It was remarkable to see two studies and an NIH blog suggesting that a biomarker may have been found for chronic fatigue syndrome (ME/CFS) get published on the same day. The effort to promote and link these studies together worked and numerous media outlets have covered them. Part I of this series examined the large study coming out of Ian Lipkin’s ME/CFS research center.
Part II of this series checks out the Xiong/Oh paper, “Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients“, coming out of Derya Unutmaz’s NIH-funded research center at the Jackson Lab. This study was focused on the gut microbiome and the metabolome. In a twist, it compared short-duration patients (<4 years) with long-duration patients (>10 years) and in doing so, came up with a new hypothesis for how chronic fatigue syndrome (ME/CFS) begins.
The Unutmaz study piggybacked on an earlier Mady Hornig/Ian Lipkin study which suggested that shorter-duration ME/CFS patients had a dramatically different immune profile than longer-duration patients. In fact, the immune profiles of the two groups were reversed: the shorter-duration patients showed a highly upregulated immune system while the longer-duration patients showed possible evidence of immune exhaustion. Back in 2015, Mady Hornig suggested looking in the gut to find out why that had happened.
As Lipkin did in a past paper, the authors found that integrating all the variables – the microbiome and metabolite findings, as well as several models – helped them to best differentiate ME/CFS from the healthy controls. That suggests that large, multi-dimensional studies are the most effective at understanding this disorder.
When it came to distinguishing the ME/CFS patients from the age and sex-matched healthy controls it wasn’t the low butyrate but the low “evenness” found in the ME/CFS patients’ microbiome that really set them apart. Less common bacteria that produced compounds like tryptophan, butyrate, and propionic acid were less abundant. (The Williams Lipkin study also found a depletion of rarer microbes). That, of course, brings up the question of what could throw the microbiome off in that way. The authors noted that similar pattern has been found in the microbiome of “frail older adults”.
Cell Membranes – Again…
With regard to microbial genes, people with ME/CFS displayed decreased genes involved in the production of betaine (an anti-inflammatory), sphingomyelin, serotonin, and cholesterol. Sphingomyelin was also found reduced in Lipkin’s peroxisome study as well as low cholesterol.
Both appear to fit with Lipkin’s findings suggesting that high levels of cellular membrane damage are present. The cell membrane theme popped up again in the metabolomics results when lipid and cholesterol metabolites were found to discriminate ME/CFS patients from the healthy controls.
More Gut Issues at First, More Metabolic Issues Later
Interestingly, the greatest dysbiosis (i.e. the greatest gut flora alterations), reduced plasma isobutyrate, and more gut symptoms were found in the shorter-term patients (<10 years). Over time, the gut flora of the longer-term patients (>10 years) appears to have rebounded to some extent. While media reports and the abstract emphasized that the pattern the microbiome in the older ME/CFS patients still displayed low levels of the less common bacteria, including several butyrate producers. F. prausnitzii – highlighted in the Lipkin group’s paper – was also found reduced.
With two cholesterol and several lipid metabolites discriminating the longer-duration ME/CFS patients from healthy controls, the older group displayed more metabolic abnormalities. (Again, the damaged cellular membrane theme (cholesterol, lipids) pops up). Plus, the longer-duration patients were more apt to pick up a fibromyalgia diagnosis, had a trend towards worsening sleep problems, and had more PEM; i.e. things had not gotten better after ten years.
In a finding that bodes well for the future, six out of the ten metabolic biomarkers the Unutmaz team identified in this paper were also highlighted by the Lipkin team and Hanson teams (Germain) in their large metabolomic studies. That suggests these large studies are also coming up with some core metabolic abnormalities.
The similarities didn’t stop there, though. The overlap between the pathway abnormalities Naviaux found in his 2016 ground-breaking metabolomics paper and these more recent papers is rather remarkable as well. Naviaux’s study predicted many of the themes that are now popping up now including sphingolipids, phospholipids, cholesterol, purine, microbiome, branched-chain amino acid, peroxisomal (peroxisomes!), and mitochondrial metabolism.
Take purines. Back in 2017, Naviaux singled out purines. In 2023, the Unutmaz team highlighted a reduction in xanthines – a purine base.
Likewise, a small 2020 Japanese study had similar findings: an emphasis on microbiome and lipoproteins and cell membranes (all healthy lipoproteins reduced; all unhealthy lipoproteins increased), and reduced levels of Faecalibacterium.
Pentoxyifylline for Long COVID and ME/CFS?
The low levels of xanthines are interesting given that xanthines increase central nervous system alertness. Some people with ME/CFS/long COVID have used methylated xanthines such as caffeine, pentoxifylline and theobromine (found in dark chocolate) to increase alertness.
I have in my notes this, from a doctor, apparently. Unfortunately, I have no idea who it came from.
“I’ve had great success treating patients with LC with pentoxifylline. I also have them use nattokinase 4000fu and asa81mg. In 7-10 days the brain fog starts to lift and then the fatigue!! It is inexpensive and accessible; fairly safe. Just watch for bleeding when combining with other anticoagulants.”
