Freddy’s Narrations!
(Thanks so much to Freddy for coming on board Health Rising’s narration team :))
The GIST
The Blog
THE GIST
- A recent Australian study from the Open Medicine Foundation used metabolomic data from over 1,000 ME/CFS patients in the UK Biobank to look for biomarkers.
- The 168 biomarkers associated with ME/CFS were dominated by … guess what? Lipid (fats)! Seeing lipids pop up in ME/CFS is fast becoming not a surprise anymore. Fats (lipids) provide the most concentrated energy source in the body, and metabolomic and other studies suggest that fatty acid synthesis – and that means mitochondrial energy production – is not going so well in ME/CFS.
- One particular biomarker – total triglyceride to phosphoglyceride ratio (TG/PG) – stood out – and was associated with a 50% higher risk of having ME/CFS. A high TG/PG ratio seems like a recipe for problems with energy production as it could result in low mitochondrial output (often associated with oxidative stress) and damaged cellular membranes (caused by oxidative stress). This ratio is often used to assess metabolic and cardiovascular disorders.
- Given the recent blog on the potential for metabolic syndrome to show up in these diseases, it’s worthwhile noting that high TG/PG ratios are also found in metabolic syndrome and insulin resistance. (Ouch!)
- These findings are smack on with past study findings suggesting that the cellular membranes in ME/CFS patients are being “destabilized” (ripped apart by free radicals), that cell signaling is being disrupted (cells may be dead in the water and unresponsive), and that there is dysregulated immune cell functioning.
- The increased alanine and BCAA levels in females, in particular, suggested, for the first time I can remember, a metabolic reason why more women may have ME/CFS. It turns out that women, more so than men, rely on a process called anaplerosis to replenish their mitochondria that emphasizes amino acid uptake.
- If the mitochondria are being depleted too rapidly, women’s bodies will start to break down tissues to supply the needed amino acids. That could result in the preferential use of amino acids (instead of the more efficient fatty acids or carbohydrates) to drive the mitochondria.
- While this study did not produce a metabolomic signature it did emphasize, once again, the role that lipid problems appear to play in ME/CFS.
- The authors also built a model they plan to use in future studies as the ME/CFS data from other large biobanks becomes available.
- Note that this study – and the study featured in the last blog – were supported entirely by non-profits – in this case the Open Medicine Foundation and the Mason Foundation.
- Also note that thanks to two generous donors (who provided $800,000 – nice!) the Open Medicine Foundation has embarked on a big BioQuest biomarker study which plans to measure over 10,000 proteins and metabolites in blood samples of up to 1,200 patients and controls (whoa!). Hopefully, that will be the study that finally provides us with the elusive biomarkers researchers have been searching for. The study has partly been funded.
This Australian study – which was designed by Chris Armstrong and Katherine Huang of the Melbourne ME/CFS Collaboration, and funded by the Open Medicine Foundation and the Mason Foundation – used UK Biobank data (lots of it) to produce this unique study.
This study shows how helpful it is to be embedded in a huge multi-disease database. Mixed in with the UK Biobank’s 500,000 samples are over 2,000 samples from people diagnosed with ME/CFS.
The hunt was on to put the pieces together and find a biomarker.
(The UK Biobank is different from ME/CFS UK Biobank which contains blood from about 600 donors, or the Decode ME project which contains 25,000 DNA samples. The UK Biobank collected its samples from 2006-2010 and is following the participants for 30 years.)
Because the UK Biobank data is open, the Australian team didn’t need to get blood and do a metabolomic study – it simply needed to access and analyze the data that was already in the biobank. With that, a hunt for the elusive biomarker for ME/CFS was on.
Results
Those Lipids…Again!
Triglycerides showed up big time in ME/CFS.
The 168 biomarkers associated with ME/CFS were dominated by … lipid (fats) biomarkers! Seeing lipids pop up in ME/CFS is fast becoming not a surprise anymore.
Fats (lipids) provide the most concentrated energy source in the body, and metabolomic and other studies suggest that fatty acid synthesis is not going so well in ME/CFS. It doesn’t appear that the fatty acids are getting to the mitochondria like they should, leaving the mitochondria to rely on less energy-rich amino acids for energy.
A Nasty Ratio
The strongest biomarker association found was the total triglyceride to phosphoglyceride ratio (TG/PG), where a standard deviation (SD) increase in the biomarker was associated with a 50% higher risk of having ME/CFS. (In a normal bell-shaped curve, almost 70% of the data fit within 1 standard deviation – meaning that anyone with a 30% higher than average TP/PG ratio had an almost 50% higher risk of having ME/CFS.)
