Microbiome Disturbances Reported as Signature of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

New research reveals differences in the gut microbiomes of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) compared to those of healthy controls. ME/CFS is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, among other symptoms. Although the cause of ME/CFS is unknown, many patients report an antecedent infectious disease. The plausibility of an infectious trigger is supported by the recent emergence of Long COVID (or post-acute sequelae of SARS-CoV-2 infection), wherein an infection results in persistent disability with symptoms similar to those observed in ME/CFS.

The study was led by scientists at the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health, as part of the Center for Solutions for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, an inter-disciplinary, inter-institutional research group dedicated to understanding the biology of the disease in order to develop effective means to diagnose, treat and prevent it. Findings appear in the journal Cell Host & Microbe.

The researchers conducted metagenomic and metabolomic analyses of fecal samples collected from a geographically diverse cohort of 106 cases and 91 healthy controls from five sites across the United States. Results revealed differences in gut microbiome diversity, abundance, functional biological pathways, and interactions between bacteria. Cases and controls were matched for age, sex, geography, and socioeconomic status.

Their findings indicate that differences in gut microbes could serve as biomarkers to aid in diagnosis of ME/CFS. Diagnosis of ME/CFS currently relies on clinical criteria and symptoms.

Gut bacteria Faecalibacterium prausnitzii and Eubacterium rectale, which are both normally abundant and health-promoting, were reduced in ME/CFS participants. Loss of these important bacteria in the gut of ME/CFS patients contributed to a deficient microbial capacity for synthesizing butyrate, a multifunctional bacterial metabolite with anti-inflammatory properties and the main fuel for the body’s colon cells. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity in ME/CFS, providing a potential direct link between the microbiome and disease symptoms.

While health-promoting, butyrate-producing bacteria were decreased, other species had increased relative abundance in ME/CFS compared to healthy controls, including Enterocloster bolteae which in other research has correlated with fatigue in multiple sclerosis. Another, Ruminococcus gnavus, has been associated with inflammatory bowel disease.

Beyond differences in the abundance of microbes in ME/CFS, the researchers also found evidence for substantial differences in the ways in which bacterial species interact or communicate with each other in the microbiome, which is made up of hundreds to thousands of bacterial species co-existing together and competing in their intestinal environment.  

“The gut microbiome is a complex ecological community teeming with diverse inter-species interactions that can be beneficial or harmful. Our research finds that in people with ME/CFS, there can be extensive rewiring of the networks of bacteria in this system,” says study senior author Brent L. Williams, PhD, assistant professor of epidemiology in CII at Columbia Mailman School of Public Health.

“Understanding the connection between ME/CFS and disturbances in the gut microbiome may lead to ways to classify the disease and targets for therapeutic trials,” adds co-author W. Ian Lipkin, MD, CII director and John Snow Professor of Epidemiology at Columbia Mailman School.

The study’s first author is Cheng Guo, PhD, senior programmer analyst at CII. Additional co-authors are listed in the publication.

The article was submitted as a co-submission with a group at the Jackson Laboratory that has also studied the microbiome in ME/CFS. Both groups’ articles appear in the same issue of Cell Host & Microbe.

The research was funded by the Chronic Fatigue Initiative of the Hutchins Family Foundation, a National Institutes of Health (NIH) grant to the Center for Solutions for ME/CFS at Columbia University (grant number 1U54AI138370), NIH grant R56AI120724, and anonymous donors through the Crowdfunding Microbe Discovery Project.

The authors declare no competing interests.

About ME/CFS

Experts estimate there are between 800,000 and 2 million Americans with ME/CFS, a complex, debilitating disorder characterized by extreme fatigue after exertion and other symptoms including muscle and joint pain, cognitive dysfunction, sleep disturbance, and orthostatic intolerance. Currently, there is no diagnostic test for the disease; instead, patients are diagnosed based on a clinical examination and history and an exclusion of other disorders.

Prior Research on ME/CFS

In a 2022 study, CII researchers identified abnormal levels of specific plasma metabolites, indicative of peroxisomal dysfunction and abnormalities in lipid remodeling and the tricarboxylic acid cycle in ME/CFS.

In a 2017 study, CII scientists discovered abnormal levels of specific gut bacteria related to ME/CFS in patients with and without concurrent irritable bowel syndrome, IBS. A year later, another study identified a constellation of metabolites related to ME/CFS, providing the ability to predict whether or not someone has the disorder with a confidence of 84 percent.

In a 2015 study, CII researchers identified distinct immune changes in patients diagnosed with ME/CFS. These immune signatures represented the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages. In a 2012 study, researchers ruled out a purported link between a mouse retrovirus called XMRV and ME/CFS.