The 120th edition of the Research Digest brings together recent research exploring ME/CFS, long COVID, fibromyalgia, and post-viral conditions. The articles included highlight advances in understanding the biological, genetic, and immunological factors underlying these illnesses, as well as potential markers for diagnosis and severity. Together, they provide a snapshot of current developments and emerging insights that are helping to shape future research and inform clinical and advocacy efforts in this field.
Contributing Digesters: Imogen, Solène, Jyothsna and Simone.
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HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity
Authors: Giménez-Orenga K, Martín-Martínez E, Nathanson L, Oltra E (Catholic University of Valencia, Spain)
Publication: eLife (May 2025).
Link: https://elifesciences.org/articles/104441
Easy Read Overview: Human endogenous retroviruses (HERVs) are ancient viral DNA that make up about 8% of human genes. This study looked at HERV activity in women with ME/CFS, fibromyalgia, both conditions, and healthy controls. The results showed that each patient group had a different HERV profile compared to healthy people. ME/CFS patients had the greatest changes, and two subgroups were found that linked to how severe their illness was. The findings suggest HERV patterns could help explain these conditions and may even be used as biomarkers to identify illness type and severity.
Human endogenous retroviruses (HERVs) are ancient pieces of viral DNA that became part of human DNA millions of years ago. HERVs are estimated to make up 8% of the human genome. While the role of HERVs in the human body is not fully understood, advances in sequencing technology have revealed their participation in physiological processes, including coordinating the immune response, shaping neurological functions, and interacting with the microbiota. Viruses are known to cause major changes in the host cells’ gene expression, which may lead to the derepression of HERV sequences. This study examines HERV activation in female ME/CFS and fibromyalgia (FM) patients to better understand the origins of these conditions and their frequent co-occurrence.
This study had 43 participants: eight with ME/CFS (Canadian Consensus Criteria and International Consensus Criteria), 10 with FM (American College of Rheumatology criteria), 16 co-diagnosed and nine healthy controls. Blood samples were taken from all participants, and transcriptome analysis undertaken.
The authors found that the HERV profile of patients with ME/CFS, FM and those co-diagnosed were unique and could be differentiated from healthy controls. HERV expression was most greatly dysregulated in ME/CFS patients. Within this group, two distinct subgroups were identified that correlated with disease severity, with the more severe subgroup exhibiting greater dysregulation. These results suggest that HERV dysregulation not only plays a role in the development of ME/CFS but could be used to classify disease severity.
The HERV profile of co-diagnosed patients was closest to healthy controls, suggesting that epigenetic changes are less involved for these patients.
This study demonstrates the potential of HERV expression profiles as biomarkers for ME/CFS, FM and the definition of co-diagnosis.
Gastrointestinal barrier disruption in post-COVID syndrome fatigue patients
Authors: Rohrhofer J, Wolflehner V, Schweighardt J, Koidl L, Stingl M, Zehetmayer S,…,Untersmayr E (Medical University of Vienna, Austria)
Publication: Allegy (May 2025)
Link: https://onlinelibrary.wiley.com/doi/full/10.1111/all.16593
Easy Read Overview: This study looked at how COVID-19 affects the gut and whether this is linked to post-COVID-19 syndrome (PCS) with fatigue and other symptoms. People with PCS fatigue had more gut problems before, during, and after infection, and showed higher levels of certain blood markers that suggest a “leaky” gut and ongoing inflammation. The findings suggest that gut problems before COVID-19 may increase the risk of PCS fatigue, and tracking gut health could help doctors predict and manage it.
Approximately 10% of COVID-19 patients experience persistent symptoms after contracting SARS-CoV-2, a condition known as Post-COVID Syndrome (PCS). In this study, the authors studied the effects of SARS-CoV-2 infection on the gastrointestinal (GI) tract and their association with specific symptoms (i.e., PCS with fatigue, post-exertional malaise, orthostatic, autonomous, and neurocognitive dysregulations).
Thirty participants with PCS and fatigue, 30 SARS-CoV-2 convalescent participants, 16 SARS-CoV-2 naïve ME/CFS participants (Institute of Medicine criteria), and 30 SARS-CoV-2 naïve healthy participants (healthy controls) were recruited between April 2021 and August 2022. Medical record data were combined with blood, saliva, and stool sample analyses by RT-PCR to evaluate the viral load of body fluids. Apart from the symptoms during and after the disease, the authors also analysed complaints before SARS-CoV-2 infection to identify predictive markers and potential risk factors.
No significant differences in fecal pro-inflammatory marker levels or in the fecal microbiome were found between groups. No viral RNA was detected in body fluids (i.e., blood, saliva, and stool). However, GI complaints before, during, and after SARS-CoV-2 infection were associated with PCS fatigue. Serum lipopolysaccharide-binding protein (LBP) levels were significantly higher in the PCS fatigue group compared to the other groups, indicating intestinal barrier leakage. In addition, this group showed significantly higher IL-6 levels and reduced levels of TNF-α and IL-1-β in serum. Finally, sCD14 levels were significantly lower in PCS fatigue patients compared to the other groups.
