then you have the need for someone who is a master at explaining methodologies to work out, if this still needs comparators, how to note that this is a good methodology vs the tendency for someone to instinctively think 'same conditions' involves having all of your sample doing the same thing at the same time etc.