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Elevated Antibody Levels Identified in Patients With Severe Chronic Fatigue Syndrome

NEW YORK — Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) show elevated levels of antibodies against a type of bacteria typically found in the human gut, according to a new study. The findings not only point to a potential new diagnostic strategy for ME/CFS but also may yield insights into long COVID, which can have similar symptoms.

ME/CFS is characterized by persistent and debilitating fatigue, along with a range of other symptoms such as muscle and joint pain, sore throat, and digestive issues. Its etiology and pathogenesis remain unclear and diagnosis is typically achieved by questionnaires rather than molecular markers.

Recent efforts to identify biomarkers have linked the immune system and gut microbiota dysbiosis to the condition, but potential interactions between adaptive immune responses and the microbiota in ME/CFS have not been fully characterized. To investigate, scientists from the Weizmann Institute of Science used phage immunoprecipitation sequencing (PhIP-seq) to profile antibody responses of 40 patients with severe ME/CFS, as well as 40 healthy controls, against a library of 244,000 bacterial and viral epitopes.

As reported in Science Advances this week, they found that the ME/CFS patients exhibited high serum levels of immunoglobulin A against flagellins of Lachnospiraceae bacteria compared with the controls. Notably, a similar overrepresentation of antibodies against Lachnospiraceae flagellins has been reported in Crohn's disease, a common comorbidity in patients with severe ME/CFS. The scientists also identified lower levels of antibodies against Bacteroidetes in ME/CFS patients versus controls.

The researchers then used machine learning to determine how screening for antibodies against Lachnospiraceae could be used to diagnose ME/CFS and found that combining conventional blood tests for the disorder with antibody repertoire data significantly improved diagnosis. "Hence, antibody responses against gut microbiota detectable by PhIP-seq represent a unique layer of information beyond standard blood tests," they wrote.

In addition to their diagnostic implications, the findings also may help in the development of therapeutic strategies for ME/CFS that target the identified antibody responses. "Such efforts may include preventive vaccination with Lachnospiraceae or Bacteroidetes surface antigens to counteract anti-flagellin overreaction, as well as therapies reducing anti-flagellin binding," the study's authors wrote.

Further, the study may help inform research into long COVID patients, who experience lingering effects from SARS-CoV-2 infection that often include ME/CFS-like fatigue symptoms. "Genetic or environmental factors affecting the development of long COVID are vastly unknown, with PhIP-seq screening for [immunoglobulin] responses against microbiota antigens observed in classical ME/CFS as well as coronaviruses representing a potential avenue to pursue," the researchers stated.

The study, however, is not without its limitations. The research team noted that they only evaluated patients with severe ME/CFS and there was substantial variability in the observed antibody repertoires. "Leveraging larger ME/CFS cohorts, including different grades of disease severity, as well as multiomic analyses, could identify disease subgroups more clearly and may help to stratify patient populations for treatments," they noted.