The authors hypothesize that acute viral infections damage the cells of blood vessel walls (endothelial cells) and put them into a so-called senescent state – they become dysfunctional and permanently emit pro-inflammatory, pro-coagulatory, and vasoconstrictive signals (SASP). An immune system demonstrably impaired in ME/CFS and Long COVID is unable to eliminate these dysfunctional cells, thereby creating a self-reinforcing cycle that keeps the disease chronic. This mechanism can explain the typical symptoms such as PEM, brain fog, cerebral blood flow deficits, and gastrointestinal complaints at the level of the blood-brain barrier, the gut, and the musculature.

This paper provides a comprehensive pathophysiological framework model that, for the first time, describes endothelial senescence as a connecting core element between immune dysfunction, multi-organ involvement, and chronification in ME/CFS and Long COVID. It thereby offers a biologically plausible explanation for the broad spectrum of symptoms and identifies concrete targets for biomarkers and therapies, particularly for approaches aimed at eliminating senescent cells (senolytics) and immune modulation.

91 participants with ME/CFS following SARS-CoV-2 infection (PASC) or following vaccination (PVS) and vitamin D deficiency were treated over 12 weeks with either comprehensive vitamin D therapy (supplementation, dietary counseling, sunlight, exercise) or vitamin D supplements alone. The intervention group showed a significantly greater reduction in symptoms (-6.7 vs. -1.2 symptoms) and a significantly greater increase in serum vitamin D levels. Notably, 16 out of 46 participants in the intervention group no longer met the diagnostic criteria for ME/CFS, compared to only 1 person in the control group.

This study is one of the first randomized controlled trials to investigate a therapeutic approach specifically for ME/CFS following COVID-19 and vaccination. It provides evidence that vitamin D deficiency could be a relevant, modifiable factor in a subset of those affected. However, it should be noted that the study only included individuals with confirmed vitamin D deficiency, the intervention combined several components, and the study design (open-label) is susceptible to expectation effects – the results are therefore not transferable to all individuals with ME/CFS.

Based on 34 studies of good to high quality, researchers investigated which subsystems of working memory are affected in ME/CFS. The results demonstrate a statistically significant and large effect size for impairments in verbal working memory – that is, the short-term processing of linguistic information – while no significant difference from healthy individuals was found in visual working memory. This distinction is clinically meaningful, as it may explain why those affected have particular difficulty with language-intensive everyday tasks such as conversations, reading, or talking on the phone.

This paper is important because, for the first time based on a comprehensive meta-analysis, it precisely differentiates which memory components are actually impaired in ME/CFS. The so-called 'brain fog' experience of those affected thereby becomes empirically more tangible and is attributed to specific cognitive subsystems. The findings can improve clinical care, enable more targeted research, and help to better document the cognitive symptoms to third parties (e.g., employers, insurance companies).

The study used publicly available gene and protein expression data from the mapMECFS repository as well as data from the large DecodeME genome study to identify common patterns across various tissue types. In doing so, two independent studies revealed decreased levels of the mitochondrial genes MT-RNR1 and MT-RNR2, while other mitochondrial genes were found to be more highly expressed in platelets – both findings point to a dysregulation of mitochondrial function. Based on the identified genes, more than 100 already approved medications were also identified that target these genes and could serve as a starting point for therapeutic studies.

This study is important because, through the systematic integration of multiple independent datasets, it places the hypothesis of mitochondrial dysfunction in ME/CFS on a broader evidential foundation. At the same time, it openly demonstrates that the overlap of specific genes between studies is still limited – an honest finding that underscores the need for larger, standardized studies. Particularly valuable is the translational approach of identifying concrete, already approved agents as potential treatment candidates, which paves the way toward clinical trials.

Extracellular vesicles (EVs) are tiny membrane-bound particles secreted by cells that transport signaling molecules. In this study, EVs from the blood of women with post-infectious ME/CFS – including Post-COVID-19 ME/CFS – were analyzed. Altered proteins (hemoglobin subunit alpha, IGFBP-ALS) as well as a significantly reduced expression of the microRNA molecule hsa-let-7b-5p were found, which is associated with greater fatigue, pain, and immune activation.

ME/CFS has until now suffered from the absence of objective biological markers. This study identifies for the first time specific EV cargo molecules – in particular the miRNA molecule hsa-let-7b-5p – that correlate with clinical severity and could be used both for diagnosis and for the subdivision of patient groups (e.g. post-COVID vs. other triggers). This opens up a promising pathway toward blood tests that could make ME/CFS objectively detectable.

The article summarizes the current state of research on severe ME/CFS and describes how the condition can be objectified through 2-day exercise tests (CPET), as a diagnostic biomarker is lacking. Decades of underfunding have resulted in there being no effective treatments to this day. The COVID-19 pandemic has significantly increased the number of those affected by post-infectious conditions that meet ME/CFS criteria and has intensified the pressure on research.

The article provides an important inventory of the most severe ME/CFS cases and highlights the dramatic gap in care: despite extreme impairment – in some cases more severe than in other serious illnesses – effective therapies are lacking. It underscores the urgent need for targeted biomedical research and draws attention to the particular vulnerability of severely affected individuals, whose reality often remains invisible in public and scientific awareness.

ME/CFS is classified as a multisystemic biological disease – explicitly not a mental disorder – characterized by severe fatigue, cognitive impairments, sleep disturbances, autonomic dysfunction, and post-exertional malaise (PEM). The underlying mechanisms under discussion include immune dysregulation (NK cell and T cell dysfunction, elevated cytokine levels, autoantibodies), hormonal dysregulation, and oxidative stress. The paper also emphasizes that poor treatment outcomes are frequently attributable to delayed or incorrect diagnoses, inadequate training of physicians, and misinformation.

