There was a time that the HPA axis was “it” in chronic fatigue syndrome. More studies have been done on the powerful glucocorticoid hormone cortisol than other factor in ME/CFS, and it’s not hard to understand why. Cortisol not only plays a major role in the stress response and getting the body the energy it needs, but it’s also an important immune regulator. The low cortisol levels in ME/CFS seemed to fit it perfectly: not only did people with ME/CFS report feeling both wired and tired, but their immune systems seemed to be shifted in just the direction one would expect.
The cortisol levels turned out to be only mildly low, though, and then only in the morning, suggesting that cortisol by itself was not “it” for a disease as disabling as chronic fatigue syndrome. Other studies suggested, however, that other problems might exist in the fantastically complex HPA axis. One study showing a reduced responsiveness to cortisol suggested that cortisol levels might not need to be low for significant problems to show up.
Then Broderick’s model suggested that HPA axis issues probably played a major role in this disease. As with most measures in ME/CFS, it seems that crude measures like cortisol levels just don’t work well. You have to stimulate something, or see how it interacts, or see how the network it’s embedded with is doing to get the real story. In other words, you have to dig deeper.
That’s exactly what Patrick McGowan has done. McGowan is from Canada – yet another country with a kind of Dr. Jekyll and Mr. Hyde-like history with ME/CFS. Canada, of course, birthed the Canadian Consensus Criteria – the most influential criteria in ME/CFS’s recent history, and the first to make post-exertional malaise a hallmark symptom. (Bruce Carruthers, the lead author of the Criteria, recently died.)
Canada has also given ME/CFS some notable researchers including Patrick McGowan, Lasker Award winner Mark Houghton, the data miners and modelers Gordon Broderick and Travis Crawford of Dr. Klimas’ Institute for Neuroimmune Studies, David Patrick as well as some prominent MD’s; Dr. Byron Hyde, Dr. Bested, Dr. Kerr, Dr. Eleanor Stein and others.
Canada also had its Dr. Jekyll and Mr. Hyde-ish side. British Columbia produced one of the rare centers for ME/CFS (good) which Dr. Bested rather quickly resigned from (bad). Canada also opened up a grant package for ME/CFS (good) and then put someone who didn’t believe ME/CFS was a disease in charge of its application review (bad).
Introduced to ME/CFS via the Solve ME/CFS Initiative grant, McGowan’s earlier epigenetics study highlighted immune changes. Then McGowan scored a big private foundation grant. Now he, his University of Toronto PhD student, Wilfred de Vega, and Suzanne Vernon (who introduced McGowan to ME/CFS) have produced a fascinating study.
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Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) Wilfred C. de Vega 1,2, Santiago Herrera 1,6, Suzanne D. Vernon 5,7 and Patrick O. McGowan 1,2,3,4. Medical Genomics (2017) 10:11 DOI 10.1186/s12920-017-0248-3
Part of the way experiences get embedded in our biology is through direct changes to how our genes work. This is part of what’s become a paradigm shift in the way that biologists think about development. Patrick McGowan
The study examined potential epigenetic modifications in 480,000 loci in the PBMC’s (immune cells) of about 75 ME/CFS patients and healthy controls. That was a pretty good project all in itself, but what came next was much better. De Vega and McGowan stimulated and suppressed glucocorticoid genes and then checked to see if epigenetic modifications were a factor in them.
Epigenetics research explores alterations that affect which genes get expressed or not expressed. It turns out that genetics is much more complicated than first thought. We have a genetic template which remains unchanged throughout our lifetime, but other factors can change which genes get expressed or not. It’s as if we evolve into very different people over time.
Epigenetics could be particularly important for ME/CFS because of the triggers often associated with its onset. Each trigger, each infection, powerful stress event or toxin has the potential to alter a person’s epigenetics – and thus turn off or on some of their genes. If you’re looking for some sort of system reset – some way to suddenly and permanently alter a person’s biology – an infection-triggered epigenetic change would seemingly fit the bill.
The study found that about 12,000 or 2 1/2% of the epigenetic loci were altered in the ME/CFS patients vs the controls. A linear regression analysis indicating that the epigenetic changes impact ME/CFS patients’ quality of life suggested that McGowan had indeed found something clinically meaningful.
A pathway analysis indicated that the epigenetically modified genes mostly participated in cellular regulation and metabolic pathways (neuronal cell development, signal transduction, metabolic regulation and transcription regulation). McGowan’s study, of course, is just the latest in a string of studies implicating metabolism in ME/CFS. It suggests that some epigenetic modifying event (infection?, toxin?, stress?) could have blunted the ability of ME/CFS patients’ immune cells to produce energy.