That’s not chicken feed. This ratio is commonly used to assess metabolic and lipid health. A high TG/PG ratio has been associated with metabolic disorders, cardiovascular risk, or conditions like non-alcoholic fatty liver disease.
It can also indicate problems with energy production. Triglycerides (TG) get a bad rep because high levels can result in inflammation and insulin resistance. Triglycerides, though, are also the main way our bodies store energy. They are broken down into fatty acids during exercise and used to produce ATP.
Phosphoglycerides, on the other hand, are a main component of cellular membranes including mitochondrial membranes – which play a critical role in ATP production.
High TG levels could indicate that problems utilizing those fatty acids may be present – and problems with fatty acid metabolism are precisely what we’ve seen in ME/CFS. The low phosphoglyceride levels suggest problems with the cellular membranes exist. Put those together and you potentially have a recipe for damaged mitochondria – low mitochondrial output (often associated with oxidative stress) and damaged cellular membranes (caused by oxidative stress).
Given the recent blog on the potential for metabolic syndrome to show up in these diseases, it’s worthwhile noting that high TG/PG ratios are also found in metabolic syndrome and insulin resistance. High TG/PG ratios have also been associated with increased levels of visceral fat – the fat that gets packed into our muscles and organs – which is pathogenic – and a reason, if you can afford to (and dare to :)) get your levels of visceral fat assessed using a Dexan scan.
In this case, the authors noted that the findings pinpoint a triglyceride and cholesterol transport problem. That finding fits with another Open Medicine Foundation-funded study by Alain Moreau in Canada, which found high levels of a microRNA that may be inhibiting lipid metabolism.
That inhibition could lead to increased levels of VLDL particles and triglycerides, both of which signal metabolic difficulties and could result in impaired glucose metabolism, insulin resistance, atherosclerosis, and other problems. Indeed, both VLDL particles and glucose levels (possibly a sign of insulin resistance) were increased.
These findings are smack on with past study findings suggesting that the cellular membranes in ME/CFS patients are being “destabilized” (ripped apart by free radicals), that cell signaling is being disrupted (cells may be dead in the water and unresponsive), and that there is dysregulated immune cell functioning.
New Metabolic Hypothesis Emerges
As it has in other studies, a gender gap emerged – and in a most interesting way. Increased alanine levels in females in particular and elevated levels of BCAAs suggested that in females, the preferential breakdown of amino acids (rather than fats or carbohydrates) for energy was exacerbated.
With that, the authors came up with a fascinating new metabolic reason why more females than males get ME/CFS: their increased usage of a process called anaplerosis. Anaplerosis refers to how women – more so than men – use amino acids to replenish the intermediates in the TCA, or Krebs cycle, in the mitochondria.
You may recognize some of these intermediates, as, if memory serves, at least two of them (oxaloacetate, citrate) have been found reduced in ME/CFS. They include oxaloacetate, citrate, isocitrate, α-Ketoglutarate, succinyl-CoA, succinate, fumarate, and malate. A recent blog reported that oxaloacetate supplementation can be very helpful in some people with ME/CFS.
Many processes (increased energy demand, metabolic disorders, oxidative stress, problems with anaplerosis, hypoxia (low oxygen conditions), Warburg effect, and others) can drain these intermediates from the Krebs cycle – triggering efforts to get more amino acids to replenish them and keep the cycle going.
This could lead to the body breaking down muscle tissue to supply the amino acids needed. Reduced levels of the intermediates in the Krebs cycle in women, in particular, then, could lead to the increased use of amino acids that we’ve seen time and time again in metabolomic studies – and help explain why women are more vulnerable to ME/CFS.
Low Cortisol Connection Too?
The authors also proposed that the fatty acid dysregulation could play a role in “the most reliable biomarker in ME/CFS research” and possibly a key factor in long COVID – low cortisol levels. This is because cortisol is synthesized from cholesterol, and fatty acids affect cholesterol availability.
Check out all the red lines. Those are the ME/CFS patients – they demonstrated a propensity to stand out relative to the control groups.
The Hunt for a Biomarker (Biomarkers) Continues
When researchers want to find a biomarker (or biomarkers), they often reach for metabolomics. This is because metabolomics data is so comprehensive – covering all systems – and because it provides a snapshot of one’s current physiological state.
