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

[Consul]

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

 

[Consul]

SDMA and ADMA are both regulators and competitive inhibitors of nitric oxide (NO) production. NO aids in vascular maintenance in healthy individuals [33], and decreased NO production is associated with endothelial dysfunction and cardiovascular disease [34]. ADMA can be removed through urinary excretion or it can be degraded in the liver [35]. 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.

...

While kynurenate is the only tryptophan compound with correlations in both the time point and the ratio sides of the heatmap, the differences seen in plasma and urine correlations in the other eight compounds, which appear at various locations in the tryptophan pathway, attest to a profound dysregulation of this pathway in the ME/CFS patients compared to the controls. Additionally, another compound on the heatmap, quinolinate, is the metabolite that links tryptophan metabolism to nicotinate and nicotinamide metabolism, which is a crucial pathway for the formation of NAD+ and NADP+. A dysregulation in the kynurenate pathway has been hypothesized to be the underlying cause of ME/CFS pathophysiology due to its central role in cellular energy production and involvement in mediating the immune response as reviewed by Kavyani et al. [45].

 

[keepontruckin]

twitter
Maureen Hanson

@DrMaureenHanson

Despite a small sample size, our pilot study on the urine metabolome turned out to be much more interesting than we expected. ME/CFS subjects lack a large number of significant changes in the metabolome that occur in controls in response to exercise.

 

[Wishful]

I can certainly accept the part about the kynurenine pathway. I had a strong negative reaction to niacin, which I assumed meant that it was reducing the amount of QUIN catalyzed into nicotinate, resulting in excessive QUIN (neurotoxin). I also had bad reaction to proline for a while, not too long ago.

 

[Consul]

So what is causing this static metabolism that doesnt respond to exercise?

Im guessing (newbishly) there needs to be transcription changes in the cells to change the metabolism but for some reason the outside signals that are supposed to facilitate this change doesnt get through. I recently suggested second messenger dysfunction in mecfs because there appears to be various problems with calcium in mecfs and a genetic study pointed at an enzyme that regulates cGMP and cAMP.

edit: I think the research from Staines and Gradisnik increased in market cap from this. Without proper calcium signalling the metabolism might just be like a sack of potatoes that doesnt even know you are exercising.

 

[SWAlexander]

A Question from
Dr. Nina Kreddig
I wonder if this is in any way related to ammonia resulting from digesting animal protein. This ammonia needs to be broken down by BH4, and if you don’t have enough of that you might be missing out on other functions of BH4

I think, this question could be answered by a Gene Test for GS224 Tetrahydrobiopterin deficiency.
About the DiseaseTetrahydrobiopterin (BH4) is essential for the biosynthesis of dopamine, noradrenaline, and serotonin, which serve as cofactors for tyrosine hydroxylase (TH) and tryptophan hydroxylase. GTP cyclohydrolase (GCH) is the first and rate-limiting enzyme for BH4 biosynthesis. https://rarediseases.info.nih.gov/diseases/7751/tetrahydrobiopterin-deficiency

Tetrahydrobiopterin Supplementation: Elevation of Tissue Biopterin Levels Accompanied by a Relative Increase in Dihydrobiopterin in the Blood and the Role of Probenecid-Sensitive Uptake in Scavenging Dihydrobiopterin in the Liver and Kidney of Rats
https://pubmed.ncbi.nlm.nih.gov/27711248/

 

[Consul]

A Question from
Dr. Nina Kreddig
I wonder if this is in any way related to ammonia resulting from digesting animal protein. This ammonia needs to be broken down by BH4, and if you don’t have enough of that you might be missing out on other functions of BH4

I think, this question could be answered by a Gene Test for GS224 Tetrahydrobiopterin deficiency.
About the DiseaseTetrahydrobiopterin (BH4) is essential for the biosynthesis of dopamine, noradrenaline, and serotonin, which serve as cofactors for tyrosine hydroxylase (TH) and tryptophan hydroxylase. GTP cyclohydrolase (GCH) is the first and rate-limiting enzyme for BH4 biosynthesis. https://rarediseases.info.nih.gov/diseases/7751/tetrahydrobiopterin-deficiency

Tetrahydrobiopterin Supplementation: Elevation of Tissue Biopterin Levels Accompanied by a Relative Increase in Dihydrobiopterin in the Blood and the Role of Probenecid-Sensitive Uptake in Scavenging Dihydrobiopterin in the Liver and Kidney of Rats
https://pubmed.ncbi.nlm.nih.gov/27711248/

Is BH4 involved in breakdown of ammonia?

