Preprint Systems Modeling Reveals Shared Metabolic Dysregulation and Novel Therapeutic Treatments in ME/CFS and Long COVID, 2024, Gong-Hua et al

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex, multisystemic conditions that pose ongoing challenges to healthcare professionals. Emerging research suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating possible shared metabolic dysfunctions.

This study aims to systematically explore these shared metabolic disturbances and their potential treatments. Utilizing our novel metabolic modeling method, GPMM, we identified the key metabolic irregularities in patients with ME/CFS and Long COVID, notably the downregulation of the alanine and aspartate metabolism pathway, and the arginine and proline metabolism pathway. Genome-wide knockout analyses indicated that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. Further metabolic assessments in Long COVID patients highlighted the significant downregulation of ASP in both blood and muscle, supporting our predictions.

Consequently, we propose that the combination of l-ornithine and l-aspartate (LOLA) offers a promising approach to alleviate metabolic symptoms in both ME/CFS and Long COVID patients. This study not only elucidates the shared metabolic pathways in ME/CFS and Long COVID but also positions LOLA as a viable candidate for future clinical trials.

https://www.biorxiv.org/content/10.1101/2024.06.17.599450v1?ct=

 

First off it’s good to see research on LC and ME/CFS coming out of China.

It seems like they used a novel metabolic modeling method called GPMM (Genome-wide precision metabolic modeling), which is something the authors for example used, or possibly introduced, in this paper https://pubmed.ncbi.nlm.nih.gov/35343058/ (not well cited).

To run their model on ME the authors simply used the data from the intramural study. Which means that it seems to have sparked some international interest. To run their model on LC they used the data by Wüst et al.

 

Also, two of the authors are listed as at Massachusetts General Hospital, Harvard Medical School.

 

I have been taking part on meetings with the team of Wenzhong Xiao since last November and witnessed their work on using computational methods to identify research "hotspots". Really impressed with their work and there are more upcoming targets which are very interesting IMHO. Note that LOLA is used for managing hepatic encephalopathy :

https://www.elsevier.es/en-revista-...-l-ornithine-l-aspartate-in-S1665268119316084

 

Quoting Hutan from another thread.

 

I cannot comment on the merits of their method, but I think it's excellent that people on this forum and elsewhere are analysing and re-analysing some of the data from the intramural study. I do think it contains some valuable information (for example on diagnostic accuracy, POTS/POT/OI, etc).

One of the more interesting findings of the intramural study to me, which wasn't reported in the paper, were the differences in ANA levels between patients and controls. 24% of ME/CFS patients had positive antinuclear antibodies and only 5% of controls (supplementary material 9). @MelbME do you think there is any aspect under which this can be re-analysed or dived into?

 

ANA levels have been observed to be elevated in ME cohorts on several occasions from memory. It would be good to know if this is a predisposing factor or an issue of under diagnosing other autoimmune issues or if it's a developed phenomenon.

I will chat to Wenzhong next week and ask him about the data, I'll ask if he's looking into it more.

 

I think this is an interesting paper. I would be interested in the outcome of this treatment concept as well. Difficult part is working out how to get metabolites like these to the tissues of need.

 

According to KEGG - ASN is asparagine (link to abbreviations)

From Pathway for alanine, aspartate, glutamate

L-alanine <----- L-aspartate -----> L-asparagine

 

If I am reading this right their ME/CFS data is the RNAseq data from the Wallitt study muscle samples.

DNA -> RNA -> protein -> metabolic function.

This paper seems to say: RNA = metabolic function = treatment target.

Am I missing something?

"GPMM 10 integrates protein abundance estimates from gene expression data" from RNAseq?

"significant metabolic commonalities" using RNA data in one disease case and metabolite data in the other?

"I think he said that he feels confident that...they are unravelling the causes of ME/CFS"

Back to the paper:
"Consequently, we propose that the combination of l-ornithine and l-aspartate (LOLA) offers a promising approach to alleviate metabolic symptoms in both ME/CFS and Long COVID patients. This study not only elucidates the shared metabolic pathways in ME/CFS and Long COVID but also positions LOLA as a viable candidate for future clinical trials"

I suspect that this isn't at where they think it is yet. That is my good-faith assessment.

 

Pathway analyses are a bit clunky. They are simply a guide to suggest that metabolites in this network of pathways are enriched.

They help to focus ideas.

Aspartate and alanine pathway includes aspartate and asparagine.

 

Edit : Asparagine is referred to as a non-essential amino acid i.e. the body can make it.

It occurs to me that if ASN turns out to be important in keeping people well, and in avoiding ME/CFS, then perhaps there are genetic problems in the creation of ASN in some people.

Edit 2 : I've just managed to screw up my post by unwise deletion of bits of it!

 

I don't know if they do know what's happening in the pathway. Statisticians typically stick to reporting facts rather than interpreting them in my experience.

My guess is that the conclusion of asp and asn is largely driven by what they saw in the pathway. But yes, that doesn't seem to be revealed explicitly from what I can see.

 

Asparagine is simply aspartate with an NH3 added.
Alanine is pyruvate with an NH3 added.

Adding Asparagine or Aspartate would probably produce a similar outcome though asparagine comes with more NH3.

 

The increasing emphasis on amino acid metabolism in ME/CFS seems interesting. A shift in metabolism that might in a crude sense be 'anti-inflammatory rather than inflammatory might make some sense.

I doubt, however, that simply increasing availability of substrates for down regulated pathways would be likely to help. It is very likely that the pathways are down regulated as part of an adaptive diversion of resources and adding in substrate may simply aggravate things. An analogy would be pouring in protein to patients with nephrotic syndrome.

The solution will be to find out why the pathway is downrgulated and address that mechanism I think.

 

In strongly agreeing with this I would also add as a general comment to readers that I think tissue context always needs to be front and centre when we think about these metabolic questions. Eg a T cell upregulating glycolysis or a muscle cell doing so can be driven by mechanisms not even present in the other cell type.