Early in the paper, the authors noted that ME/CFS metabolomics studies have produced a list of possible biomarkers (energy, amino acid, and lipid metabolism, the urea cycle, and oxidative stress), but a conclusive biomarker panel has yet to be verified. (Note that the fact that all of these can be connected suggests they’re on the right track.)
At the end of this study, we still don’t have a signature biomarker – and maybe that was to be expected. My understanding is that metabolomics analyses have improved significantly over time. Because this original metabolomics work was done years ago, the metabolomics data may not be as thorough or as accurate as metabolomic analyses that are done today.
Plus, this wasn’t exactly the most well-defined group. The ME/CFS participants simply reported getting an ME/CFS diagnosis and were probably healthier than most people with ME/CFS. Even with these provisos, the study produced results that are in sync with what we know so far.
Next Steps
What’s next? Bigger and better studies.
These big public data sets are like gold to the researchers to take the time to analyze them. It simply takes an alert team to find the data and analyze it – and this is just the beginning of a continuing process for this Australian team.
When they designed a “disease detection model” that could estimate the likelihood of someone coming down with a disease, they did so with a look forward to the future. In this study, the model – which included metabolomic biomarkers and other data – did pretty well predicting who had ME/CFS.
Future studies will do better. As deep phenotyping (metabolomics, proteomics, transcriptomics, etc.) data becomes available from other public, large databanks such as the UK ME/CFS Biobank, DecodeME, and All of Us, the model the team created should become ever more effective, putting them closer to understanding ME/CFS. The UK Biobank, for instance, is over time, continuing to release imaging, genomics and proteomics data, that they (and other researchers) can use to better understand ME/CFS and related diseases.
(There’s also the RECOVER Long COVID databank – which would be enormous and enormously helpful – if RECOVER ever gets around to doing “deep phenotyping”. Time will tell!)
Health Rising’s previous blog, and this one, highlight the critical role non-profits play in forwarding ME/CFS and long-COVID research. This study, as was noted before, was funded entirely by two research foundations – the Open Medicine Foundation and the Mason Foundation.
The OMF’s BioQuest Biomarker Study
On that note, thanks to two generous donors, the hunt for the elusive ME/CFS biomarkers just heated up. The OMF recently announced that it’s received funding ($800K) to begin a mega biomarker study. The BioQuest study plans to measure over 10,000 proteins and metabolites in blood samples of up to 1,200 patients and controls (whoa!). One of the hardest parts – getting the samples – has already been done. What’s left is testing and analyzing them.
The team will use artificial intelligence techniques to attempt to identify 5-20 protein/metabolite biomarkers. With the initial funding in place, the team is finalizing the study design and obtaining the approvals needed to begin testing the samples. Then the testing will begin…
- Check out the study here.
Good luck to them!
Health Rising’s BIG (little) Donation Drive Update
Where is that darn biomarker? We’ll let you know when we find it!
Thanks to the over 270 people who have gifted Health Rising with over $45,000 to date.
Metabolomic studies have proved to play a key role in helping to understand ME/CFS and related diseases – and that’s why Health Rising consistently covers them. With their focus on metabolism and molecular interactions, they’re also amongst the most difficult studies to understand – but what the heck? We’re here to understand ME/CFS and related diseases and that means digging into them as best we can.
If that kind of commitment supports you – please support us during our year-end (year beginning :)) donation drive!
Hi Cort, hoping most studies are not re discovering findings and instead focusing on needed information for treatments. Sigh
Yes, we seem to have many of these sorts of studies over the past 3-4 years. Don’t really seem to be driving knowledge forward.
Fingers crossed on the rapamycin studies.
Such a complex disease requires a lot of background knowledge and research and I find it more than understandable that this takes a lot of time. Then there are also the major hurdles of funding, which also takes up a lot of time.
I’ve been ill for 13 years and I’m just delighted that research has picked up speed in recent years. And the constant stream of new findings and the never-ending urge to research gives me courage and hope and, of course, increases our knowledge of the processes involved until there is a breakthrough one day in which direction our disease is heading.
I don;t think this study really had a chance of breaking things open – it had too many proviso’s – but I was pleased with it because it highlighted lipids again – and validating findings is VERY important. Research rarely get anywhere with a single finding – particularly in this field with its small studies findings have to be validated again and again to get standing.
The fact that this study did that – with a rather different but large ME/CFS population was really outstanding IMO. With several studies getting simnilar findings I think we look forward to the next step: an in-depth investigations of the lipid situation – which is tied in with energy production and and so much more.
