Category: Etiology

Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum

Abstract:

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome is a disease of uncertain aetiology that affects up to 400,000 individuals in the UK. Exposure of cultured cells to the sera of people with ME has been proposed to cause phenotypic changes in these cells in vitro when compared to sera from healthy controls. ME serum factors causing these changes could inform the development of diagnostic tests.

In this study, we performed a large-scale, pre-registered replication of an experiment from Fluge et al (2016) that reported an increase in maximal respiratory capacity in healthy myoblasts after treatment with serum from people with ME compared to serum from healthy controls.

We replicated the original experiment with a larger sample size, using sera from 67 people with ME and 53 controls to treat healthy cultured myoblasts, and generated results from over 1,700 mitochondrial stress tests performed with a Seahorse Bioanalyser. We observed no significant differences between treatment with ME or healthy control sera for our primary outcome of interest, oxygen consumption rate at maximal respiratory capacity.

Results from our study provide strong evidence against the hypothesis that ME blood factors differentially affect healthy myoblast mitochondrial phenotypes in vitro.

Source: Ryback AA, Hillier CB, Loureiro CM, Ponting CP, Dalton CF. Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum. PLoS One. 2026 Feb 3;21(2):e0341334. doi: 10.1371/journal.pone.0341334. PMID: 41632778; PMCID: PMC12867253. https://pmc.ncbi.nlm.nih.gov/articles/PMC12867253/ (Full text)

ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis

Highlights:

  • Subset of ME/CFS cases proposed to be caused by a ‘noisy’ latent HSV-1 infection within the brain.
  • HSV-1 proposed to cause local sickness behaviour-like response in the brain.
  • IL-1β, IL-6, TNF-α in the brain proposed to increase sensations of fatigue and pain.

Abstract:

This work presents the hypothesis that a Herpes Simplex Virus 1 (HSV-1) infection in the brain is a significant contributor to the symptoms experienced by a subset of ME/CFS patients. In these patients, an HSV-1 infection has spread from the trigeminal ganglia to the brain, leading to a sickness behaviour-like response that amplifies sensations such as fatigue, pain, and nausea. The hypothesis proposes that ME/CFS is a heterogeneous condition, with a ‘noisy’ latent HSV-1 infection of the brain, and an enduring sickness behaviour-style immune response, an underlying factor for a subset of patients.
Source: John Campbell. ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis. Medical Hypotheses, Volume 204, 2025, 111788. ISSN 0306-9877 https://doi.org/10.1016/j.mehy.2025.111788. https://www.sciencedirect.com/science/article/abs/pii/S0306987725002270 (Full text)

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles

Abstract:

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome.
Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples.
There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified.
These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.
Source: Tobi, M., Chaudhari, D., Ryan, E. P., Rossi, N. F., Koka, O., Baxter, B., Tipton, M., Dutt, T. S., Tobi, Y., McVicker, B., & Angoa-Perez, M. (2025). Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles. Biomolecules, 15(7), 928. https://doi.org/10.3390/biom15070928 https://www.mdpi.com/2218-273X/15/7/928 (Full text)

A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID

Abstract:
The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies.
We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders.
We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a “mechanical basis.” We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei.
This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS.
Source: Wood, J., Varley, T., Hartman, J., Melia, N., Kaufman, D., & Falor, T. (2025). A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID. Preprints. https://doi.org/10.20944/preprints202506.0874.v1 https://www.preprints.org/manuscript/202506.0874/v1 (Full text)

Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis

Abstract:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed.

This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001).

Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects.

As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Source: Kaczmarek MP. Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS One. 2023 Dec 29;18(12):e0296060. doi: 10.1371/journal.pone.0296060. PMID: 38157384; PMCID: PMC10756525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756525/ (Full text)

Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study

Abstract:

Background: Previous serological studies have indicated an association between viruses and atypical pathogens and Chronic Fatigue Syndrome (CFS). This study aims to investigate the correlation between infections from common pathogens, including typical bacteria, and the subsequent risk of developing CFS. The analysis is based on data from Taiwan’s National Health Insurance Research Database.

Methods: From 2000 to 2017, we included a total of 395,811 cases aged 20 years or older newly diagnosed with infection. The cases were matched 1:1 with controls using a propensity score and were followed up until diagnoses of CFS were made.

Results: The Cox proportional hazards regression analysis was used to estimate the relationship between infection and the subsequent risk of CFS. The incidence density rates among non-infection and infection population were 3.67 and 5.40 per 1000 person-years, respectively (adjusted hazard ratio [HR] = 1.5, with a 95% confidence interval [CI] 1.47-1.54). Patients infected with Varicella-zoster virus, Mycobacterium tuberculosis, Escherichia coli, Candida, Salmonella, Staphylococcus aureus and influenza virus had a significantly higher risk of CFS than those without these pathogens (p < 0.05). Patients taking doxycycline, azithromycin, moxifloxacin, levofloxacin, or ciprofloxacin had a significantly lower risk of CFS than patients in the corresponding control group (p < 0.05).

