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Studies Tie Gut Microbiome, Metabolites to Chronic Fatigue Syndrome

NEW YORK – Two new studies by independent research teams suggest gut microbial communities and related metabolites may differ between individuals with or without myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a heterogeneous condition marked by symptoms affecting everything from energy metabolism to neurological function and immune features.

The findings highlight potential treatment targets, while pointing to some of the disease features and possible biomarkers that distinguish relatively short-term versions of the disease (occurring over fewer than four years) with long-term ME/CFS cases that span more than a decade.

For the first of the studies, appearing in Cell Host and Microbe on Wednesday, researchers at the Jackson Laboratory, University of Connecticut Health Center, and the Bateman Horne Center turned to shotgun metagenomic sequencing to profile gut microbial representatives and genes in fecal samples from 74 short-term ME/CFS cases, 75 long-term ME/CFS disease patients, and 79 age- and sex-matched controls.

"Taken together, our study presents a high-resolution, multi-cohort, and multiomics analysis, and provides a mechanistic hypothes[is] of host-microbiome interactions in ME/CFS," senior and corresponding author Julia Oh, a Jackson Laboratory researcher, and her colleagues wrote.

Along with corresponding blood plasma metabolomic profiles and clinical reports for the patients, the metagenomic sequences revealed ME/CFS-related shifts in the gut microbiome and plasma metabolites relative to the unaffected individuals, including lower-than-usual blood plasma levels of an immune-related fatty acid called butyrate and dialed-down levels of butyrate-producing gut microbes.

"It’s important to note that this research shows correlation, not causation, between these microbiome changes and ME/CFS," Oh said in a statement. "But these findings are the prelude to many other mechanistic experiments that we hope to do to understand more about ME/CFS and its underlying causes."

Members of that team also took a closer look at the gut microbial and blood metabolite features that seemed to distinguish individuals with short-term from those with long-term ME/CFS. While microbial dysbiosis was the most pronounced feature in short-term ME/CFS patients, these microbiome shifts tended to resolve in the long-term cases. Instead, individuals with long-term symptoms typically had more extensive metabolite alterations and clinical symptoms.

"[W]e identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts," the researchers reported. "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."

For another study appearing in Cell Host and Microbe, a team from Columbia University, Brigham and Women's Hospital, and other centers presented findings from their own microbiome-centered analyses of ME/CFS, which included metagenomic sequencing on fecal samples from 106 individuals with the condition and 91 unaffected controls.

Their new microbiome results build on a blood metabolomic analysis of the ME/CFS cases and controls published in the International Journal of Molecular Sciences last summer, and the researchers relied on functional metagenomics, qPCR, and fecal short-chain fatty acid-focused metabolomic experiments to follow up on their sequencing results.

Again, the gut microbiome features pointed to lower-than-usual butyrate synthesis levels in individuals with ME/CFS, as well as changes in the prevalence of microbes that produce other compounds, such as acetate or lactate.

"Our study … demonstrates significant differences in bacterial diversity, abundance, function, [short-chain fatty acid] metabolism, and co-abundance network topology," the authors explained, noting that their results "provide unique insights into microbiome disturbances and the functional consequences of dysbiosis that may contribute to the manifestation of symptoms in ME/CFS and identify potentially actionable targets for disease classification and therapeutic testing."

In the metagenomic sequence analysis, for example, the team saw a dip in the relative and absolute abundance of beneficial gut microbes in the Faecalibacterium, Eubacterium, and Roseburia genera — including the F. prausnitzii and E. rectale species — in fecal samples from individuals with ME/CFs.

When it came to symptom severity, meanwhile, the researchers noted that at least one of the species, F. prausnitzii, was present at lower levels in ME/CFS patients with the most pronounced fatigue symptoms, and had more elevated representation in the gut microbiomes of individuals with more modest fatigue.

"While these findings don't unequivocally demonstrate causative relationships between disturbances in the microbiome and symptoms, these microbiome-symptom relationships present potentially actionable, manipulatable targets for future therapeutic trials," senior and corresponding author Brent Williams, a researcher at Columbia University, said in a statement.

"These trials could perhaps focus on dietary, probiotic, prebiotic, or synbiotic interventions," Williams added, "and could provide direct evidence that gut bacteria influence chronic symptom presentation.”