Stress-Induced Transcriptomic Changes in Females with ME/CFS Reveal Disrupted Immune Signatures, 2023, van Booven et al.

[Sly Saint]

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs).

Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.

https://www.mdpi.com/1422-0067/24/3/2698

 

[CRG]

20 female ME/CFS v 20 female healthy controls, so smallish study, but looks sound:

Conclusions

"Overall, our results indicate that female ME/CFS patients respond differently to an exercise challenge that stimulates PEM, as compared to female HCs. Under maximum stress, ME/CFS patients are unable to facilitate transcriptomic changes in the cells of their immune system that would allow them to permit recovery. Meanwhile, in response to stress, HCs make several transcriptomic changes related to the integrity and function of their immune cells. During recovery, ME/CFS immune cells have dysfunctional cytokine signaling networks and are vulnerable to cell death due to poor defense systems and dysregulated epigenetic regulation of apoptotic pathways, whereas HCs regulate their lymphocytes and inactivate the inflammatory response. The findings presented in our study will help to advance our understanding of the pathways and genes that are relevant to PEM and fatigue tied to ME/CFS, with the goal of identifying targets to improve diagnosis and identify more targeted therapeutic options for female ME/CFS patients"

 

[Trish]

I don't understand why the title is 'stress induced changes...' surely it would be more accurate to say 'exercise induced...' We have enough problems with our problems being attributed to psychological stress.

 

[Hoopoe]

This is the second study that has found a lack of response to exercise at some timepoint, compared to controls who have some kind of response.

 

[CRG]

I don't understand why the title is 'stress induced changes...' surely it would be more accurate to say 'exercise induced...' We have enough problems with our problems being attributed to psychological stress.

The conflict goes back to early stress research: "Stress was originally defined as the non-specific response of the body to any noxious stimulus."

Inevitably there's an enduring psych versus physio turf war: Stress revisited: A critical evaluation of the stress concept

Abstract
"With the steadily increasing number of publications in the field of stress research it has become evident that the conventional usage of the stress concept bears considerable problems. The use of the term ‘stress’ to conditions ranging from even the mildest challenging stimulation to severely aversive conditions, is in our view inappropriate. Review of the literature reveals that the physiological ‘stress’ response to appetitive, rewarding stimuli that are often not considered to be stressors can be as large as the response to negative stimuli. Analysis of the physiological response during exercise supports the view that the magnitude of the neuroendocrine response reflects the metabolic and physiological demands required for behavioural activity. We propose that the term ‘stress’ should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability. Physiologically, stress seems to be characterized by either the absence of an anticipatory response (unpredictable) or a reduced recovery (uncontrollable) of the neuroendocrine reaction. The consequences of this restricted definition for stress research and the interpretation of results in terms of the adaptive and/or maladaptive nature of the response are discussed."

 

[Mij]

I don't understand why the title is 'stress induced changes...' surely it would be more accurate to say 'exercise induced...' We have enough problems with our problems being attributed to psychological stress.

This is medical literature language so I'm ok with it. I've read numerous papers that mention exercise-induced stress behaviour.

 

[NelliePledge]

I don't understand why the title is 'stress induced changes...' surely it would be more accurate to say 'exercise induced...' We have enough problems with our problems being attributed to psychological stress.

Yep - if they’d said physical stress it would be clear.

 

[FMMM1]

This is the second study that has found a lack of response to exercise at some timepoint, compared to controls who have some kind of response.

Could you reference the other/previous study? Was there a thread on it here?

 

[FMMM1]

Given @Jonathan Edwards expertise it would be interesting to get his views.

"Overall, our results indicate that female ME/CFS patients respond differently to an exercise challenge that stimulates PEM, as compared to female HCs. Under maximum stress, ME/CFS patients are unable to facilitate transcriptomic changes in the cells of their immune system that would allow them to permit recovery.

Wonder if this could relate to lack of sedentary controls?

 

[Hoopoe]

Could you reference the other/previous study? Was there a thread on it here?

Figure 11 published in Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome

The figure shows a metabolite in patients that changes much less between several timepoints compared to the controls. On some level there appears to be a lack of response to exercise. Sadly we don't know what that metabolite is.

 

[Creekside]

I accepted the word "stress" as meaning stress on the muscles, rather than the psychological meaning of the word. That's the engineer in me, not thinking along soft-science lines.

I do think the paper is important. I believe that PEM is triggered by the immune system's response to muscle damage, rather than the mitochondrial demands. Elevated mitochondrial demands are the obvious correlation with physical exertion, but the immune response is also a strong correlation. I could do considerable exertion (hours of hiking/biking/digging) without triggering PEM, yet less than a minute of unaccustomed exertion (washing a window, or climbing a ladder) would trigger PEM, so I've always assumed it was due to the muscle cells being damaged by unaccustomed strain, resulting in an immune response. The 24 hr delay in my PEM fits the well-known rise in IFN-g after exertion. Since I couldn't tell the difference between my PEM and the symptoms from viral infections (also involving elevated IFN-g), that's more evidence for that theory.

I think if they'd taken samples 24 hrs after exertion, they'd have found even more differences between PWME and the controls. I hope someone repeats the study, with more people (males too), later samples (24 hrs), physically-limited controls (not healthy, fully active ones), and samples from within the brain, rather than the spine.

 

[Jonathan Edwards]

All I can see in the abstract and conclusions are vague suppositions about regulation of some unspecified immune response. A decent paper gives you some data, without too much interpretation.

If there are interesting results here, why not tell us?

 

[Sean]

I think if they'd taken samples 24 hrs after exertion, they'd have found even more differences between PWME and the controls.

Failure to use a repeat test protocol is indefensible at this stage in the history of ME.

