New path

The Roadmap initiative is about charting a new path for ME/CFS at the NIH.

The Metabolism webinar is part of the ME/CFS Research Roadmap effort. The effort was put together by Dr. Koroshetz and Vicky Whittemore as a way to advance chronic fatigue syndrome (ME/CFS) research at the NIH. The Roadmap effort was conceived pre-COVID, then was derailed for several years by the COVID-19 pandemic, and took life again about a year ago. Because this is an NIH-created and produced effort it has a unique cachet at the NIH and it’s hoped that it will, as other Roadmaps have done in the past, boost interest in and funding for ME/CFS.

It’s a big effort. The Metabolism webinar is just one of 8 webinars that will go to form a report to the NINDS leadership and NIH for setting research priorities for chronic fatigue syndrome research.

Because these Roadmap lectures are designed to flesh out the way forward, they will all at some point focus on not what’s happening but what they believe should be happening, and why the researchers believe the NIH should invest more in ME/CFS.

The Metabolism Webinar 

Dr. Shuzhao Li Ph.D. – associate professor investigator at the Jackson Laboratory.  Dr. Li is a leading expert in the field of metabolomics for precision medicine, iShuzhao Limmunometabolomics, and multi-omics modeling of the immune system.

After Chris Wikman told his ME/CFS story, Dr. Shuzhao Li led off with a fascinating and helpful talk on metabolomics. In the last ME/CFS NIH conference, the metabolomic speaker talked very little about ME/CFS but a lot about how far the metabolomics needed to go. He actually seemed apologetic about the state of the field.

Five years later, Li was excited – not apologetic. Li talked about the major steps forward the metabolomic and immunology fields have taken recently. Highlighting the inconsistencies in the immune results we’ve seen in ME/CFS for decades, Li encouragingly said there is an answer for that and that it’s not surprising – given the relative newness of the field – that we’re getting inconsistent results. Making sense of it – if I got it right – requires bigger studies that look at more factors. Once that happens, things start making sense.

He talked about a vaccination study done outside of ME/CFS which looked at virtually everything (cytokines, metabolites, cells, genes) over various time points. Once they did that, they could start to see how the different factors interacted. A gene network, for instance, was linked to a metabolite network. They could even see how a change on day 3 in metabolites showed up in changes to an immune gene network several days later, and they made special note of the gut microbiome’s effect on the immune system.

One of his post-docs (Minghao) ended up dedicating most of two years to working on the massive ME/CFS dataset that Derya Unutmaz and his group at the NIH-funded Jackson lab had produced.

The study had 78 patients who’d had ME/CFS for over 10 years (n=78), 75 patients for less than 4 years, and 96 healthy controls – in other words, it was a nice, big, meaty NIH study – the kind we want more of.

Duration Matters

The first takeaway was that the cell populations – the immune cells found in each cohort – were different – and the people with longer-duration ME/CFS had the most unusual sets of immune cells. The same pattern prevailed with the metabolomics assays – the longer-duration ME/CFS patients had more unusual lipid findings than the shorter-duration ME/CFS patients and the healthy controls.

Sand clock Enschede

Not surprisingly, duration mattered – the longer the patients had been ill, the more lipid abnormalities and toxins they found.

Lipids showed up big time. That was a nice finding – as several of Hanson’s and Lipkin’s NIH-funded studies have also emphasized abnormalities in the lipids or fats that surround our cells. Even better, the Li study appears to have plucked out many of the same fats – the carnitines, ceramides, cholesterols, and sphingolipids that the other studies found. Since everything that happens in a cell is triggered by a receptor on the surface of the cell, lipid problems could cause a lot of mischief.

The really surprising finding for Li, though, was the high number of xenobiotics; i.e. toxins found in the ME/CFS patients – particularly the longer-term patients.

When they assessed the patients a year later, they found just what we would want them to find – consistent results. With this study, then, we appear to have consistency not just between the patients in this study (all from the Bateman Horne Center) but consistency between the different cohorts and different laboratories in the Hanson and Lipkin studies.

Li then used three different methods – multi-omics factorial analysis or latent factorial analysis, multiscale modeling, and tests to assess the impacts metabolites and individual immune cells have on each other.

The multi-omics factorial analysis again showed that the data from the two visits were consistent with each other and they found a quite changed ecosystem in the ME/CFS patients. Some lipids (lysophospholipids) in the ME/CFS patients, for instance, were associated with dramatic changes in their CD4 T-cells but didn’t have an impact on the healthy controls.

