Understanding Myalgic Encephalomyelitis/Chronic fatigue syndrome

The Challenge: Understanding Myalgic Encephalomyelitis/Chronic fatigue syndrome

ME/CFS is a complex, debilitating illness. The syndrome manifests as severe fatigue, post-exertional malaise (PEM), muscle and joint pain, headaches, sleep problems, hypersensitivity to sensory stimuli, and gastrointestinal (GI) symptoms. ME/CFS affects up to 2.5 million people in the US alone.¹ The human microbiome has recently emerged as a potential contributor to ME/CFS. The microbiome can have a significant impact on metabolic health. For example, the metabolic products of gut microbiota can feed into host pathways as energy sources. The microbiome can modulate host physiology via direct stimulatory effects or through secondary pathways coupled to metabolic processes. Our limited understanding of the underlying biological mechanisms of ME/CFS is a major impediment to identifying and developing both specific therapies and reliable biomarker-based diagnostics. Metabolomics can provide a more comprehensive understanding of the metabolic changes that occur in ME/CFS, which may aid in developing more targeted and effective treatments for this illness.

Metabolon Insight: Metabolomics Can Help Identify Novel Biomarkers of ME/CFS

This study utilized the Global Discovery Panel to profile the plasma of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) and healthy controls (n = 79). ² The panel’s unrivaled coverage of up to 5,400 metabolites offered this group the most comprehensive solution to identify potential biomarkers of ME/CSF progression between short- and long-term cohorts.

The Solution: Metabolomics Reveals a Link Between the Microbiome and Host Disease

Shotgun metagenomic sequencing of fecal samples from ME/CFS patients and controls revealed that the gut microbiome of ME/CFS patients is characterized by broad dysbiosis, with a less diverse gut microbiome community. Differences in the gut microbiome were more pronounced in short-term ME/CFS patients compared with long-term patients and controls. Low-abundance microbes comprised the most discriminatory features, including microbes implicated in tryptophan, butyrate, and propionic acid production that were largely depleted in ME/CFS.
Metabolomics identified 1,278 metabolites in the plasma samples of ME/CFS patients and controls. Unlike trends observed in the shotgun sequencing data, with the greatest dysbiosis observed in short-term patients, long-term patients had more metabolic aberrations differentiating them from healthy controls, especially in sphingolipids and diacylglycerol metabolites. Interestingly, most metabolic species either decreased across experimental groups (control > short-term > long-term; eg, xanthine), or increased (control < short-term < long-term; eg, sphingomyelins, diacylglycerol, phosphatidylcholine, and ceramides), suggesting that metabolic irregularities associated with ME/CFS gradually worsen over time. Strikingly, a depletion of butyrate-synthesizing microbes in the fecal samples of ME/CFS was also reflected in the metabolomics analysis of plasma samples. This suggests that changes in the ability of the gut microbiome to metabolize or synthesize butyrate are reflected in the host’s levels of butyrate.

The Outcome: Metabolon Uncovers Disease Features and Biomarkers of ME/CFS

The Global Discovery Panel helped this research group better understand the underlying molecular mechanisms of ME/CFS and identify potential biomarkers of ME/CFS progression. Multi-omics analysis of shotgun sequencing and metabolomics data revealed possible functional mechanisms that may be responsible for the onset and duration of the disease. These mechanisms include a decrease in microbial butyrate biosynthesis and a reduction in plasma butyrate. 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.