information gathering

The goal – gather different types of information into one coherent whole.

The “omics” studies (genomics, metabolomics, proteomics, transcriptomics) are all the rage. These studies are attempting to get at the molecular roots of chronic fatigue syndrome (ME/CFS), but there’s a problem. ME/CFS is probably not just a “genomics” disease, a metabolic disease, or a disease of the microbiome. It’s probably all of these.

That means we have to find some way to integrate these findings with each other and that’s what this 2020 Japanese study attempted to do. The study, “Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population“, assessed the metabolome, immunophenotype, transcriptome, and microbiome as well as standard lab tests, and gave 48 ME/CFS and 52 healthy controls questionnaires, activity measurements, simple cognitive tests, and sleep assessments.

The Gist

  • In an attempt to integrate findings from several different systems together and get a more complete picture of ME/CFS a Japanese study combined metabolome, immunophenotype, transcriptome, lipidome and microbiome results as well as standard lab tests, a sleep, and basic cognitive test together.
  • The metabolome, transcriptome and immune results were not particularly revealing. The lipid and microbiome results were.
  • A “strong negative association” between the amount of the butyrate-producing Faecalbacterium (F. prausnitzii) and the number of sleep awakenings was particularly interesting given past studies suggesting that butyrate-producing bacteria are deficient in ME/CFS and sleep studies indicating that increased sleep awakenings are present.
  • All eight of the lipid tests were abnormal in the ME/CFS group: all the inflammatory lipids were increased and all the healthy lipids were decreased – suggesting, as other studies have, that people with ME/CFS may be at increased risk of a cardiovascular disease.
  • The study also suggested that the lipid and microbiome changes occur relatively early in the illness – prior to the three-year mark.
  • The study had some interesting findings but was relatively primitive as well with low numbers of metabolites, immune cells, antibodies, the small laboratory panel, etc. Much, much bigger, and more comprehensive multisystemic studies are surely coming in long COVID, and at least one – the combination study from the NIH-funded ME/CFS research centers – should be as well.
Gathering over 70,000 data points, they found significant differences between healthy controls and people with ME/CFS in nine clinical laboratory tests (reduced urea, uric acid, creatine kinase, bilirubin, high-density lipoproteins; and increased cholesterol, triglycerides, thyroid-stimulating hormone), eight lipoprotein fractions (all healthy lipoproteins reduced; all unhealthy lipoproteins increased), two immune cell types, and six different bacterial genera.

Note that none of the metabolites provided much help distinguishing the ME/CFS patients from the healthy controls and only two immune cells did; instead, it was the clinical lab tests, the microbiome, and the lipoprotein levels that were most changed in the ME/CFS patients. Of the six most distinguishing markers, the microbiome and the lipoproteins stood out – taking five of the six top places.

Gut-Sleep Connection

Gut bacteria proved to have a strong effect. The authors noted there was a strong negative correlation between the abundance of bacteria from the Faecalibacterium genera abundance and the number of awakenings during sleep; that is, the more  Faecalibacterium present, the fewer the awakenings, and presumably the better the sleep.

That was encouraging as sleep awakenings appear to be a particularly important aspect of sleep in both ME/CFS and fibromyalgia.

This isn’t the first time that reduced levels of Faecalibacterium have been associated with ME/CFS or with problems sleeping. Only one bacteria – F. prausnitzii – makes up the Faecalibacterium genus. F. prausnitzii is an important producer of butyrate – a gut lining protector and anti-inflammatory. Several studies suggest butyrate production is low in ME/CFS. Since inflammation has been associated with poorer sleep, an inflammatory gut could potentially interfere with sleep. Several animal studies have found that butyrate enhances sleep.

Enhancing Butyrate and Gut Health in ME/CFS, Fibromyalgia, Long COVID and Allied Disorders

Other gut measures have been associated with sleep as well. Gut flora diversity is reduced in ME/CFS but increased gut flora diversity has been associated with increased sleep quality and efficiency and total sleep times and reduced inflammatory markers. Conversely, poor sleep may impact the gut flora: even short-term sleep deprivation was shown to alter the gut bacteria.  The gut bacteria that are enhanced by poor sleep can induce fatigue.