The bottom line – the immune, metabolomic, and clinical data were all correlated, and that was good news. The goal is to be able to form a story, and it’s data like that that can form a story. The other interesting news is that that the immune-metabolite connection involved a lot of metabolites derived from the gut – suggesting, as other studies have, that the gut may play a major role.

Li didn’t say much about where the high levels of toxins (xenobiotics) came from or the role they may play. He called them the “exposome” which refers to the “environmental exposures that an individual encounters throughout life”.

Room For Improvement


In a surprise finding, more xenobiotics or toxins were found in the ME/CFS patients.

While the study provided some intriguing findings – we’ll learn more about them in the paper – it’s also clear that the metabolomics field still has a ways to go to achieve its potential. The 1,000 metabolites they sampled, for instance, only captured a part of the potential metabolome data. Given how important metabolomics has been to ME/CFS, further advances in the field will only bring more insights. Li also stated that the “systems immunology field” which assesses how the immune system interacts with other systems needs more work.

We’ll know much more about this very complex study when the paper or papers come out. It presented some nice validation of other study findings – indicating that our researchers are on the right track – but not enough clarity regarding what’s causing what. We’re not at the point yet where researchers can point to a critical pathway or metabolite and state this should be treated in a clinical trial.

The Future of Personalized Treatment?

While the metabolomics field is not yet mature, Derya Unutmaz of Jackson Labs made it clear that when it came to treatments, he thought it was the future. He believes these metabolomics analyses will lend themselves to personalized treatments. Note that a study found that some metabolite changes came first and resulted in immune dysfunction. If primary metabolite alterations can be identified, then they should be assessed in a blood test. If the blood test is positive, then ways could be found to alter the metabolite levels through diet or drugs.

Unutmaz thought the metabolite-immune connection was particularly fruitful given the high numbers of metabolites found in ME/CFS that were associated with the gut microbiome – which lends itself to manipulation. That was interesting given that, if memory serves, the LIINC group’s findings focused on a gut coronavirus reservoir. Could the same be true with ME/CFS and Epstein-Barr, or another virus?

Jessica Maya Ph.D. – Cornell University – Maureen Hanson’s Lab – Immunometabolism

Metabolism plays a key role in our immune response. To activate and help fight off an invader, our immune cells must rev up their engines dramatically. When they’re not activated, they rely on aerobic energy production to keep their engines purring, but when activated, they switch and rely on glycolysis (anaerobic energy production) to get moving.

As with the immune studies, the metabolic studies (which often assess immune cells) have been inconsistent as well. Why? Again we saw a reason that we’ve been hearing about for decades – small sample sizes – but a different one showed up this time – throwing all the immune cells found in the blood together and then assessing them as a whole..

Instead of throwing all the peripheral blood monocular cells (PBMCs – monocytes, NK cells, T cells, B cells, dendritic cells) together in one batch (as is usually done) and analyzing them as a whole, Maya separated out the 2 kinds of T cells and NK cells and analyzed them that way.

T-cell exhaustion

Jessica Maya found exhausted T-cells. T-cell exhaustion has been found in both ME/CFS and long COVID.

She found that the T cells were stuck in a hypometabolic state – they couldn’t rev up their engines enough to get going – and were in a state of exhaustion: i.e.; they weren’t able to proliferate properly, they had trouble killing infected cells, and they died off more quickly than normal. That’s not a good finding for one of the key virus-fighting immune cells in the body, but it makes sense with what we know about ME/CFS.

Liisa Selin’s recent paper on T cells in both ME/CFS and long COVID stated that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα.

Maya reported that other studies suggest that other immune cells (neutrophils, monocytes) may also be exhausted. and she reported a possible reason – the altered fatty acid/lipid profiles that Li found in the first presentation. Since fatty acids are important for energy production, the altered lipid profiles found in past studies could help explain why.

In the end, she brought us back to the promise of the single-cell analyses and outlined the many, many different analyses, as well as other techniques, that could help understand the metabolism of immune cells in ME/CFS.

Dr. Jiabao Xu, PhD – Collaborator with Karl Morten –  A Biomarker in the Making? Raman Spectroscopy


Jiabao Xu’s focus is on using Raman spectroscopy to deciper ME/CFS, long COVID and chronic Lyme diseases, as well as inflammatory autoimmune diseases.

The Raman spectroscopy findings suggesting that a biomarker might be in sight made big waves in the ME/CFS world and it was good to see Jiabao Xu talk about them and what’s needed to move forward.

Once again, we were back to… single cell tests. No more throwing a bunch of immune cells into a pot (or test tube) – and hoping that something pops out. The focus now is on testing each immune cell by itself.