The University Health Network, Toronto, has included pentoxifylline in its RECLAIM suite of treatment trials. Pentoxifylline is an old, reportedly safe, and inexpensive drug that has been found to do a bunch of things that could potentially be helpful in these diseases, including inhibiting the pro-inflammatory cytokine tumor necrosis factor, and improving blood vessel functioning by decreasing viscosity, lowering fibrinogen, and opening constricted blood vessels.
WebMD states pentoxifylline “increases the amount of oxygen that can be delivered by the blood when the muscles need more (such as during exercise) thereby increasing walking distance and duration.” Pentoxifylline – which I’ve never heard of until the last couple of months – sounds like a potentially good fit for long COVID and ME/CFS. It’s another new possibility that the long-COVID pandemic has uncovered.
A Gut Origin Hypothesis
Oh and the Unutmaz team providing an intriguing gut origin hypothesis for ME/CFS. They believe that the “modest but widespread” gut changes they’ve found occurring early in the disease could produce “cascading events” that have “cumulative and long-term effects”. They believe it may all begin with the loss of butyrate and tryptophan-producing bacteria, in particular. That loss ends up producing the “irreversible and unrecoverable” metabolite changes found later in the disease.
(They aren’t saying that the condition is irreversible; indeed, at the end of the paper they look forward to treatments. They appear to be saying even the partial recovery of the microbiome they saw in the longer-term patients isn’t enough to reverse the changes that end up occurring at the metabolic level. Indeed, the longer-term patients are sicker than ever.)
They were able to point to a study suggesting that an early depletion of butyrate-producing bacteria may precede ischemic heart disease and that the depletion occurs prior to that disease presenting itself. That suggests that determining how butyrate and tryptophan-producing bacteria get depleted in the first place (viruses? stomach flu? Giardia? pharmaceutical drugs?) should become a major theme. (Several years before I came down with ME/CFS, I experienced a Giardia infection while backpacking. Could that have been my trigger?).
Interestingly, the cardiovascular study showed that statins helped to restore the microbiome and improve the health of heart disease patients. Bruce Patterson is using them in long COVID and ME/CFS, and in 2020, Japanese researchers, noting that statins can reduce awakenings during sleep, suggested they be tried in ME/CFS. A recent fibromyalgia study suggested they might be helpful in that disease as well.
The Unutmaz team also pointed out the possibility that a similar microbiome soup (reduced butyrate, short-chain fatty acids, tryptophan) might precede other disorders as well. Given F. prausnitzii’s sensitivity to inflammatory environments, the Lipkin team questioned whether some sort of gut inflammation might spark its decline.
Still Homeless at the NIH
Both studies came from the NIH-funded ME/CFS research centers (Ian Lipkin’s/Derya Unutmaz’s) and they underscore why these centers are so valuable and why more and bigger centers are needed. The NIH is one of the few places that routinely provides the funding necessary for big studies like these that are crucial for moving fields forward.
Getting results like this proves that these Centers work, demonstrates that ME/CFS is not simply some sort of “wastebasket” disease that is not amenable to study, and shows that this field is missing precisely what we’ve been arguing it’s missing all along – large, rigorously put together studies.
- This is the 2nd part of a series of blogs exploring the recent NIH-funded gut studies that may have produced a biomarker for ME/CFS. This study from the Unutmaz research center largely replicated the low butyrate and short-chain fatty acid problems found in the Lipkin center study as well as others.
- Inspired by an earlier study that found dramatic differences in immune functioning in shorter vs longer-duration patients, this study compared a shorter-duration (< 4 years) and a long-duration group (>10 years).
- When it came to distinguishing the ME/CFS patients from the age and sex-matched healthy controls it wasn’t the low butyrate but the low “evenness” found in the ME/CFS patients’ microbiome that really set them apart. Less common bacteria that produced compounds like tryptophan, butyrate, and propionic acid were less abundant.
- Possible cell membrane damage reared its head again when a microbial gene analysis found reduced expression of genes associated with cholesterol and lipids as well as serotonin.
- The greatest dysbiosis (i.e. the greatest gut flora alteration, reduced butyrate levels) and more gut symptoms were found in the shorter-term patients (<10 years).
- With two cholesterol and several lipid metabolites discriminating the longer-duration ME/CFS patients from healthy controls, the older group displayed more metabolic abnormalities, were more likely to pick up a fibromyalgia diagnosis, had a trend towards worsening sleep problems, and had more PEM; i.e. things had not gotten better after ten years.
- Bob Naviaux’s 2016 paper also predicted many of the findings researchers are coming up with today. In a finding that bodes well for the future, six out of the ten metabolic biomarkers the Unutmaz team identified in this paper were also highlighted by the Lipkin team and Hanson teams (Germain) in their large metabolomic studies. That suggests these large studies are also coming up with some core metabolic abnormalities.