Lipoprotein levels were also associated with reduced sleep. The choice to dig into the lipoproteins and measure eight of them was interesting and paid off. All the lipoprotein markers were “off”: the healthy low-density lipoproteins were decreased and the inflammatory high-density lipoproteins were increased. Increased levels of both triglycerides – recently highlighted in a study from the Lipkin ME/CFS group – as well as levels of the “bad” type of cholesterol,  VLDL – particularly stood out.

ME/CFS Metabolomic Study Points to a Potential Cause of Mitochondrial Dysfunction

Note that two of the three elements of a lipoprotein – the triglyceride and cholesterol center, surrounded by a phospholipid outer shell – showed up in the recent metabolomic study from the Lipkin ME/CFS research center. The same pattern prevailed: triglycerides – which can enhance oxidative stress, were high – and phospholipids – which enhance the integrity of the cell membrane, were low in that study.

This pattern as well as arterial stiffness has been found several times in ME/CFS and suggests an increased risk of cardiovascular disease is present.


Increased levels of inflammatory lipoproteins have been found several times in ME/CFS.

Noting that statins – cholesterol-reducing drugs – have been associated with reduced sleep awakenings, the authors wondered whether they might be helpful in ME/CFS. Statins, interestingly, did not affect sleep duration and efficiency, entry to stage I sleep, or time to achieve stage I sleep but did significantly reduce sleep awakenings. Statins can produce quite a few side effects including, apparently, a reduction in CoQ10 levels, but a recent fibromyalgia study did not find evidence that statins increased symptoms in FM, and concluded that statin therapy could be helpful in people with abnormal levels of lipids such as triglycerides and cholesterol.

Increased levels of bacteria from the Coprobacillus genus were associated with an increased time required to solve a math puzzle as well.

Lastly, the study found that the increased lipoprotein levels and microbiome changes appeared to occur early in the illness (<3 years) and that the microbiome actually improved after that. Long-COVID studies suggest that a shift to an inflammatory microbiome occurs very quickly in the illness as well.

Bigger, Better Studies Coming

more complex data sets coming

The study used pretty basic data. The long COVID and the NIH intramural study should assess much more comprehensive data sets.

This study came to some interesting conclusions, but it’s not the study we’re looking for. For all its complexity, it was in many ways quite basic. It measured only 40 metabolites (compared to 880 in a recent study), did what looked like a standard laboratory panel, assessed 20 of perhaps hundreds of different immune cells, just 20 antibodies (not including anti-GPCR autoantibodies), and 20 bacterial genera (no bacterial species). Plus, the sleep and cognitive assessments were pretty simple, and the cognitive test had not been validated.

Treatment Takeaways

  • The authors proposed that statins might help with both the lipid profile and sleep in ME/CFS. Statin can lower CoQ10 levels and produce a number of side effects. A fibromyalgia study, though, did not find that they increased symptoms.
  • The butyrate bacteria-sleep awakenings connection was intriguing and suggested that increasing these bacteria may be helpful. Check out some ways here.

The studies we’re looking for will be much bigger, more comprehensive, and better focused. The NIH-funded long-COVID research, with its methodological consistencies and its data core, appears to be designed to produce just these kinds of studies. We should also expect something of this type from the NIH-funded research centers in their combination study. Basically, what we want are large studies that can link the different clues from different systems together to provide a coherent narrative or story that explains these diseases. Gut bacteria, say, are linked with neuroinflammation, which shuts down the motor centers of the brain – or something like that.

These studies could include the results from a full-blown 900-metabolite analysis, large autoantibody panel, microbiome data down to the species, large immune panels, proteins from a proteome analysis, etc. combined with a sleep study, exercise, tilt table, and cognitive testing in a large number of patients.


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