Search Results (234)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene (OPRM1) promoter methylation, play a role in this dysfunction. Using a repeated-measures design, 28 ME/CFS/FM patients and 26 matched healthy controls visited the hospital twice within four days. Assessments included blood sampling for epigenetic analysis, a clinical questionnaire battery, and quantitative sensory testing (QST). Global DNA (hydroxy)methylation was quantified via liquid chromatography–tandem mass spectrometry, and targeted pyrosequencing was performed on promoter regions of OPRM1, COMT, and BDNF. ME/CFS/FM patients reported significantly worse symptom outcomes. No differences in global (hydroxy)methylation were found. Patients showed significantly higher OPRM1 promoter methylation, which remained after adjusting for symptom severity and QST findings. Across timepoints, OPRM1 methylation consistently correlated with BDNF Promoter I and Exon III methylation. This is, to the best of our knowledge, the first study examining OPRM1 methylation in ME/CFS/FM. Increased OPRM1 methylation in patients, independent of symptoms or pain sensitivity measures, supports the hypothesis of dysregulated opioidergic signaling in these conditions. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, whose hallmark characteristic is post-exertional malaise (PEM). It can affect many organs and systems, leading to severe impairment of patients’ quality of life. Although numerous post-infectious, immunological, neurological, metabolic, and endocrine alterations have been documented, neither a definitive diagnostic marker nor approved treatments are available. The etiology and pathophysiology remain incompletely understood; however, emerging evidence suggests that the gut microbiome plays a role in immune responses and the development of ME/CFS. It is hypothesized that specific disturbances in gut microbiome composition, known as dysbiosis, may compromise the integrity of the intestinal barrier. This consequently leads to translocation of microbial components, which further triggers an immune response and systemic inflammation complicating the clinical presentation of ME/CFS. Furthermore, in terms of the so-called gut–brain axis, microbiome changes may lead to distinct neurocognitive impairments observed in ME/CFS patients. This review offers the readers a broad perspective on the topic on ME/CFS, with a particular emphasis on the interplay between the gut microbiome and disease mechanisms. Last but not least, recent data on potential treatment strategies for intestinal dysbiosis in ME/CFS patients have been included. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities. Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component. Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut–brain axis. Neuroendocrine findings such as hypothalamic–pituitary–adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities. Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise. Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical condition characterized by extreme fatigue lasting at least 6 months. Based upon case reports, patients infected with Babesia or Bartonella spp. have reported a history of chronic fatigue and concurrent neurological symptoms. In this study, 50 study participants reporting fatigue lasting from six months to 19 years and one or more neurological symptoms were selected. PCR assays were used to amplify Babesia and Bartonella spp. DNA from blood and enrichment blood cultures. Using targeted qPCR amplification and DNA sequencing, infection with Babesia spp., Bartonella spp. or both genera was confirmed in 10, 11, and 2 individuals, respectively. Of 50 participants, 12 (24%, 95% CI: 12–36%) were infected with a Babesia species, while Bartonella species infection was documented in 13/50 individuals (26%, 95% CI: 13.8–38.2%). This study provides documentation supporting a potential role for Babesia and Bartonella infection in patients with presentations consistent with ME/CFS. Prospective case–control studies, using highly sensitive direct pathogen detection techniques, are needed to determine whether or the extent to which infection with members of these two genera contributes to or causes ME/CFS. Full article

Objectives: Neurodivergent (ND) individuals (e.g., autistic people) are more likely to experience health problems that are characterised by ‘Central Sensitisation’ (CS). Recent research suggests that a so-called ‘Long-COVID’ syndrome might also be explained by a heightened response to internal physiological stimuli, much like in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The primary objective of this study was to establish whether individuals who scored highly on a measure of CS would be more likely to experience long-term symptoms of COVID-19. A secondary aim considered if having a Type D personality was also linked to ongoing COVID-19 symptoms. Method: Using a standardised assessment tool, we examined whether traits associated with autism would predict long-term COVID-19 symptoms in 267 Healthcare Workers (HCWs). We also used a measure of Type D personality to establish if negative affect and social inhibition were related to Long-COVID. Results: A higher number of autistic traits predicted COVID-19 symptoms that lasted more than 12 weeks regardless of formal autism diagnosis. A personality measure also showed that negative affect was associated with experiencing COVID-19 symptoms for 4–12 weeks, though the direction of causality in this case is uncertain. Conclusions: Our main findings were (i) more HCWs scored above threshold for neurodivergence than those who were self-declared as having been diagnosed as neurodivergent; (ii) while there was no association between long-term COVID-19 and self-declared neurodivergent status, scores for the ‘sensory reactivity’ item of a standardised autism scale was predictive of COVID-19 symptoms lasting beyond 12 weeks post-infection; and (iii) HCWs with Type D Personality were not more likely to experience long-term COVID-19. Full article

