The NIH ME/CFS Gut Studies Pt. I: A Biomarker for Chronic Fatigue Syndrome (ME/CFS)?

by Cort Johnson | Feb 10, 2023 | Gut, Microbiome, Research | 89 comments

A biomarker may have been found that could facilitate the production of treatment trials.

The fact that two NIH-funded chronic fatigue syndrome (ME/CFS) gut studies were published on the same day wasn’t an accident – an effort was clearly made to highlight their findings. Indeed, they were accompanied by an NIH blog, “Studies find that microbiome changes may be a signature for ME/CFS“, suggesting that their results – which mirrored each other – indicated that a biomarker may have been found.

Vicky Whittemore Ph.D., program director for the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) said:

“These findings provide unique insights into the role the microbiome plays in the disease and suggest that certain differences in gut microbes could serve as biomarkers for ME/CFS,”

Given how conservative the NIH is, any talk about a biomarker is noteworthy. The NIH, though, wasn’t exactly out on the skinny branches with that possibility. The studies were big enough (>200 people per study) and rigorous enough so that any common findings would automatically bring up talk of a biomarker.

It appears that researchers are starting to zero in on some core and reproducible findings in the gut in ME/CFS. That’s a pretty good trick given how many bacterial species researchers plow through in these studies.

The key finding from both studies concerned low relative abundances of butyrate-producing bacteria, with the Guo study highlighting low levels of several bacterial species (Faecalibacterium prausnitzii), Eubacterium rectale), and the Xiong study reporting that the gut disruption was much worse in the shorter duration (<4 years) compared to longer duration patients (>10 years) who had worsened metabolic issues.

The Lipkin Group Study

Several hurdles the Guo/Williams study (“Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS“) from the Lipkin group had to surmount made it clear that its results were designed to stand the test of time. Instead of studying a single, geographically isolated study population, the participants came from across the U.S. Instead of one sample taken at one point in time, the participants provided four samples spread across a year. Getting positive results from different groups spread over a long time period signaled stability; i.e., these are results we should be able to count on.

Just about every major gut assessment (gut microbiome diversity, microbiome abundances, functional pathways, and interactions) was altered in the ME/CFS patients vs the controls. The low abundance of two common bacterial species that figure prominently in butyrate production (Faecalibacterium prausnitzii, Eubacterium rectale) stood out. Butyrate is an important anti-inflammatory that helps gut health in multiple ways.

Multiple tests (functional metagenomics, qPCR, metabolomics analysis of fecal short-chain fatty acids) confirmed on the ground level what the microbiome analysis suggested had happened: ME/CFS patients’ guts are plagued by a reduction in butyrate synthesis. Several analyses also showed that in every case, if you have ME/CFS and IBS, gut issues at the pathophysiological level were more severe.

Reduced butyrate levels could lead to leaky gut syndrome and inflammation in the body and brain.

The more the Lipkin group dug into butyrate production, the more they found. Four pathways of bacterial butyrate production exist: the acetyl-CoA pathway, the glutarate pathway, the lysine pathway, and the 4-aminobutyrate pathway (Figure 3C). While three of the pathways appeared to be intact, a metagenomic analysis found what appeared to be a remarkable disruption in the acetyl-CoA pathway, with deficiencies found in virtually every gene in that pathway. Finding such a narrow zone of disruption is encouraging as it provides an easier target for potential treatments.

Low butyrate levels could impact everything from colon health to inflammation, T-cell regulation, and integrity of the gut lining. The low acetate levels that were also found could potentially feed right into the low butyrate findings as acetate is a preferred food for butyrate-producing bacteria.

The low butyrate levels could also be contributing to the increased “bacterial load” found in the ME/CFS patients’ guts. Since butyrate has antibacterial properties, the low butyrate levels may be impeding the ability to control bacterial growth.

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

F. prausnitizii stood out because it’s been found reduced in at least one fibromyalgia study and three ME/CFS studies. This odd bacterium, which does not produce spores and moves around very little, makes up a full 5% of the bacteria found in our guts. Through its fermentation of dietary fiber, F. prausnitizi produces butyrate and other short-chain fatty acids, as well as an important anti-inflammatory product. It’s been called “a potential biosensor of human health”.

The findings played out on a symptom level as well: the less F. prausnitzii a person had, the more fatigued they were. Interestingly, reduced levels of F prausnitizii have been associated with fatigue in inflammatory bowel disease.

We’ve seen evidence of “rewirings” of the immune system in ME/CFS before, and now these researchers reported that an “extensive rewiring” of the microbiome had occurred as well. Again highlighting its potential importance, in what appeared to constitute a kind of ecosystem shift, F. prausnitzii appeared to play a bigger role in the ME/CFS microbiome than in healthy controls.