Conclusion: Our population-based retrospective cohort study found that infection with common pathogens, including bacteria, viruses, is associated with an increased risk of developing CFS.

Source: Chang H, Kuo CF, Yu TS, Ke LY, Hung CL, Tsai SY. Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study. J Transl Med. 2023 Nov 11;21(1):804. doi: 10.1186/s12967-023-04636-z. PMID: 37951920. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04636-z (Full text)

Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis

Abstract:

Background: Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients.

Methods: We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections’ contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased).

Results: Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a “moderate association” by Cohen’s d test) compared to both healthy and diseased controls.

Conclusion: This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.

Source: Hwang, JH., Lee, JS., Oh, HM. et al. Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis. J Transl Med 21, 763 (2023). https://doi.org/10.1186/s12967-023-04635-0 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04635-0 (Full text)

Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue

Abstract

Background: Causative genetic variants cannot yet be found for many disorders with a clear heritable component, including chronic fatigue disorders like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These conditions may involve genes in difficult-to-align genomic regions that are refractory to short read approaches. Structural variants in these regions can be particularly hard to detect or define with short reads, yet may account for a significant number of cases. Long read sequencing can overcome these difficulties but so far little data is available regarding the specific analytical challenges inherent in such regions, which need to be taken into account to ensure that variants are correctly identified.

Research into chronic fatigue disorders faces the additional challenge that the heterogeneous patient population likely encompasses multiple aetiologies with overlapping symptoms, rather than a single disease entity, such that each individual abnormality may lack statistical significance within a larger sample. Better delineation of patient subgroups is needed to target research and treatment.

Methods: We use nanopore sequencing in a case of unexplained severe fatigue to identify and fully characterise a large inversion in a highly homologous region spanning the AKR1C gene locus, which was indicated but could not be resolved by short-read sequencing. We then use GC-MS/MS serum steroid analysis to investigate the functional consequences.

Results: Several commonly used bioinformatics tools are confounded by the homology but a combined approach including visual inspection allows the variant to be accurately resolved. The DNA inversion appears to increase the expression of AKR1C2 while limiting AKR1C1 activity, resulting in a relative increase of inhibitory neurosteroids and impaired progesterone metabolism.

Conclusions: This study provides an example of how long read sequencing can improve diagnostic yield in research and clinical care, and highlights some of the analytical challenges presented by regions containing tandem arrays of genes. It also proposes a novel gene associated with a specific disease aetiology that may be an underlying cause of complex chronic fatigue and possibly other conditions too. It reveals biomarkers that could be assessed in a larger cohort, potentially identifying a subset of patients who might respond to treatments suggested by the aetiology.

Source: Julia Oakley, Martin Hill, Adam Giess, Mélanie Tanguy, Greg Elgar. Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue. ResearchSquare [Preprint] https://www.researchsquare.com/article/rs-3218228/v2 (Full text)

The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome

ME/CFS is a disabling and often severe disease, so-far incurable, that has long been associated with discrete outbreaks and sporadic incidents of viral-like illness. First, a word about the controversial name. The designation “Myalgic Encephalomyelitis” (abbreviated ME) originated following an outbreak at London’s Royal Free Hospital in 1955. More than 200 members of the hospital staff became disabled [1]. Melvin Ramsay, MD, eventually published important case descriptions in Lancet [2]. He coined “ME” based on predominant symptoms of muscle pain (myalgia) and effects on the brain (encephalo), spinal cord (myel), and inflammation (itis). For 32 years, “ME” was deemed acceptable until, in 1987, the Centers for Disease Control (CDC) convened an extramural committee to change the name. CDC did so in response to a series of outbreaks of a similar, if not identical, illness in the United States, introducing “chronic fatigue syndrome” in 1988 [3].

Because the CDC name trivializes the serious nature of the disease, the patient community and many medical professionals prefer ME, which continues to be widely used in the United Kingdom and Europe. In 2015, a US Institute of Medicine (IOM) committee recommended yet another name, Systemic Exertion Intolerance Disease [4], which has been largely ignored. Should inflammation of the brain and spinal cord be definitively shown with modern methods, the name Myalgic Encephalomyelitis will finally be vindicated. The compromise name ME/CFS is now used most frequently and will be used here despite its faults.

Source: Hanson MR (2023) The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome. PLoS Pathog 19(8): e1011523. https://doi.org/10.1371/journal.ppat.1011523 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011523 (Full text)

 

Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

  • Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
  • Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
  • Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
  • Enhanced IL-10 regulatory response may drive the observed immunosuppression.
  • Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.

Abstract:

The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear.

Relying on data from two independent cohorts of ME/CFS and control study participants, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

Source: Melanie Uhde, Alyssa C. Indart, Peter H.R. Green, Robert H. Yolken, Dane B. Cook, Sanjay K. Shukla, Suzanne D. Vernon, Armin Alaedini.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome. Brain, Behavior, & Immunity – Health, 2023, 100627. ISSN 2666-3546, https://doi.org/10.1016/j.bbih.2023.100627.
https://www.sciencedirect.com/science/article/pii/S2666354623000418 (Full text)