Background: COVID-19 has taken millions of lives and continues to affect people worldwide. Post-Acute Sequelae of SARS-CoV-2 Infection (also known as Post-Acute Sequelae of COVID-19 (PASC) or more commonly, Long COVID) occurs in the aftermath of COVID-19 and is poorly understood despite its widespread effects. Methods: We created a machine-learning model that distinguishes PASC from PASC-similar diseases. The model was trained to recognize PASC-dysregulated metabolites (p ≤ 0.05) using molecular descriptors. Results: Our multi-layer perceptron model accurately recognizes PASC-dysregulated metabolites in the independent testing set, with an AUC-ROC of 0.8991, and differentiates PASC from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Lyme disease, postural orthostatic tachycardia syndrome (POTS), and irritable bowel syndrome (IBS). However, it was unable to differentiate fibromyalgia (FM) from PASC. Conclusions: By creating and testing models pairwise on each of these diseases, we elucidated the unique strength of the similarity between FM and PASC relative to other PASC-similar diseases. Our approach is unique to PASC diagnosis, and our use of molecular descriptors enables our model to work with any metabolite where molecular descriptors can be identified, as these descriptors can be generated and compared for any metabolite. Our study presents a novel approach to PASC diagnosis that partially circumvents the lengthy process of exclusion, potentially facilitating faster interventions and improved patient outcomes. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17–24 million people representing approximately 1% of the population are afflicted worldwide. In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent. This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent. The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases. Full article

Background: Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a debilitating condition characterized by persistent fatigue and multisystemic symptoms, such as cognitive impairment, musculoskeletal pain, and post-exertional malaise. Recently, parallels have been drawn between ME/CFS and Long COVID, a post-viral syndrome following infection with SARS-CoV-2, which shares many clinical features with CFS. Both conditions involve chronic immune activation, raising questions about their immunopathological overlap. Objectives: This study aimed to compare immune biomarkers between patients with ME/CFS or Long COVID and healthy controls to explore shared immune dysfunction. Methods: We analyzed lymphocyte subsets, cytokine profiles, psychological status and their correlations in 190 participants, 65 with CFS, 54 with Long COVID, and 70 healthy controls. Results: When compared to healthy subjects, results in both conditions were marked by lower levels of lymphocytes (CFS—2.472 × 10⁹/L, p = 0.006, LC—2.051 × 10⁹/L, p = 0.009), CD8⁺ T cells (CFS—0.394 × 10⁹/L, p = 0.001, LC—0.404 × 10⁹/L, p = 0.001), and NK cells (CFS—0.205 × 10⁹/L, p = 0.001, LC—0.180 × 10⁹/L, p = 0.001), and higher levels of proinflammatory cytokines such as IL-6 (CFS—3.35 pg/mL, p = 0.050 LC—4.04 pg/mL, p = 0.001), TNF (CFS—2.64 pg/mL, p = 0.023, LC—2.50 pg/mL, p = 0.025), IL-4 (CFS—3.72 pg/mL, p = 0.041, LC—3.45 pg/mL, p = 0.048), and IL-10 (CFS—2.29 pg/mL, p = 0.039, LC—2.25 pg/mL, p = 0.018). Conclusions: Notably, there were no significant differences between CFS and Long COVID patients in the tested biomarkers. These results demonstrate that ME/CFS and Long COVID display comparable immune and inflammatory profiles, with no significant biomarker differences observed between the two groups. Full article