Besides the obvious excitement of possibly finding a key factor (low energy production) that seems to fit so well with ME/CFS, the string of studies with metabolic findings is notable for the diverse ways that conclusion is being drawn. From earlier gene expression studies to McGowan’s epigenetic study, to the Naviaux and Armstrong metabolomic findings, to the Stanford mitochondrial study, to Workwell’s exercise studies – researchers seem to be circling around the same fascinatingly simple and yet compelling idea: that blunted energy production is behind the fatigue, post-exertional malaise and other problems in ME/CFS.
Just how the energy problems occur isn’t yet clear. Citing Maes’s works – and thereby implicating Shungu’s – McGowan suggested oxidative stress could come into play. Shungu’s duo finding of both reduced levels of antioxidants (glutathione) and increased levels of free radicals in the brains of ME/CFS patients could, by itself be enough to hamper the energy producing ability of ME/CFS patients’ immune cells.
The Hypersensitive Glucocorticoid Subset
The glucocorticoid sensitivity test suggested that two types of ME/CFS exist: one subset of patients over-reacts to glucocorticoids such as cortisol, while the other reacts normally.
Several analyses suggested that thirteen loci or sites which had undergone epigenetic shifts were associated with the glucocorticoid hypersensitive group – a finding that McGowan stated should be treated with caution. The function of seven of those sites was unclear, but of the six others, two-thirds were involved in, once again, cellular metabolism (e.g. energy production).
Given how important glucocorticoids are to immune regulation, it’s possible that McGowan has uncovered an immune-stressed subset of ME/CFS patients. The hypersensitivity found – to a T-cell mitogen – also suggests that T-cells – long dismissed in ME/CFS but now under intense study by Mark Davis who has reportedly found something, and Dervya Unutmaz of the Jackson Hole Labs – may be misbehaving.
(An earlier study found that T-cell cytotoxicity, like NK cell cytotoxicity, was reduced. Both Ron Davis and Dr. Koroshetz of NINDS recently referred to exciting preliminary T-cell findings from Mark Davis’s Stanford lab. Given Derya Unutmaz’s expertise in T-cells, its possible that it was T-cell data which helped get him his big NIH grant as well. Could McGowan have uncovered the epigenetic modifications behind Davis’ and Unutmaz’s findings?
If McGowan’s work is validated, it could suggest that somewhere, something happened (an infection, toxin, stress) to hamper cellular metabolism in just about everyone with ME/CFS. Baked onto that in some people is an immune system that isn’t being regulated properly. McGowan’s results could also explain why the HPA axis results have been so wishy-washy as well (they didn’t contain the right patients.). It could also eventually provide biomarkers for the glucocorticoid sensitivity subset.
The next step is to see if the glucocorticoid sensitivity shows up in “real life”: in altered mRNA and protein levels at baseline, and then after the cells have been tweaked with glucocorticoid stressors and/or by exercise.
If that’s successful, then McGowan may have found targets that can be addressed with drugs. Targets are precisely what’s been missing in the big “omics” (genomics, metabolomics, proteomics) studies thus far. These complex studies can filter through reams of data to identify important pathways or groups of genes, but the gold at the end of the rainbow for ME/CFS patients are specific targets that drugs can be found or developed for.
With the exception of Bob Naviaux thus far, that’s been missing. Naviaux is unusual in that his metabolomics results suggest a hypothesis, a target and a drug (Suramin). A blog on Naviaux’s exciting results in his small autism study will be coming up shortly.
Another great article Cort!! Boy we seem to be getting closer and closer to a magic pill and it’s pretty exciting!!
It’s hard to form conclusions from needle-in-haystack type studies like this that generate lots of results, that may or may not be noise.
The Dexamethasone suppression assay results are interesting, as a subgrouping marker. But the methylation associations with the hypothesised receptor sensitivity are well, questionable. None of those loci are statistically significant on their own and it smells of over-fitting…
The methylation associations that were statistically significant don’t look that exciting, but I’d have to have a deeper look to see if anything sticks out (and beware of confirmation bias).
Let’s hope we get some more specific associations soon.
O Canada and Jekyll and Hyde???
It is very sad that you don’t mention the name of Dr.Byron Hyde in the right contest. He is an renown specialist for fibromyalgia, one of the pioneers in the field. Someone writing about fibromyalgia should be familiar with his name. Yes, he is Canadian and he has nothing to do with Dr. Jekyll and Mr. Hyde.
I attended a talk by Dr. Hyde. His dedication to FM research definitely deserves to be recognized. I enjoyed his fascinating talk and Dr. Hyde was very generous in taking time to answer many questions from the audience.
Definitely a lapse – I agree! (I knew I was missing someone…) I will include him and update the blog post. My apologies to Dr. Hyde who has such an interesting and creative approach to ME/CFS. Thanks for pointing him out.
