Previously undetectable biomarkers in gut microbiome may predict 'invisible' chronic fatigue syndrome, long COVID - July 25, 2025

bad1080

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article:
Millions suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition often overlooked due to the lack of diagnostic tools, may be closer to personalized care, according to new research that shows how the disease disrupts interactions between the microbiome, immune system, and metabolism.

The findings—potentially relevant to long COVID due to its similarity with ME/CFS—come from data on 249 individuals analyzed using a new artificial intelligence (AI) platform that identifies disease biomarkers from stool, blood, and other routine lab tests.

"Our study achieved 90% accuracy in distinguishing individuals with chronic fatigue syndrome, which is significant because doctors currently lack reliable biomarkers for diagnosis," said study author Dr. Derya Unutmaz, Professor of immunology at The Jackson Laboratory (JAX).
https://medicalxpress.com/news/2025-07-previously-undetectable-biomarkers-gut-microbiome.html

study (paywalled):
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data and detailed clinical symptoms. By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct a unique connectivity map spanning the microbiome, immune system and plasma metabolome in health and ME/CFS adjusted for age, gender and additional clinical factors. This map uncovers altered associations between microbial metabolism (for example, short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFN-γ and GzA. Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing unique mechanisms—specifically, how multi-omics dynamics are associated to the disease’s heterogeneous symptoms.
https://www.nature.com/articles/s41591-025-03788-3

edit: preprint of said study (w/o paywall):
https://www.biorxiv.org/content/10.1101/2024.06.24.600378v1.full
https://pmc.ncbi.nlm.nih.gov/articles/PMC11230215/
 
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ME/CFS patients also had lower levels of butyrate, a beneficial fatty acid produced in the gut, along with other nutrients essential for metabolism, inflammation control, and energy. Patients with elevated levels of tryptophan, benzoate, and other markers indicated a microbial imbalance. Heightened inflammatory responses, particularly involving MAIT cells sensitive to gut microbial health, were also observed.

"MAIT cells bridge gut health to broader immune functions, and their disruption alongside butyrate and tryptophan pathways, normally anti-inflammatory, suggests a profound imbalance," said Unutmaz.

Thank you for posting this. Excellent article; this really has my attention. Very compelling and exciting.

"Our goal is to build a detailed map of how the immune system interacts with gut bacteria and the chemicals they produce," Oh said. "By connecting these dots we can start to understand what's driving the disease and pave the way for genuinely precise medicine that has long been out of reach."

They should do a collaboration with Dr. Alessio Fasano, who discovered that gut dysbiosis is the initial trigger that causes Celiac Disease in genetically susceptible people.
 
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The precursor study conducted in 2023 by the same authors in the OP reveals the following (not behind a paywall):
  • Butyrate is lower in CFS/ME when compared to controls
  • At least 2 specific species of butyrate-producing commensal bacteria are lower in CFS/ME participants when compared to controls (this was found in all 4 CFS/ME cohorts in this study): they are Faecalibacterium prausnitzii and Roseburia Inulinivorans (see Figure 5 in the study)
  • Long-term CFS/ME have an over-abundance of two gut bacteria; they are: Flavonifractor plautii and Ruthenibacterium Lactatiformans

Multi-‘omics of gut microbiome-host interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients​

https://pubmed.ncbi.nlm.nih.gov/36758521/

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 (<4y, n=75) or long-term disease (>10y, n=79) compared to healthy controls (n=79).

Other information about F. prausnitzii:
https://www.frontiersin.org/journal...iology/articles/10.3389/fcimb.2018.00281/full
F. prausnitzii
prevalence and abundance are reduced under certain disorders such as:
  • celiac disease
  • obesity
  • type 2 diabetes
  • appendicitis
  • chronic diarrhea
  • irritable bowel syndrome (IBS) of alternating type
  • colorectal cancer (CRC)
  • and particularly in IBD

https://drc.bmj.com/content/11/3/e003101

Numerous studies have correlated the reduction of F. prausnitzii abundance with many disease states, including:
  • irritable bowel syndrome
  • Crohn’s disease
  • obesity
  • asthma
  • major depressive disorder
  • metabolic diseases in humans
  • altered glucose metabolism
  • diabetes
 
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bad1080

Senior Member
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i keep reading about f. prausnitzii but whether it is cause or effect of said illnesses remains to be seen. a couple people did not get it to improve after supplementation, confirmed through stool analysis. so my guess is it is either more complicated or an effect rather than a cause.
remember correlation isn't causation.

edit: added the preprint of the study to the OP (not paywalled)
 
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From the link w/o paywall in the OP:

Based on BioMapAI’s outputs and network analyses, we propose that the shift in disease pathology in ME/CFS is linked to the topological interaction of the gut microbiome, immune function, and metabolome. (Figure 5). A decrease in key microbes, including Faecalibacterium prausnitzii, and resultant dysfunction of microbial metabolic pathways such as butyrate, tryptophan, and BCAA, contributed to critical ME/CFS phenotypes, particularly pain and gastrointestinal abnormalities. In healthy individuals, these microbial metabolites regulate mucosal immune cells, including Th17, Th22, and Treg cells, an interaction that is dysfunctional in ME/CFS resulting in elevated pro-inflammatory interactions via elevated activation of γδ T cells and CD8 MAIT cells

This breakdown in the host metabolic microbiome balance were collectively associated with fatigue, emotional and sleeping problems, supporting recent findings underscoring microbial mechanisms in the gut-brain axis that occur via modulation of plasma metabolites

Symptomatologically, the gut microbiome was expectedly linked to gastrointestinal issues and unexpectedly, to pain, fatigue, and mental health problems

But I noticed they said "contributed" rather than "caused," but they do seem to be saying that that the reduction of that microbe and other "key" microbes gets the whole process going.
 
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i keep reading about f. prausnitzii but whether it is cause or effect of said illnesses remains to be seen. a couple people did not get it to improve after supplementation, confirmed through stool analysis. so my guess is it is either more complicated or an effect rather than a cause.
remember correlation isn't causation.

edit: added the preprint of the study to the OP (not paywalled)
Do you mean that some people supplemented with f prausnitzii but the supplementation did not cause an increase in f prausnitzii in their microbiomes?

It seems this microbe prefers inulin and fructo-oligosaccharides as its food/prebiotic.
 
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