Preprint Medrix: Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in ME/CFS - Helliwell, Tate et al -2022

Preprint
Medrix Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Helliwell A.M., Stockwell P.A., Edgar C.D., Chatererjee A., & Tate W.P.


Abstract (242)
Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity throughout the ongoing illness. Patients experience relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but the dynamic changes specific to each individual patient are unknown. Precision medicine can determine how each patient responds individually during variations in their long-term illness. We apply precision medicine here to map genomic changes in two selected ME/CFS patients through a relapse recovery cycle.

Results
DNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) from two patients and a healthy age/gender matched control in a longitudinal study to capture a patient relapse. Reduced representation DNA methylation sequencing profiles were obtained from each time point spanning the relapse recovery cycle. Both patients throughout the time course showed a significantly larger methylome variability (10-20 fold) compared with the control. During the relapse changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated respectively with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions occurring during the relapse.

Conclusions
Severe health relapses in ME/CFS patients result in functionally important changes in their DNA methylomes that, while differing among patients, lead to similar compromised physiology. DNA methylation that is a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency.

 

Spotted the paper in a tweet by prof. Kunst with the comment:

Wow. This important new preprint demonstrates epigenetic changes in #MECFS patients during relapses/crashes. These patients showed "functionally important changes in their DNA methylomes that lead to compromised physiology".

 

This sounds like a completely new approach. Very small N, obviously, but this sounds (in my ignorance) as though it could be exciting.

What do you think, @Jonathan Edwards and @Simon M?

 

I often wonder what could be found with in-depth lab testing during my prolonged crashes. They make me feel very unwell and can last weeks or months.

I once had a test done by chance during a crash with predominant gastrointestinal symptoms and it found fecal zonulin at levels 4 times the maximum normal. It's a biomarker for compromised gut barrier integrity. Normally during relapses I don't leave the house much and don't try to solve any problems so I don't get tested, but that time I only had to provide a stool sample from home.

 

I am pretty sure he was inspired by another scientist that did a very long expensive study on himself in the States. With limited funding this was a very smart study in my opinion. I hope he does another one with Male subjects due to sex differences.
It is good to see in-depth longitudinal work.

 

I really like Warren Tate, and I like the idea behind this paper even if I didn't follow all of the methylation discussion. The choice for the terms "recovery" and "relapse" seems really poor, the author's use them to describe variations or changes in health status rather than indicative of recovering and relapse from a state of health to a state of illness. My own condition seems far more consistent overtime than these patients who showed pretty significant changes in overall health in the 11 months they were followed.

It would be easier to follow if they were saying this month was a PEM period versus just a decline in health status versus a true relapse/remission. They also go "off scale" into the negatives which I found a little confusing along with the terminology. I think the patients would be able to identify periods of PEM but maybe that is more difficult.

 

N is too small to draw any conclusions. But I agree, the approach is very interesting (and could also be applied to other biomolecules). I haven't read this paper but I have been extremely impressed by the methodological rigour in earlier Warren Tate studies. What we need now is a much bigger epigenetics study using the same approach.

 

"Severe health relapses in ME/CFS patients result in functionally important changes in their DNA methylomes that, while differing among patients, lead to similar compromised physiology"
I don't understand the certainty about implied causal route. Surely all that can be said is that:

'severe health relapses in ME/CFS patients "are accompanied by" functionally important changes in their DNA methylomes that, while differing among patients, "indicate disturbed metabolic, immune and inflammatory functions which in turn imply" similar compromised physiology' ?

 

A key limitation of all of these types of studies regardless of sample size is that it is focused on a narrow range of cells (T cells, B cells, NK cells, macrophages and Myeloid dendritic cells) and isn't necessarily generalisable to what is going on in other tissues of the body.

Also note prior small study:
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00960-z

 

I would like to see a cerebral blood flow study during a relapse compared to a non-relapse state.

 

Full article with pdf?
https://www.mdpi.com/1422-0067/23/19/11852

 

the reviewers report might be of interest.
https://www.mdpi.com/1422-0067/23/19/11852/review_report

 

This is a good study to look at what is happening to 2 patients with ME. If there had been no changes that would have given certain information but the findings mean something. The next step is to see if other patients have the same thing.