Raman spectroscopy demonstrates the remarkable steps that have been made in the medical field. Xu started off by saying, “as we all know every molecule in our body is constantly vibrating”. That was news to me, but it turns out that Raman spectroscopy measures the “vibrations” in a sample by bouncing light off it and assessing the wavelengths found. By doing that, it can tell what kind of molecule is present. (So simple! (lol).)

Raman spectroscopy is special because it doesn’t disturb the cells; is very sensitive; and because it can handle water, it can assess cells in their natural environments. It can also assess cells at the “subcellular” level. When used with machine learning (artificial intelligence), it does very well at diagnosing diseases.

Raman spectroscopy was first used in ME/CFS on a small scale: it assessed the PBMCs in just 12 patients and 12 controls but was successful. The next study was larger (n=89) and included multiple sclerosis (MS) patients. This time, it used both PBMCs and single-cell testing and was able to differentiate ME/CFS from MS and healthy controls (90% accuracy) and mild, moderate, and severe ME/CFS patients from each other (84% accuracy) – something that has rarely, if ever, been done in a diagnostic study. Accuracy, sensitivity (91%), and specificity (93%) were all particularly high for the ME/CFS group. And there you have it – a potential biomarker for ME/CFS that could be done with a couple of droplets of blood and can be used with frozen blood as well.

That was best accomplished by using single-cell assessments. When they turned the Raman spectroscopy onto a metabolic analysis which suggested that tryptophan metabolism, in particular, was dysregulated in ME/CFS – possibly resulting in inflammation, the production of neurotoxic compounds, and lower serotonin levels in the brain.


  • The ME/CFS Research Roadmap effort was put together by Dr. Koroshetz and Vicky Whittemore as a way to advance chronic fatigue syndrome (ME/CFS) research at the NIH. The Metabolism webinar is just one of 8 webinars that will go to form a report to the NINDS leadership and NIH for setting research priorities for MECFS, and hopefully increase funding.
  • Dr. Shuzhao Li Ph.D. of the Jackson Labs talked of a large NIH-funded project which – as other studies have – found evidence of problems with the lipids that surround our cells, plus – in a surprise – he found higher than normal levels of xenobiotics, or toxins. The lipid issue could affect everything from cell viability to energy production to very basic cellular operations. The longer a person had had ME/CFS, the more lipid abnormalities and toxins they had.
  • While this study did not identify a specific cause, Derya Unutmaz of Jackson Labs metabolomics analyses will lend themselves to personalized treatments, first via a blood test, and then via diet/drugs to alter the metabolite levels. He noted that many of the altered metabolites in this study came from the gut.
  • Jessica Maya of Maureen Hanson’s Cornell lab found that ME/CFS patients’ T cells were stuck in a hypometabolic state – they couldn’t rev up their engines enough to get going – and were in a state of exhaustion: i.e.; they weren’t able to proliferate properly, they had trouble killing infected cells, and they died off more quickly than normal.
  • Maya reported that other studies suggest that other immune cells (neutrophils, monocytes) may also be exhausted, and that the altered fatty acid/lipid profiles that Li found in the first presentation could be the reason.
  • Wenzhong Xiao, the co-director of the Open Medicine Foundation’s Ronald G. Tompkins Harvard ME/CFS Collaboration, asked why the metabolomic results have not been as consistent as we want and why we do not yet have a metabolic signature. Aside from the routine answers – small sample sizes, non-standardized sampling, etc. – he suggested that we have to look deeper – at the tissues.
  • He reported that the muscles of intensive care unit patients still sometimes cannot produce energy even 2 years after they’ve left the ICU. Modeling results suggested – surprise, surprise – that oxaloacetate, a supplement now being explored in ME/CFS, would help.
  • Now they’re employing a similar approach at the Open Medicine Foundation-funded Harvard Collaborative ME/CFS Center. With their muscle biopsy studies, they hope to find similar ways to get ME/CFS patients’ muscles going again.
Concerning lipids, they found decreased cholesterol levels and altered fatty acid acids – suggesting that the lipids are being broken down to produce energy.

Morten’s group plans next to continue to focus on single-cell assessments and include long COVID and chronic Lyme syndrome in their next efforts to validate their approach. (She noted how often he heard ME/CFS being discussed in a recent Lyme conference – a good sign – and how after a chronic Lyme patient was cured, they got the same old Lyme symptoms after coming down with the coronavirus.) They also want to look more deeply at the metabolism, and metabolic and energetic pathways of the immune cells involved in ME/CFS.

Wengzhong Xiao – Down to the Tissues. Do the Muscles Have it?

