Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients, 2023, Xiong

Andy

Andy

Retired committee member
Study now printed, see https://www.s4me.info/threads/prepr...syndrome-me-cfs-2021-xiong.23022/#post-459931 for abstract and link

Preprint: Multi-omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2021, Xiong

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system, debilitating disability manifesting as severe fatigue and post-exertional malaise. The chronic dysfunctions in ME/CFS are increasingly recognized as significant health factors with potential parallels with "long COVID". However, the etiology of ME/CFS remains elusive with limited high-resolution human studies. In addition, reliable biomarker-based diagnostics have not been well-established, but may assist in disease classification, particularly during different temporal phases of the disease.

Here, we performed deep multi-omics (shotgun metagenomics of gut microbiota and plasma metabolomics) and clinical phenotyping of healthy controls (n=79) vs. two cohorts of ME/CFS patients: those with short-term disease (<4 years, n=75), and patients with long-term disease (>10y, n=79). Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities.

We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways.

Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls.

Taken together, our study presents the highest resolution, multi-cohort and multi-omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Open access, https://www.biorxiv.org/content/10.1101/2021.10.27.466150v1
 
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JAX Research on Microbiome Changes in Short- and Long-Term ME/CFS is now Available Online

We are very excited to announce that in collaboration with the lab of Julia Oh at The Jackson Laboratory, which studies the microbiome in ME/CFS for the JAX CRC, we have just posted the full preprint of our new ME/CFS microbiome paper on BioRxiv, which will continue to be updated following reviewer comment and peer-review. In this detailed study led by Ruoyun Xiong, we did deep multi-omics, where we performed shotgun metagenomics of the gut microbiota and plasma metabolomics in 79 healthy controls and two cohorts of ME/CFS patients: 75 with short-term disease (<4 years), and 79 patients with long-term disease (>10 years). We also correlated these data to clinical information collected from subject questionnaires, and built multiple state-of-the-art classifiers that were able to differentiate short or long-term ME/CFS from each other, or ME/CFS from healthy controls.

https://jaxmecfs.com/2021/10/29/jax...and-long-term-me-cfs-is-now-available-online/
 
I'm sure my microbiome would be abnormal. There are so many foods and food families I need to avoid that my food diversity is greatly reduced. For many PWME, reduced activity levels might also affect the microbiome. Studies such as this really should use controls with similarly reduced dietary variability and activity levels.
 
I came across this news item just after reading this thread, and it seems to fit it: https://newatlas.com/health-wellbeing/microbiome-gut-bacteria-inflammation-colitis-pgp/

"But more recently P-gp has been found to also play a key anti-inflammatory role in the gut, producing molecules known as endocannabinoids which suppress inflammation.

In cases of chronic intestinal inflammation, such as ulcerative colitis, P-gp expression is reduced. And in those cases of intestinal inflammation researchers also detected major imbalances in gut bacteria populations. But before now it hasn’t been clear exactly how the microbiome could be influencing P-gp expression.

The new research found P-gp expression is influenced by a combination of gut bacteria metabolites. Most importantly the research found P-gp expression is not regulated by one single metabolite or species of bacteria. Instead, P-gp expression is induced by a synergistic combination of a short-chain fatty acid known as butyrate and three secondary bile acids (LCA, DCA, and UDCA).

Optimal P-gp expression was detected only when all of these molecules were working in concert with one another. Merran Dunford, a researcher from the University of Bath working on the study, says the big finding here is the discovery of a cross-talk mechanism highlighting how a healthy microbiome can communicate with the immune systems to keep inflammatory activity in the gut in balance."
 
Creekside said:
I'm sure my microbiome would be abnormal. There are so many foods and food families I need to avoid that my food diversity is greatly reduced. For many PWME, reduced activity levels might also affect the microbiome. Studies such as this really should use controls with similarly reduced dietary variability and activity levels.
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This! So much this. And include a dietitician when reviewing people's diet.