Plus we got a new hypothesis why more women than men get ME/CFS. That hypothesis centered on a reduction in the intermediate substances that help drive the Krebs cycle. So now – we have an arrow pointing at the Krebs cycle – which oxaloacetate plays a big part in – and which is being investigated as a treatment.
So to me – it seems like this study is linking different factors together – a good sign that researchers are onto something 🙂
Fair enough.
BTW, something you didn’t really highlight is that inflammation showed up big time again, with levels of GlycA being among a handful of the most significant biomarkers.
There can be no doubt now that ME/CFS is an inflammatory illness.
I suspect that inflammation is the driver of the other things, rather than the other way around.
Hello Matthias,I had ME/CFS since contrating (MONO)EBV Virus in Oct 1,2008 at age 48 and now soon to be 65 yr old still living with this dreadful disease or Syndrom and I agree with year.When I started going into bad episode I can feal the inflamation start coming up my spine and back of my neck into the brain cavity.It wreaks havoc and causes me sever brain fog and my eyesight gets more blurry and the all over Joint and muscle pain intensivies the pain in my head is not like a headache or migraine its the fealing of inflamation of the brain and you cant thank like a normal person can and this waxes and Wayne’s 24/7. 365 days a year My extremities feel so heavy.Have to lay down to rest my neck because I have episodes like my neck cant support my head.My legs and especially my feet deals like I am wearing Concrete Shoes and many days a month afters sleeping in get up in sever pain.Pain wakes me up 1 to up to 3 times a night several times a week.When I do get a good deep sleep I got up in pain take my medications ,get a coffee then go back to sleep again and some days I sleep a lot.Fatigue sucks.But I just wanted you to know that Inflamation plays a major role in ME/CFS.The first 3 years the inflamation in my brain cavity was so sever my dad allways told me my eyes looked like they were going to pop out of my sockets.Now 16 going on 17 yrs with ME/CFS still living with all the same symptoms.I get hot and then cold i use the Walgreens Didgetal Thermometer and have body Tempiture Fluctuates some where between 96.9 to little over 101 Degree’s.Primary care doctors and hospitals use these damn point and shoot thermometers.My primary care doctor even agrees that the Walgreens Didgetal Thermometer is the most accurate.Doctors and hospitals need to go back to the Didgetal.Those point and shoot thermometers are best used in automotive for checking tempitures of brake calibers,hot wheels(Rims that are hot is truly a sign of wore out wheel bearings or CV Joints,and point and shoot thermometers are good for checking the air conditioning condenser .The bottom of a/c condenser should read a certain tempiture than the to off the condenser.Anyway we live with this,suffer with this and pray a lot that God will deliver these popular well known ME/CFS researchers and biochemists etc and possibly diagnostic biomarkers that all will agree upon and pray for a Miracle.You take care my friend
David downer….have you tried changing your diet?
You won’t notice a change in diet helping you overnight….some people it takes months before they notice any effect….that’s why people give up with diet changes,…they don’t see any improvement after the first month or so.
Some people are so deep into this they can’t see the forest for the trees.
These studies are making significant strides towards identifying a specific Biomarker for ME/CFS, a breakthrough that could revolutionize the speed and accuracy of diagnoses, offering hope for the future.
Indeed, inflammation is a significant contributor to ME/CFS, indicating that our immune system is under stress. However, it’s important to note that the very definition of ME/CFS does specifically refer to inflammation in the brain and spinal cord, but rather to a complex set of symptoms that can include neurological, immune, and energy metabolism dysfunctions.
I have had ME/CFS for over twenty years, and I have improved by Pacing and focusing on my Digestion and Gut. I have alway thought I was not getting the energy from my food and my nutrient absorbtion was poor. I also noticed that I have a insulan resistance problem, so put weight on easily. To me these studies just confirm this rearch is on the money.
It’s good to see the increase in funding into this illness.
Exactly ! Anaplerosis and a deficit of the internediate substances which are normally borrowed out, but in the case of CFS fail to be put back
I agree with “Seattle.” While the studies reported appear to be elegant and are likely well-designed and well-executed, they seem to focus almost exclusively on what’s wrong rather than how to fix it. For those of us suffering from ME/CFS, it does little if any good to recognize that people “understand“ us or the source of our misery. I continue to marvel at how little I read about the investigation or development of solutions. It’s most discouraging. Reminds me a little of the old saying, “Fiddling while Rome burns.”