Wenzhong Xiao wears many hats, including the co-director of the Open Medicine Foundation’s Ronald G. Tompkins Harvard ME/CFS Collaboration,  Director of the Immuno-Metabolic Computational Center at Mass General, leader of the Computational Genomics Group – Stanford Genome Center; Director of the Open Medicine Foundation-Supported Computational Research Center for Complex Diseases.

Xiao started with the 2016 Naviaux metabolomics paper that really got things going concerning metabolomics in ME/CFS. The paper proposed that ME/CFS patients were in a state of hypometabolism; i.e. they were unable to generate normal amounts of energy at the molecular level.

Noting that the results have not been as consistent as we want, and that we do not yet have a metabolic signature, he addressed some reasons why. Different platforms (NMR vs mass spec) assess different metabolites. Metabolomics is also very sensitive to things like diet, activity levels, drugs, sleep status, the quality of the assays used, etc.

He recommended that ME/CFS researchers use the same standard operating procedures when it comes to sample collection, sample processing, assays, and patient and healthy controls selection. (We’ve seen these types of recommendations again and again, and it’s this kind of standardization that makes the RECOVER studies into long COVID potentially so valuable.)

Next Xiao asked how testing for metabolites in the plasma could tell us what’s causing ME/CFS. He noted that when Naviaux compared the metabolites in the cerebral spinal fluid with those in the plasma, he found few correlates; i.e. the metabolite analysis of the blood didn’t tell him much about what’s happening in the brain. For instance, nothing was found in the blood that could inform us about the status of dopamine in the cerebral spinal fluid.

The takeaway – one that we’re increasingly seeing in ME/CFS and long COVID – is to examine the tissues, and that’s what David Systrom and Xiao are doing with their muscle biopsy study.

The goal is to find the “bottlenecks” that are shutting down or impairing the metabolic pathways. When they did this using muscle biopsies in ICU patients, they found that even 2 years after being in the ICU, their muscles were still unable to generate much ATP.

When they employed modeling to find a way to get their muscles working again, what did they come up with but oxaloacetate (!). This was years before oxaloacetate showed up on the scene in ME/CFS. (Dr. David Kaufman chanced on it, as I remember, after looking at metabolomic studies in ME/CFS.)

Oxaloacetate: the Best Mitochondrial Supplement for ME/CFS (and Long COVID?)

Now that they’re employing a similar approach at the Open Medicine Foundation-funded Harvard Collaborative ME/CFS Center. With their muscle biopsy studies, they hope to find similar ways to get ME/CFS patients’ muscles going again. Speaking of muscle studies – we are suddenly awash in ME/CFS muscle studies!

The Open Medicine Foundation is leading the way with two muscle studies – one of which is employing a 2-day exercise test. Plus, Paul Hwang and Avindra Nath at the NIH are continuing to extend the muscle cell findings that sparked Hwang’s exciting WASF3 paper, and Rob Wust and his Solve M.E. Ramsay award will be examining ME/CFS muscles after exercise as well. Plus, we’ve recently had some muscle findings that Klaus Wirth believes tell us something fundamental about this disease.

The muscles are finally starting to get their due.

The Muscle ME/CFS Connection – Could it Tell the Tale?


While we still lack a specific target – a metabolite or group of metabolites that researchers agree are the cause or a cause of ME/CFS – it was heartening to see the lipids pop up once again and to see the metabolomic, lab, and clinical results jive. It was also good to see a gut emphasis as the gut is one of the more easily manipulated organs. On that note, Derya Unutmaz held out metabolites as the future of personalized treatments. We’re certainly not there yet, but innovative doctors will take results like these and test them out – as David Kaufman is doing with oxaloacetate – and a blog on lipid replacement therapy is coming up.

The increased levels of xenobiotics (toxins) were new, and one wonders what they signify. The T-cell exhaustion finding, on the other hand, helps to validate past findings and may be a prelude to future findings … could all the immune cells in ME/CFS be exhausted? Finally, the increased emphasis on digging deep into the muscles is nothing but encouraging, and one hopes that Wengzhong can duplicate his ICU findings and find a way to get ME/CFS patients’ muscles moving again.


Interested in this Approach to ME/CFS/FM and Similar Diseases? Please Support Health Rising and Keep the Information Flowing





Like the blog you're reading? Don't miss another one.

Get the most in-depth information available on the latest ME/CFS and FM treatment and research findings by registering for Health Rising's free  ME/CFS and Fibromyalgia blog here.

Stay on Top of the News!

Subscribe To Health Rising’s Free Information on Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM), Long COVID and Related Diseases.

Thank you for signing up!

Pin It on Pinterest

Share This