 

[SWAlexander]

Is BH4 involved in breakdown of ammonia?

Herbert Renz-Polster
asked the question:
"Janet, this is such an interesting presentation! Would you please make Rob Phair aware of this old publication of post-ischemic ammonia profiles in #MECFS pts which may indeed indicate an „ammonia problem“ in ME/CFS:"
in reference to, Use of Dynamic Tests of Muscle Function and Histomorphometry of Quadriceps Muscle Biopsies in the Investigation of Patients with Chronic Alcohol Misuse and Chronic Fatigue Syndrome: https://journals.sagepub.com/doi/10.1177/000456329403100507

This could be a part of the answer.
Synthesis and hydrolysis of NaZn(BH4)3 and its ammoniates: https://pubs.rsc.org/ko/content/articlelanding/2017/ta/c7ta05082h

other connection:
Tetrahydrobiopterin Supplementation: Elevation of Tissue Biopterin Levels Accompanied by a Relative Increase in Dihydrobiopterin in the Blood and the Role of Probenecid-Sensitive Uptake in Scavenging Dihydrobiopterin in the Liver and Kidney of Rats
Abstract
Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS) and aromatic amino acid hydroxylases. BH4 and 7,8-dihydrobiopterin (BH2) are metabolically interchangeable at the expense of NADPH. Exogenously administered BH4 can be metabolized by the body, similar to vitamins.
https://pubmed.ncbi.nlm.nih.gov/27711248/

 

[Consul]

This could be a part of the answer.
Synthesis and hydrolysis of NaZn(BH4)3 and its ammoniates:

Thats a paper on materials chemistry.

other connection:

I dont see a connection here either.

 

[SWAlexander]

I dont see a connection here either.

Maybe this paper comes closer to being related to ammonia.

 

[Murph]

This chart was so amazing I did a deep dive to see if it really was showing an incredible difference.

It looks so strong I wondered if there was a data handling error. So I dove in.
I ended up teaching myself how to do a Benjamini-Hochberg correction for multiple comparisons in order to replicate their analysis!

In the end I concluded that actually the results are sound ! Which is pretty amazing. here's another way of looking at it, with raw p valyes instead of log scaled q values. What you observe is that yep, the pattern is far stronger in controls than patients. There really is a difference in urine after exercise provocation.

The fact the difference here is so stark sends the following message: if your study doesn't include exercise provocation, you probably won't find anything.

 

[BrightCandle]

The fact the difference here is so stark sends the following message: if your study doesn't include exercise provocation, you probably won't find anything.

Also if your drug study doesn't include this test and improve the results its probably worthless. This is a solid biomarker for drug development to use.

 

[Violeta]

Maybe this paper comes closer to being related to ammonia. file:///home/chronos/u-42ae873a533d7fee4fe722a2e44efc2089ea38b1/MyFiles/Downloads/Tetrahydrobiopterin.pdf

"Xanthurenic acid is a quinolinemonocarboxylic acid that is quinoline-2-carboxylic acid substituted by hydroxy groups at C-4 and C-8. It has a role as a metabotropic glutamate receptor agonist, an iron chelator, a vesicular glutamate transport inhibitor and an animal metabolite."

I don't know anything about this, yet, but it looks like something I don't want a lot of hanging around in my body.

Oh no, I sent it without the link and am having trouble adding the link. It's a good study.

 

[Violeta]

Maybe this paper comes closer to being related to ammonia.

This paper may have the answer to the very thing I was going to look for today...what is the root cause of low dopamine.

Thank you for finding and posting it, @SWAlexander.

 

[Husband of]

Would be interesting to replicate not just with more people but testing the response 48 hrs after, 72 hours after, etc.

important to understand if there is a response ever.

ehat does it mean if not?
That breaking muscle down through exercise would not yield regrow the and therefore cause de conditioning?

 

[pattismith]

Is BH4 involved in breakdown of ammonia?

The only link I found between the Urea Cycle and the BH4 is that BH4 allows production of Citrulline from Arginine; both belonging to the Urea Cycle.

But I can't see a reason to think BH4 is helping to clear ammonia....