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!
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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.
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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.