- The low xanthine levels suggest that pentoxifylline, an old, reportedly safe, and inexpensive drug that increases the amount of oxygen that can be delivered by the blood to the muscles might be helpful. Canada’s RECLAIM study is assessing this drug in long COVID.
- The Unutmaz team proposed that the depletion of butyrate early in the disease could pave the way for the metabolic abnormalities found later and pointed to a heart disease which suggested a similar scenario exists in that disease.
- These studies from two of the NIH-funded research centers highlight how important centers like these that can produce large and complex studies are. That showed up in spades when the leaders of both studies used their similar results to vigorously push for treatment trials – something the NIH has shied away from in the past in ME/CFS.
- Despite the attention given to ME/CFS by long COVID, and the research centers’ results, many Institutes that provided funding during the first NIH centers’ contract refused to provide even minimal funding this time around. Two NIH Institutes (NAIAD, NINDS) stepped forward to make up the gap but the ME/CFS research centers remain woefully underfunded for a disease of this prevalence and scope.
- An archaic and inefficient funding mechanism that relies on Institutes which bear no responsibility for ME/CFS to provide funding for it is at the root of the problem. ME/CFS is still homeless at the NIH and until it finds a home; i.e until it finds an Institute that is willing to give it its due, it’s hard to see how – short of a Congressional authorization – funding will grow at a suitable pace for those suffering from it.
- We’ll see what happens with the Nath studies. Nath’s intramural project was designed to give the NIH results it could use for future ME/CFS studies. Nath has said the project was successful. Time will tell if Nath’s project will prompt the NIH to do what it’s never done before: fully fund ME/CFS research.
With no Institute willing to take ME/CFS on, ME/CFS has been dependent for about 20 years upon funding from a variety of Institutes – none of which have responsibility for it. That approach was predicted to be a failure at the time and it has been. ME/CFS funding actually declined dramatically during that period and only began to rise again when Francis Collins committed the NIH to reinvigorate ME/CFS research. This time around, many of the contributing Centers refused to provide even minimal funding for ME/CFS.
Something obviously changed between the awarding of the first Center’s 5-year contract and this one to have those Centers drop out. It certainly wasn’t poor results – the Centers have proven themselves. It’s pure speculation, but one wonders if Francis Collins’s retirement had something to do with it. Perhaps Collins – who did reinvigorate ME/CFS research – made it known that he wanted to see more support from the Institutes.
In any case, the departure of many of the Institutes left NIAID (National Institute of Allergy and Infectious Diseases) and NINDS (National Institute of Neurological Diseases and Stroke) to pick up the slack. Thankfully, they did – but only up to the level of funding provided during the pre-COVID contract. While that’s appreciated, it’s also clear that neither Institute is willing to step forward and commit to supporting ME/CFS at the level its seriousness and prevalence indicate it should be supported.
So here we are with a bunch of successful studies that are clearly moving this disease forward in ways that it has not before – and in ways that the NIH has stated it’s wanted to see – and the NIH’s reward has been … more of the same.
Avindra Nath has stated that the intramural study – which Collins designed to produce results the NIH could follow up on – was successful. That’s good news – but with ME/CFS still dependent on this archaic and ineffective funding base – we’ll see what happens.
The most important outcome of this study was that it largely replicated the results of past NIH studies as well as others – thus appearing to provide a solid base of microbiome and metabolic results that focus on a deficiency of butyrate and other short-chain fatty acids and metabolites associated with cell membrane damage.
The senior authors of both papers clearly viewed the studies as stepping stones to more studies and treatment trials. Now they have a target – F. prausnitzii and butyrate-producing bacteria – it’s time to go after it.
Julia Oh stated she viewed the studies as “the prelude to many other mechanistic experiments that we hope to do to understand more about ME/CFS and its underlying causes.” Brent Williams echoed her assessment, stating, “these microbiome-symptom relationships present potentially actionable, manipulatable targets for future therapeutic trials… These trials could perhaps focus on dietary, probiotic, prebiotic, or synbiotic interventions and could provide direct evidence that gut bacteria influence chronic symptom presentation.”
It appears that animal models – a key tool in disease research that the Simmaron team is developing – are now on the table as well. Williams noted that “A tractable mouse model to study the gut microbiome disturbances found in ME/CFS would provide an important tool to evaluate causal hypotheses, mechanisms, and treatments”.
Despite the excellent results, ME/CFS is still clearly hampered by an inefficient funding mechanism at the NIH that relies on the goodwill of Institutes that have no responsibility for the disease. The inadequacy of that approach showed up in spades this year, when, despite the attention given to ME/CFS by long COVID, and the research centers’ results, many Institutes that provided funding during the first NIH centers contract refused to provide even minimal funding this time around.
Short of a Congressional mandate that the NIH fund ME/CFS more, it’s hard to see how major increases in funding for ME/CFS will occur given the current funding situation. We’ll see what happens when the Nath studies come out but if a long COVID pandemic didn’t do it and a successful research centers program didn’t either, one wonders what will.
- Up next – The Gut Pt. III – Two ME/CFS patients seek to dramatically alter their microbiome and achieve health
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