The Gist

This is new… Two NIH-funded research center studies were published simultaneously and were accompanied by an NIH blog. There was a reason for all this synchronicity – the two large studies confirmed each other’s findings – leading the NIH to publish a blog suggesting that a biomarker may have been found.
The biomarker concerns low levels of the anti-inflammatory and gut-protective substance butyrate in the guts of ME/CFS patients.
Part 1 of the 2-part blog series concerns a paper from the Lipkin group. With its large number (>200) of geographically diverse patients, and its multiple sampling times, this study was designed to produce results you can take to the bank.
Just about every major gut assessment (gut microbiome diversity, microbiome abundances, functional pathways, and interactions) were found to be altered in the ME/CFS patients vs the controls.
The study assessed butyrate production in multiple ways – via microbiome analysis, aPCR, and metabolomics – and in every case found evidence of low butyrate.
The low abundance of two common bacterial species that figure prominently in butyrate production (Faecalibacterium prausnitzii, Eubacterium rectale) stood out. F. prausnitizii has been found reduced in at least one fibromyalgia study and three ME/CFS studies. Called “a potential biosensor of human health”, it produces butyrate and other short-chain fatty acids, as well as an important anti-inflammatory product.
An “extensive rewiring” of the gut microbiome that prominently featured F. prausnitzii was also found. Plus, a metagenomic analysis found what appeared to be a remarkable disruption in the acetyl-CoA pathway of butyrate production, with deficiencies found in virtually every gene in that pathway.
Other evidence of possibly increased lactate production and mucin (the protective substance that clothes the gut walls) degradation was found.
Because physical activity increases butyrate levels, the inability to engage in much physical activity could play a role in reduced butyrate levels in ME/CFS. The second paper, though, which found more gut disruption in shorter duration patients and more metabolic problems in longer duration – and presumably less active – ME/CFS patients argues against that conclusion. Still, activity levels will need to be taken into account in future studies.
Even if low activity levels are impacting butyrate production, the low butyrate levels may need to be addressed before people with ME/CFS can exercise again. This is because butyrate protects against leaky gut and one study showed that exercise dramatically increased leaky gut and inflammation in ME/CFS.
We still don’t know if the gut findings are secondary to the disease or play a more primary role. Similar gut findings in several ME/CFS studies, though, are clearly opening the possibility of treatment trials and other studies that perturb the gut to see if symptoms improve.

Some evidence of increased lactate production was found as well. One of the increased bacteria (fecal C. bolteae) found in ME/CFS has been associated with autism and autoimmune disease, and was positively correlated with fatigue in multiple sclerosis. Another increased bacteria called R. gnavus just happens to degrade mucin – the protective substance that clothes the gut walls – suggesting a kind of gut wall double whammy may have occurred in ME/CFS: lower levels of the protective butyrate in conjunction with higher levels of the gut wall degrader, R. gnavus, could spell bad news for the gut lining.

Another factor might be in play, though. Animal models and some human studies have found that physical activity results in higher levels of butyrate producers like F. prausnitzii’. That suggests that the reduced butyrate production found in ME/CFS, could, at least in part, be due to the dramatically reduced physical activity the disease produces.

On that note, it’s interesting that longer-duration ME/CFS patients in the Oh study who have more severe metabolic issues – and are presumably less active – didn’t display as severe butyrate depletion (or other gut issues) as the shorter-duration patients in the study. That suggests that if reduced activity plays a role in lower butyrate production in ME/CFS, it may play only a partial role. It’s clear, though, that activity levels will need to be taken into account at some point in these studies.

If some of these gut changes are caused by low activity levels, they would still need to be dealt with as reduced butyrate production would surely contribute to the leaky gut and exercise problems found in ME/CFS. We saw dramatic evidence of this when exercise dramatically increased leaky gut and inflammation in ME/CFS compared to healthy controls. Even if the reduced butyrate production is the result of reduced activity, that problem will probably need to be resolved before people with ME/CFS can begin to engage in strenuous exercise again.

It was good to see F. prausnitzii levels correlated with fatigue, but we still don’t know the real impact the gut issues have on symptoms. We don’t know if they are a secondary outcome of the disease or play a primary role. It will take treatment trials and other studies that perturb the gut to see if symptoms improve to answer that question. The fact that a clear abnormality (Iow butyrate levels) has shown up across multiple studies suggests that researchers are willing to take that next step and start perturbing the gut in ME/CFS to see what happens.

Coming up next – the fascinating Oh gut paper suggests how ME/CFS may have gotten started

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