While I don’t think this study was going to provide THE answer it did take advantage of a very large population of ME/CFS patients – making it very easily the largest metabolomic study ever done – and it did provide new openings. For instance, it suggested that researchers need to look into why the intermediates of the Kreb cycle are not being replenished adequately. I have never seen that mentioned before…
You can’t try to fix something unless you know what to fix and the truth is that we are far from a consensus of what has gone wrong in ME/CFS. We have possibilities – quite a few possibilities – but nothing that’s been solid enough to prompt some big treatment studies.
Once we do get there – they will show up and the fact that they are showing will be an indication that things have changed.
I agree with you Cort – exciting times for ME patients. I’ve had severe ME for decades – I’d lost hope that ME research or treatment would ever happen pre COVID.
I gave a sample for DecodeME. Latest is an Oxford biotech company called Precision Life is analysing the samples, along with samples from ME patients in the UK bio bank. They are looking for gene mutations showing subgroups within ME, and working with Metrodora to hopefully trial repurposed drugs. Full article written by Precision Life in the December 25% ME Group magazine.
On the 16th December new research announced by Action for ME – SequenceME which will use DecodeME samples. Another Oxford biotech company called Nanopore Technologies will be doing the research if they can get the £7million funding.
https://www.actionforme.org.uk/news/sequenceme/
Thank you Cort for all your hardwork. I remember the dark old days – you give us so much hope.
Thanks and thanks for all that information. Things are starting to hop! Good news to hear at the end of the year and the beginning of the new one:)
Found this update on the Precision Life website.
https://precisionlife.com/news-and-events/precisionlife-and-metrodora-institute-share-first-insights-with-metx-study-participants
Happy New Year.
I agree with Kajo; thanks for all you do for this community, Cort, a shining light in the darkness. I hope that you can keep up the good work.
The insights that surfaced in this study could prove very important – it’s a big clue that such a majority of patients are female! Perhaps the biggest “subset”.
Also very nicely done that the researchers made use of preexisting biobank data. All this data should continue to pay off in the future (and I imagine with less outlay of funds than starting from scratch each time).
Thanks for highlighting these studies & putting them into context.
Thanks – this should be just the beginning of some really big and interesting studies done using public databases.
Found an interesting summary on ME/CFS on Medscape. Check out the links for in-depth info on diagnostics and comparisons. Less helpful on treatment but if you follow the links to the Bateman Center, there are some gems.
https://www.medscape.com/viewarticle/post-exertional-malaise-fatiguing-diseases-what-know-avoid-2024a1000ot1?ecd=mkm_ret_241228_mscpmrk_rheum_top-content_etid7123733&uac=139183PJ&impID=7123733
Also finally am trying hydrogen water–and eureka! it helps! http://www.drinkhrw.com. Not sure how to describe the effects, but noticably better.
Hope I am awarded the little green wheel because I am decidedly NOT a bot!
Thanks for all your work again in 2024, Cort. Wishing you a happy new year. Let’s hope that 2025 can bring more meaningful progress. Hopefully some game changers.
I maintain that it is the brain, as I have for a long time, where the real problems lie. Inflammation contributes to these problems. I would like to see more in this area. I wonder if Andrew Miller is conducting any research at present.
I have just been reading some interesting research on GWI related to the brain and possible treatment.
Thank you so much! Does anyone know when we can expect the results of the Biomarker Study?
I know this is very hard to know and Science moves slow but as far as I understand they dont have to recruit / enroll Patients, right? So this should move somewhat fast?
I would love an overview abt planned and ongoing studies with the expected publishing date/ study endpoint.
Wishing everyone a happy new year!
I forget where it was mentioned regarding some type of difficultly with the body metabolizing fatty acids.
Curious to know if anyone has tried or looked into taking the supplement called “Fatty15”
I’ve been toying with the idea for a while now.
Product claims to improve liver and red blood cell health and:
As a pure, bioavailable, science-backed, vegan-friendly and award-winning C15:0 supplement, fatty15 actively repairs, restores and revitalizes our long-term health at the cellular level by:*
– Strengthening our cell membranes to armor our cells (and us) against age-related breakdown
– Repairing mitochondrial function, which keeps our body’s energy-producers going
– Naturally activating receptors (including PPARs and AMPK) that regulate our metabolism, immunity, mood, sleep and appetite
– Naturally inhibiting damaging pathways (including mTOR and JAK-STAT) as a means to support longevity
All in, fatty15 provides 36+ cellular benefits to support our long-term health, which is 3x more than even the purest, highest performing omega-3 (EPA).