Defined by the World Health Organization as a neurological disorder, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness, affecting millions of people worldwide. First reported in the early nineteenth century, ME/CFS is uniquely characterized by a wide array of symptoms, including fatigue, brain fog, post-exertional malaise (PEM), sleep dysfunction, and orthostatic intolerance (OI). Despite decades of extensive research, there are no effective medical treatments or simple diagnostics for ME/CFS, with an estimated 90% of patients remaining undiagnosed. The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep. A link between glymphatic dysfunction and some neurological disorders such as Alzheimer’s disease has already been established, raising the possibility of its involvement in ME/CFS. Accordingly, we believe the ME/CFS medical/scientific community will be interested in seriously considering GD an important contributor to its pathophysiology. If so, therapeutics that modulate glymphatic function may also benefit patients with ME/CFS. Full article

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-COVID Syndrome (PCS) are chronic conditions that share relevant pathophysiological mechanisms. Conventional rehabilitation programs have often been associated with patient dissatisfaction and frequent adverse events (AEs), highlighting the need for safer and more effective clinical approaches. This study aims to compare the effects of a telerehabilitation program based on conscious movement with those of conventional low-intensity exercise in individuals with ME/CFS or PCS. Methods: This is a prospective, single-blind, three-arm, parallel, superiority randomized clinical trial. A total of 147 participants (aged 18–70) with ME/CFS or PCS will be recruited and randomly assigned to one of three groups: (a) conscious movement; (b) low-intensity exercise; or c) usual care. All interventions will be delivered via telehealth over 12 weeks, with weekly 45-min sessions combining health education and individually tailored exercises. Participants will be encouraged to practice daily using the provided materials. Adherence rates and potential AEs will be recorded. The primary outcome is the total score on the 14-item Chalder Fatigue Scale at 12 weeks (post-intervention). Secondary outcomes include heart rate variability, functional performance, pain intensity and interference, mental health, interoceptive awareness, quality of life, sleep quality and fear of movement. Measurements will be collected at baseline, post-intervention, and at 3-month follow-up. Discussion: Recent evidence suggests that both autonomic and cognitive activity modulate immune function. Conscious movement, which integrates exercise with interoception and mindfulness-based strategies, may provide greater benefits than low-intensity exercise alone. Study limitations should be considered when interpreting the results. Trial registration: Registered at ClinicalTrials.gov on 15 May 2025 (NCT06978582). Protocol version 4 (29 September 2025). Ethics Committee code: 2025-0180. Full article

Early-life infections can produce durable changes in immune function and behavior. We propose a mechanistic hypothesis positioning the mechanistic target of rapamycin (mTOR) as the link between peripheral inflammation and central nervous system dysfunction in pediatric post-infectious syndromes. Based on clinical, translational, and experimental literature, we outline a stepwise pathway. First, sustained mTOR activation skews T-cell and macrophage differentiation toward pro-inflammatory and autoimmune states. Second, endothelial mTOR signaling weakens tight junctions and increases vesicular transport, compromising blood–brain barrier integrity. Third, cytokines and sometimes autoreactive cells enter the brain and engage mTOR in microglia and neurons, driving neuroinflammation, impaired synaptic maintenance and plasticity, and neurotransmitter disruption. This framework accounts for features observed in Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute neuropsychiatry syndrome (PANS/PANDAS) and yields testable predictions on pathway activity and barrier permeability. It also motivates targeted interventions that modulate mTOR-related processes in immune and endothelial compartments and within neural circuits in children. So, this article aims to outline a mechanistic framework linking infection-driven mTOR activation to post-infectious neuropsychiatric syndromes. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition without a definitive aetiology, no reliable diagnostic test, and no proven effective treatment. Despite most patients reporting a post-viral onset of illness, findings to date are conflicting on whether a single virus or multiple viral triggers are involved. Most studies to date have focused on detecting viruses in blood and circulating immune cells with relatively few investigating the presence of viruses in mucosal sites. In this review, we propose that this represents a critical gap in understanding the pathophysiology of ME/CFS knowledge, as mucosal tissues are primary entry points for most pathogens and often serve as reservoirs where viruses may persist. Consequently, they represent ideal niches for identifying persistent infections in ME/CFS. Emerging evidence from saliva and other mucosal samples in ME/CFS patients is consistent with this proposal and that latent viruses can persist and periodically reactivate in mucosal tissues from where they can potentially contribute to immune dysregulation, chronic inflammation, and increased symptom severity that defines ME/CFS. Full article