This post has been copied, and replies moved, to the thread "Can dieticians (dietitians) help with ME/CFS?".
 
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I have very little interest in the microbiome at this point. It's interesting to see that sphingomyelins and short-chain fatty acids appear again, they were prominent in some previous metablomics studies.
 
Seems to me that the question that will need to be answered (if it hasn't been already) is "are these changes due to the ME or 'just' due to being ill". Looking at whatever similar research has been done in other illnesses will be important before accepting these results as ME-specific.
 
Andy said:
Seems to me that the question that will need to be answered (if it hasn't been already) is "are these changes due to the ME or 'just' due to being ill". Looking at whatever similar research has been done in other illnesses will be important before accepting these results as ME-specific.
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Yea consequence or cause? If it's consequence then presumably you need to understand what's upstream. If it's cause then it's more interesting; Chris Armstrong (from memory) put forward the theory (webinar 2015?) that gut dysbiosis was maintaining the disease state - bi-stability if you like.

I'm guessing that this paper is suggesting gut dysbiosis is the cause.
 
Now published

Full title:: Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients

"Highlights
  • Multi-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS
  • Reduced gut microbial diversity and increased plasma sphingomyelins in ME/CFS
  • Short-term patients had more severe gut microbial dysbiosis with decreased butyrate
  • Long-term patients had more significant metabolic and clinical aberrations
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disorder manifesting as severe fatigue and post-exertional malaise. The etiology of ME/CFS remains elusive. Here, we present a deep metagenomic analysis of stool combined with plasma metabolomics and clinical phenotyping of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) compared with healthy controls (n = 79). First, we describe microbial and metabolomic dysbiosis in ME/CFS patients. Short-term patients showed significant microbial dysbiosis, while long-term patients had largely resolved microbial dysbiosis but had metabolic and clinical aberrations. Second, we identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts. These revealed potential functional mechanisms underlying disease onset and duration, including reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate. In addition to the insights derived, our data represent an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS."

Open access, https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(23)00021-5
 
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NIH news release. Article covers both this study and Preprint: Deficient butyrate-producing capacity in the gut microbiome of [ME/CFS] patients is associated with fatigue symptoms, 2021, Guo,Lipkin et al

Studies find that microbiome changes may be a signature for ME/CFS

"Researchers have found differences in the gut microbiomes of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) compared to healthy controls. Findings from two studies, published in Cell Host & Microbe and funded by the National Institutes of Health add to growing evidence that connects disruptions in the gut microbiome, the complete collection of bacteria, viruses, and fungi that live in our gastrointestinal system, to ME/CFS.

“The microbiome has emerged as a potential contributor to ME/CFS. 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,” said Vicky Whittemore, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS)."

https://www.nih.gov/news-events/news-releases/studies-find-microbiome-changes-may-be-signature-mecfs
 
Surprised by the apparent quality and length of the discussions on the paper. Especially from the Spanish people I never heard of before. Other than that this study seems more confirmatory that there is something going on in the gut but not if it's causative or a downstream effect if I'm reading correctly.
 
JemPD said:
smc expert opinion on the studies: expert reaction to two studies on the gut microbiome and ME/CFS | Science Media Centre

i cant make head or tail of any of it, am too foggy. But thought i'd post this here when i saw it on MEAfb might be of interest. Opinion from chris Ponting
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Katharine Seton has been supported in her work by Invest in ME and Solve ME. I don't recognise the Spanish researchers. But most notably there are no quotes from the usual UK-based BPS supporters (although some of the Spanish 'experts' do seem that way inclined).
 
Andy said:
Study now printed, see https://www.s4me.info/threads/prepr...syndrome-me-cfs-2021-xiong.23022/#post-459931 for abstract and link

Preprint: Multi-omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2021, Xiong

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system, debilitating disability manifesting as severe fatigue and post-exertional malaise. The chronic dysfunctions in ME/CFS are increasingly recognized as significant health factors with potential parallels with "long COVID". However, the etiology of ME/CFS remains elusive with limited high-resolution human studies. In addition, reliable biomarker-based diagnostics have not been well-established, but may assist in disease classification, particularly during different temporal phases of the disease.