 

[bobbler]

I don't understand why the title is 'stress induced changes...' surely it would be more accurate to say 'exercise induced...' We have enough problems with our problems being attributed to psychological stress.

im divided in this in actually wanting us to get ownership of the correct definition of the word back.

BPS are getting away with warping any term and sometimes corrections are due.

I can see they’ve used stress because of the maximal exercise and recovery - whilst for ME we might one day find that’s any exercise when I used to train you’d have ‘jog back recoveries’ and warm ups etc weren’t ‘stress’ but loosening in someone fit and healthy where the pint of all out sprints was indeed ‘stress’

so I think it’s a term that is needed and we need to be able to slot into - that is if exercise literature hadn’t got warped too.

I know stress is still used in engineering/physics etc as a term so I just think it’s naughty and more telling of medicines issues that they don’t differentiate or even understand that psychological, cognitive, physical stress are all different things which can be present at once - but selling it as ‘like anxiety’ is just inaccurate misinformation really. Like branding ‘virus’ as now meaning ‘colds’ (EDIT: or even worse because anxiety isn't necessarily stress of the types inferred nor vice-versa). As it’s a term that is needed it needs to be reclaimed

 

[Ravn]

All ME participants met both Fukuda and CCC. Good. There's no info about how sedentary the controls were. Not so good.

Subjects also completed a gynecologic questionnaire to ensure blood collection occurred during the first two weeks of their menstrual cycle.

A rare - and welcome - attempt at trying to account for menstrual cycle effects.

After a uniform breakfast (yogurt and banana), the subjects were given 30 min to digest while resting in comfortable position in reclining chairs

Is this a good way to try and control for digestion effects? The intention is sensible but if some of the participants normally eat low carb or keto - and this may not be evenly distributed between the two groups - what effect would the sudden introduction of high sugar foods have?

Failure to use a repeat test protocol is indefensible at this stage in the history of ME.

I disagree in this case. Whether you choose single or repeat exercise protocol depends on what a study is looking for.

This particular study wasn't a CPET study to look at ability to repeat performance or similar. Instead its aim was to look at what happens with the blood chemistry during and soon after exercise that might point to a potential PEM mechanism. A single exercise provocation is enough to achieve this. I mean, we all know that a single occasion of overexertion is plenty enough to send us into PEM.

Sure, it would have been interesting to squeeze more into this study, as is the case for most studies. But there are trade-offs to be made with respect to available funding and, most importantly, patient safety. You shouldn't subject patients to the risk of two exercise sessions if a single one is likely to give you enough data for your purpose. If anything I would have liked to see them sample at more time points after the exercise but a second exercise session really wasn't necessary here.

I don't understand why the title is 'stress induced changes...' surely it would be more accurate to say 'exercise induced...' We have enough problems with our problems being attributed to psychological stress.

I accept they use the term stress in the technical sense here and that this is strictly speaking a correct use of the term but it would have been better if they'd chosen something else, given the extremely strong association with psychological stress in most people's minds and the way this has been/is being weaponised against pwME.

This is the second study that has found a lack of response to exercise at some timepoint, compared to controls who have some kind of response.

Interesting indeed.

Figure 11 published in Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome

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

 

[Sean]

If anything I would have liked to see them sample at more time points after the exercise but a second exercise session really wasn't necessary here.

That would be good.

 

[FMMM1]

Figure 11 published in Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome

The figure shows a metabolite in patients that changes much less between several timepoints compared to the controls. On some level there appears to be a lack of response to exercise. Sadly we don't know what that metabolite is.

Apologies could you post the relevant extract - thanks

 

[Hutan]

Given that we seem to react abnormally to exertion, looking for abnormal responses in cell types and gene expression as a result of exertion seems like a really good thing to do.

Here is the data on changes in cell type abundances. There look to be some interesting things there. It's a shame there aren't scattergrams, so that we can see how much of an overlap there is between the healthy controls and women with ME/CFS. I agree with @Ravn that it would have been great if there had been more timepoints, say, a day later. And the lack of sedentary controls is a problem.

I think we probably need to know the actual (rather than relative) levels of the cells at baseline and during and after exercise to begin to work out what to make of these results. For example, activated mast cells increased immediately after exercise in healthy controls, but not in the ME/CFS sample. Is that because numbers of activated mast cells were already really high prior to exercise in the ME/CFS sample? Or because levels of activated mast cells stayed low throughout, in ME/CFS? (Or because activated mast cells did increase in ME/CFS but moved quickly into tissues?)

Unfortunately this study does not seem to provide data on actual levels of the cells, only fold changes in the levels at each time point. And there's very little discussion of the changes in cell types. If there really are distinct differences in numbers of cell types in peripheral blood after exercise, that could be an important finding.

I'd really like to see this part of the study replicated by a different group of researchers, with larger cohorts.

Table 2. Cell type abundance changes between T0 (resting) and T1 (maximal exertion)


Table 3. Cell type abundance changes between T1 (maximal exertion) and T2 (4 hours later)

Abundances of cell types were estimated using normalized gene counts.

Could this method result in incorrect estimations of cell numbers?

 

[Hutan]

The 13-fold reduction in CD8+ T cells from maximal exertion to 4 hours after in the healthy controls is particularly remarkable, compared to no significant change in CD8+T cells in the women with ME/CFS.

I've briefly tried looking to see if such a decrease following exercise is normal, but I haven't been able to find another example.

 

[Arvo]

Health Rising article about this study:

Exercise Triggers Major Immune System Letdown in ME/CFS - Health Rising

It really is a very interesting study, and another puzzle piece in the emerging picture on what exactly happens in an ME/CFS patient's body upon exertion or even exercise.