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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology. However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized.
Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library. Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria. Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS.
Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post–COVID-19 syndrome.
The ME Biobank, which is funded by the MEA Ramsay Research Fund, provided samples for this research
“We applied a PhIP-Seq workflow to compare the Ig epitope repertoires of 40 patients with severe ME/CFS and an equal number of matched healthy controls (Fig. 1B). Given the variability and uncertainty in diagnosis of ME/CFS, our cohort was represented by severe ME/CFS cases uniformly assembled by the U.K. ME/CFS Biobank (UKMEB) (58). As antibody epitope repertoires are affected by age and sex (47), the 40 healthy controls were 1:1 matched to the ME/CFS cases to eliminate any bias (Fig. 1B). The healthy controls were recruited by the UKMEB, reducing potential biases related to geography or sample handling”.
Expert comment from Professor Eleanor Riley
Professor Emerita, Immunology and Infectious Disease, University of Edinburgh and a former a member of the research team at the ME Biobank
“This study brings together two potential explanations for the underlying pathology of ME/CFS, namely a disturbance in the normal bacterial flora of the gut and a disturbance in the immune system, by looking at antibody responses to bacteria that are normally present in the gut. The methods used allowed the researchers to look for antibodies to a very large array of different organisms – and to different components of these organisms – and found some statistically significant differences in the prevalence of antibodies to some bacterial components between healthy people and people with severe ME/CFS. The authors conclude that the study provides additional evidence in favour of disturbances in the gut bacteria as a potential cause of some ME/CFS symptoms but are wisely very cautious in their interpretations.
“This caution is welcome as the study suffers from many of the limitations of recent ME/CFS research including being small in scale (only 40 patients and 40 healthy controls were tested), comparing patients only with healthy controls rather than with people with other fatiguing conditions (which would control for many of the lifestyle factors that may affect the results) and looking at only one time point in the evolution of their illness (which makes it impossible to determine whether the differences seen are causes or consequences of the disease).
“It is a sad truth that results from the vast majority of these small studies of ME/CFS fail to be confirmed in subsequent studies. This study should therefore be viewed as hypothesis generating, providing interesting new avenues for future research, rather than as being in any way conclusive.”
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association.