Here, we performed deep multi-omics (shotgun metagenomics of gut microbiota and plasma metabolomics) and clinical phenotyping of healthy controls (n=79) vs. two cohorts of ME/CFS patients: those with short-term disease (<4 years, n=75), and patients with long-term disease (>10y, n=79). Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities.

We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways.

Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls.

Taken together, our study presents the highest resolution, multi-cohort and multi-omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Open access, https://www.biorxiv.org/content/10.1101/2021.10.27.466150v1
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Rushing & duplicating(?) - preprint appeared in 2021 - finalised paper just published in 2023 (strange time lag) -

https://www.cell.com/cell-host-micr...m/retrieve/pii/S1931312823000215?showall=true
Also - NIH article referencing the above study and this one*
https://www.nih.gov/news-events/news-releases/studies-find-microbiome-changes-may-be-signature-mecfs

*https://www.cell.com/cell-host-micr...m/retrieve/pii/S193131282300029X?showall=true
 
FMMM1 said:
duplicating(?)
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Yep.

FMMM1 said:
preprint appeared in 2021 - finalised paper just published in 2023 (strange time lag)
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Why is it a strange time lag? Preprint was from Oct 2021.

Publication history of this paper.

"Published: February 8, 2023
Accepted: December 30, 2022
Received in revised form: September 14, 2022
Received: April 27, 2022"

So there was 6 months between posting their preprint, presumably receiving comments from the research community and rewriting in response to those, and then submitting to the journal. Another 5 months to presumably receive further comments from peer reviews and revise accordingly, and then re-submit. For reference, the publication history of the paper from Lipkin's team is

"Published: February 8, 2023
Accepted: January 4, 2023
Received in revised form: October 10, 2022
Received: April 29, 2022"

So the only 'strange' thing to me is that they were published in the same edition of the same journal but I would guess that was arranged deliberately.
 
Andy said:
Yep.


Why is it a strange time lag? Preprint was from Oct 2021.

Publication history of this paper.

"Published: February 8, 2023
Accepted: December 30, 2022
Received in revised form: September 14, 2022
Received: April 27, 2022"

So there was 6 months between posting their preprint, presumably receiving comments from the research community and rewriting in response to those, and then submitting to the journal. Another 5 months to presumably receive further comments from peer reviews and revise accordingly, and then re-submit. For reference, the publication history of the paper from Lipkin's team is

"Published: February 8, 2023
Accepted: January 4, 2023
Received in revised form: October 10, 2022
Received: April 29, 2022"

So the only 'strange' thing to me is that they were published in the same edition of the same journal but I would guess that was arranged deliberately.
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Suppose a year goes by - as per your comments(?) -- re-drafting could easily take 6 months and the another 6 months for peer review of changes ---
 
I'm sorry but I don't understand your post.
FMMM1 said:
Suppose a year goes by
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Yes, that's what happened.

FMMM1 said:
as per your comments(?)
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Why is the question mark in brackets? Do you mean the question mark to apply or not?

FMMM1 said:
re-drafting could easily take 6 months and the another 6 months for peer review of changes
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Right, so are you now agreeing that the time scale I described is a reasonable explanation or do you still feel that there was a "strange time lag".
 
I vaguely recall that Unutmaz got interested since MAIT cells looked different - hypothesised to be due to increased bacterial translocation or some such.

Perhaps we need GWAS i.e. to provide a reliable lead e.g. that MAIT cells are relevant. Seems we have this study but it provides no real clear lead --- post GWAS then perhaps a more focused study --- with a sub-group of people - would yield something useful -- biomarker, clues to disease mechanism ---.
 
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