Long-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome are disabling diseases characterised by ongoing fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome typically follows viral infections, whereas Long-COVID exclusively follows SARS-CoV-2 infection, with overlapping but distinct features. This review uses comprehensive searches of online databases to compare their clinical presentations, pathophysiologies, and treatments. Both Long-COVID and ME/CFS appear to involve multifactorial mechanisms, including viral persistence, immune dysregulation, endothelial dysfunction, and autoimmunity, though their relative contributions remain uncertain. Symptom management strategies are consistent, however. Cognitive behaviour therapy has been successful, and there are minimal drug treatments. Graded exercise therapy occupies a contested place, recommending individualised pacing and multidisciplinary rehabilitation. Common and exclusive mechanisms must be identified to formulate valuable therapies. A more significant body of research focusing on immune dysfunction as a pathogenic mechanism for advancing the disease and enabling more effective therapies and diagnostics is needed. Full article

Background/Objectives: Growing evidence suggests that mast cell activation (MCA) may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disorder characterized by persistent fatigue and post-exertional malaise (PEM). Particularly in relation to orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (POTS), this study aimed to investigate the prevalence and clinical relevance of MCA in an Austrian ME/CFS patient cohort. Methods: Two data sets were analyzed. The CCCFS data set, a comprehensive, patient-centered online questionnaire consisting of 687 filled surveys, focuses on patient stratification. Self-reported clinical features, disease progression, and treatment responses were analyzed. Preliminary findings were validated in a second, retrospective study, analyzing data of 383 Austrian ME/CFS patients with regard to MCA involvement and OI. Results: Among followed-up ME/CFS patients, MCA prevalence increased over the disease course, with up to 25.3% meeting the criteria for clinically relevant MCA. ME/CFS patients with Mast Cell Activation Syndrome (MCAS) and OI reported symptom alleviation significantly more often following mast cell-targeted treatment than those without MCAS (p < 0.0001). With regard to IF-channel inhibitors, ME/CFS patients diagnosed with MCAS responded more frequently than those without MCAS (p = 0.076), while no significant differences were observed in response to beta blockers (p = 0.637). In both cohorts, OI, particularly POTS, was significantly more common in patients with MCA involvement. Conclusions: MCA appears to be a frequent and clinically relevant comorbidity in ME/CFS and is associated with a higher prevalence of OI, particularly POTS. Stratifying patients based on MCA involvement may support personalized treatment approaches and improve clinical outcomes. Full article

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating complex disease with an elusive etiology, lacking objective diagnostic biomarkers. This study leverages advanced Automated Machine Learning (AutoML) to analyze plasma metabolomic and lipidomic profiles for the purpose of ME/CFS detection. Methods: We utilized a publicly available dataset comprising 888 metabolic features from 106 ME/CFS patients and 91 matched controls. Three AutoML frameworks—TPOT, Auto-Sklearn, and H2O AutoML—were benchmarked under identical time constraints. Univariate ROC and PLS-DA analyses with cross-validation, permutation testing, and VIP-based feature selection were applied to standardized, log-transformed omics data to identify significant discriminatory metabolites/lipids and assess their intercorrelations. Results: TPOT significantly outperformed its counterparts, achieving an area under the curve (AUC) of 92.1%, accuracy of 87.3%, sensitivity of 85.8%, and specificity of 89.0%. The PLS-DA model revealed a moderate but statistically significant discrimination between ME/CFS and controls. Explainable artificial intelligence (XAI) via SHAP analysis of the optimal TPOT model identified key metabolites implicating dysregulated pathways in mitochondrial energy metabolism (succinic acid, pyruvic acid, leucine), chronic inflammation (prostaglandin D₂, 11,12-EET), gut–brain axis communication (glycocholic acid), and cell membrane integrity (pc(35:2)a). Conclusions: Our results demonstrate that TPOT-derived models not only provide a highly accurate and robust diagnostic tool but also yield biologically interpretable insights into the pathophysiology of ME/CFS, highlighting its potential for clinical decision support and elucidating novel therapeutic targets. Full article