The authors identified pre-existing GI complaints, indicating an impaired GI barrier, as a risk factor for developing PCS Fatigue. Therefore, monitoring of GI symptoms and markers at baseline, during, and after a SARS-CoV-2 infection may help in predicting PCS. Gaining insights into the interplay between viral infections, immune responses, and gut barrier integrity may help improve diagnosis and treatment.
Figure: A Graphical abstract of the study that examined post-COVID fatigue syndrome and the gastrointestinal barrier. Researchers compared 30 people with post-COVID fatigue, 30 people who were convalescent after COVID-19, 16 people who had developed ME/CFS after Epstein-Barr virus and 12 healthy controls. Blood, stool and saliva were examined. Researchers found that pre-existing gastrointestinal complaints may predispose people to post-COVID fatigue.
Predisposing and precipitating factors in Epstein–Barr virus-caused myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Jason LA and Katz BZ, (Northwestern University, USA)
Publication: Microorganisms (March 2025)
Link: https://doi.org/10.3390/microorganisms13040702
Easy Read Overview: Researchers studied how Epstein–Barr virus (EBV), which causes glandular fever, may trigger ME/CFS in some people. They followed 4,501 college students, of whom 238 developed EBV infection and 55 went on to develop ME/CFS six months later. The study found that immune system problems, such as low levels of certain cytokines, and metabolic changes in glutathione and thiamine, were linked to severe ME/CFS. Stress, anxiety, and depression before illness did not explain who developed ME/CFS. The researchers concluded that more long-term studies of EBV, COVID-19, and other viral infections are needed to understand post-viral illnesses like ME/CFS and long COVID.
The risk factors for post-viral syndromes such as ME/CFS and long COVID remain largely unclear. Understanding why some people recover after viral infection and others don’t could help reveal the underlying mechanisms in post-viral conditions like ME/CFS and long COVID. The current study investigates how Epstein–Barr virus–induced infectious mononucleosis (IM), a condition linked to about 30% of ME/CFS cases, may act as a key trigger for the illness.
A cohort of 4,501 college students was recruited. General health and psychological well-being were assessed, and blood samples were measured at three time points: baseline, 6 weeks after diagnosis of IM, and six months after IM to identify risk factors for ME/CFS. Of the 4501, 238 participants developed IM. Six months later, 55 participants met the diagnostic criteria for ME/CFS. Of the 157 participants who were diagnosed with IM but did not meet the diagnostic criteria for ME/CFS, 67 served as recovered controls.
Severe ME/CFS was associated with pre-illness deficiencies in cytokines IL-5 and IL-13, gastrointestinal symptoms, and cytokine network clustering, suggesting that inflexibility in the immune system may contribute to delayed recovery. There were no significant differences in pre-illness stress, coping, anxiety or depression between those who developed ME/CFS after IM and those who recovered.
Metabolomic analysis revealed significant differences in baseline metabolites between the ME/CFS group and recovered controls. Dysregulation of metabolites such as glutathione and thiamine was identified, and predictive models achieved 97% accuracy in distinguishing severe ME/CFS cases from recovered controls. The study also highlighted similarities between ME/CFS and long COVID, including immune dysfunction and neuroinflammation, with the kynurenine pathway potentially contributing to symptoms such as brain fog and fatigue in both illnesses.
A key limitation of the study is the lack of standardised diagnostic criteria for ME/CFS and long COVID, which may limit comparability across studies.
The authors emphasise the importance of both long-term follow-up of EBV and SARS-CoV-2 infections and expanding research to other viral illnesses to better understand the underlying mechanisms in post-infection illnesses.
Scientists find link between genes and ME/chronic fatigue syndrome
Authors: Sample I
Publication: The Guardian (August 2025)
Link: https://www.theguardian.com/society/2025/aug/06/genes-me-chronic-fatigue-syndrome
This article reported the early results of the UK’s DecodeME study, the largest genetic study of ME/CFS ever conducted. Researchers found eight genetic regions that differed between people with ME/CFS and healthy people.
Professor Chris Ponting, a University of Edinburgh researcher involved in the DecodeME study, said the results were “a wake-up call”.
“These provide the first robust evidence for genetic contributions to ME,” Ponting said. “There are many genetic variants that apply across the genome that predispose people to be diagnosed with ME.”
For the study, researchers examined the DNA of 15,579 people with ME/CFS and compared it with the DNA of more than 250,000 people who didn’t have the condition. They found regions involved in the nervous system and immune response were different in people with ME/CFS.