Like snow leopard I don’t think this kind of study delivers definitive conclusions, what it does do it gives us a fair amounbt of raw data. Until we have a much stronger handle on the root cause(s) of ME these data collection studies give us vital pointers for the formation of hypotheses.
It’s only when we have enough data to form more robust hypotheses that we have a fighting chance of finding a test with both high specicivity and high sensitivity.
wouldf you start providing links to the studies you discuss please. It would be nice to see the full ‘nitty-gritty’.
I mean to but sometimes forget = thanks for the reminder.
Thank you so much Cort for keeping us updated on various research directions. I would think that a more valuable approach would be to look carefully at the metabolic, epigenetic, etc status of people who have a definite diagnosis of some fatiguing illness or injury. For example: it is appreciated that 50 % of spinal cord injury patients have life altering fatigue. There are at least several post viral / post ‘exotic organism’ infections that result in chronic fatigue.
Agreed! How interesting a comparison would be!
Nice summary and integration! The recently published open-access paper cited below links GSTM1 CpG hypermethylation (found by McGowan et al. in ME/CFS) to Th1 T-cell differentiation, reinforcing the immune connection. The increase in GSTM1 methylation with aging they found suggests that ME/CFS may reflect an accelerated implementation of metabolic adaptations to oxidative stress, probably triggered by environmental factors.
Aging-dependent DNA hypermethylation and gene expression of GSTM1 involved in T cell differentiation.
Yeh SH, Liu CL, Chang RC, Wu CC, Lin CH, Yang KD.
Oncotarget. 2017 Jul 25;8(30):48591-48602.
Thanks! Maybe it will come down to oxidative stress after all!
I am skeptical of the conclusions.If you examine a large number of epigenetic loci, you are highly likely to find a small percentage that appear to be altered just by chance. I believe that if you looked at epigenetic loci for healthy people who don’t have ME/CFS, you would also probably find that around 2 % were altered. McGowan should be getting a statistician to be involved in his studies and to review his results. My organization, Statistics Without Borders, would be happy to provide free help.
Way to go, Gary Shapiro!
The correlation of the glutocorticoid reaction and HPA axis involvement(adrenals producing cortisol and other hormones and compounds)corresponds with my own experience. I’ve had ME/CFS for 15 years. In the beginning I was blessed enough to find a homeopath who suspected I had flagging adrenals. Over time, first with his help then on my own, we began to see that ‘flagging’ became ‘failing’. I’d see that I had little to no production of cortisol a.m., the bulk of which should be in your system early in the a.m. and by afternoon or evening the levels were practically non-existent. You can go to your regular doctor but most will only do a ‘snapshot’ cortisol level in the morning, or a 24 hour cortisol urine test. They are helpful. but you need to see what it happening during a normal day, which only the 4-part saliva test can assess. In truth, you can tell on your own without a doctor using 4 part saliva tests. I’ve used Canary Club online for years and you can order the tests on your own from them, as well as hormone, thyroid, DHEA, Vit E, etc. ALL WITHOUT A DOC’S prescription. They use the SAME labs as the homeopath did (and cheaper cost to me) and although you have to pay for them yourself it was worth it since all the convention docs we were consulting didn’t or wouldn’t do the ones I needed. While finally making the decision to go on full replacement oral hydrocortisone was necessary, it didn’t make me ‘well’. But, I think it’s been one of the things that allows me to be able to take care of my basic needs, like bathing and heating up my food and so forth. While the dexamethasone suppression test is a helpful diagnostic tool, if you know that the adrenals are not functioning and you also see that your BP is super low, which indicates you might need extra sea salt each day and/or the med Florinef to keep the sodium/potassium in balance, the dexamethasone test is a sort-of moot point.
I’m a bit worried about the potential of Mestinon to make things worse in the long run. Does anyone know anything about this? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2393741/
I am new to this site; am due to see my rheumtologist tomorrow (2nd time I’ve seen this one, my previous one was brilliant with a real interest in ME/CFS). I’d just like to feel there was a point in going to see a rheumatologist, as I go away from the appointment just as uninformed as before I went. I am taking along a copy of the above paper, and am particulary interested in “…From earlier gene expression studies to McGowan’s epigenetic study, to the Naviaux and Armstrong metabolomic findings, to the Stanford mitochondrial study, to Workwell’s exercise studies – researchers seem to be circling around the same fascinatingly simple and yet compelling idea: that blunted energy production is behind the fatigue, post-exertional malaise and other problems in ME/CFS”, with a view to discussing how to address ‘blunted energy production’. I’ve subscribed to your posts. Thanks, Joe.
Keep tuned Joe – lots of work – at least for us – in this area…We should know much more over the next year or so.