This review article is relevant as it clearly positions ME/CFS as a biological disease recognized by the NIH as a chronic pain condition, and summarizes important mechanisms as well as gaps in care – particularly the problem of misdiagnosis and nociplastic pain as part of the clinical picture.

Molecular hydrogen (H2), consumed primarily as hydrogen-rich water, acts as a selective antioxidant, has anti-inflammatory properties, and supports energy metabolism in the mitochondria – all mechanisms that are impaired in ME/CFS. Three small clinical pilot studies suggest feasibility and preliminary improvements in fatigue and physical performance, but are severely limited in terms of methodology. Similar findings in Long COVID suggest that HRW may also be relevant in other post-viral fatigue syndromes.

This review systematically connects, for the first time, known ME/CFS pathomechanisms (oxidative stress, mitochondrial dysfunction, inflammation) with the therapeutic potential of molecular hydrogen, and provides a structured overview of the – still very sparse – clinical data. As a low-threshold, well-tolerated adjunct therapy, HRW is of interest to patients who are waiting for approved treatments. At the same time, the paper clearly highlights the need for larger, controlled studies with objective biomarkers.

BioMapAI is a deep neural network that simultaneously analyzed data from five different biological domains over a period of four years: gut microbiome, blood metabolites, immune cell profiles, laboratory blood values, and clinical symptoms from 249 participants. The AI identified disrupted connections between bacterial metabolism (in particular short-chain fatty acids, branched-chain amino acids, tryptophan, and benzoate), blood lipids, and bile acids. Additionally, elevated inflammatory responses were found in specific T-cell subgroups (MAIT and γδT cells), which secrete increased amounts of the inflammatory protein IFN-γ — a finding that indicates chronic activation of the mucosal immune system.

This paper is particularly significant because it is the first to use AI to create a comprehensive system map of biological disruptions in ME/CFS, mapping multiple body systems simultaneously. It provides strong evidence that ME/CFS is a measurable, biologically based disease with specific biomarkers – which could revolutionize diagnosis and future therapeutic approaches. The ability to biologically distinguish between different symptom profiles is an important step toward personalized treatment.

Researchers developed three-dimensional muscle tissue models and exposed them to the blood serum of ME/CFS and Long COVID patients. Within 48 hours, the muscles measurably lost strength while simultaneously increasing their glucose metabolism and the mitochondria enlarged — a short-term adaptive response. With prolonged exposure (96–144 hours), the mitochondria fragmented into a ring-shaped (toroidal) structure, and the muscle tissue became increasingly fragile and weak, demonstrating a hypermetabolic collapse.

This study provides, for the first time, an experimental tissue model that makes the peripheral muscle weakness in ME/CFS and Long COVID mechanistically explainable: A factor contained in the blood – still unknown, but demonstrably effective – drives muscle cells into a metabolic state of exception that ultimately leads to collapse. This explains the clinical picture of Post-Exertional Malaise (PEM) at the cellular level and opens up, for the first time, a platform for testing potential therapies directly on muscle tissue.

The study analyzed the composition of cerebrospinal fluid (CSF) from people with ME/CFS and control subjects – both at rest and after physical exertion. ME/CFS showed elevated serine levels alongside reduced 5-methyltetrahydrofolate (5MTHF), indicating a disruption in what is known as one-carbon metabolism, which is critical for, among other things, methylation processes and nerve function. Particularly striking: after exertion, metabolic byproducts were consumed in ME/CFS patients, while control subjects produced them – providing biological evidence of the phenomenon of post-exertional malaise (PEM) at the molecular level.

This study is groundbreaking because it is the first to specifically examine cerebrospinal fluid — that is, the fluid directly surrounding the brain — in ME/CFS using metabolomic and lipidomic analysis. The findings differ markedly from earlier blood plasma studies and provide direct evidence of disruptions in the central nervous system, including potential myelin dysfunction (the protective sheath around nerves) and changes in the brain's white matter. The study also provides, for the first time, biological correlates for PEM at the cerebrospinal fluid level, and opens up new research directions for therapeutic approaches such as folate-, thiamine-, or phospholipid-based interventions.

Researchers examined 6,361 blood proteins in 79 individuals with ME/CFS and 53 healthy, similarly sedentary control subjects before and after two maximal exercise tests conducted 24 hours apart. ME/CFS patients showed the most pronounced changes during the recovery phase — precisely at the time of onset of post-exertional malaise — including suppression of T and B cell immune responses, disrupted cell communication, and upregulation of glycolytic processes, indicating mitochondrial stress. Additionally, sex-specific differences in molecular responses were found, and protein changes correlated directly with symptoms such as muscle pain, recurring sore throat, and swollen lymph nodes.

This study provides, for the first time, a time-resolved, high-resolution molecular characterization of Post-Exertional Malaise in a comparatively large cohort. By comparing with control subjects who are equally sedentary, findings are not attributed to mere deconditioning, but are instead identified as disease-specific maladaptation. The results support biological explanatory models for PEM and provide concrete starting points for future biomarker development and targeted therapy research.

The authors identify several biological mechanisms that are jointly responsible for the symptoms: autoantibodies against nerve target structures, dysfunction of the inner walls of blood vessels, acquired mitochondrial damage, and a pro-inflammatory gut microbiome. In addition, they describe evolutionarily ancient neural circuits that trigger so-called 'sickness behavior' and torpor (a form of protective stupor) and are activated by neuroinflammation. The symptoms become chronic because persisting pathogen remnants and mutually reinforcing biological dysfunctions form a self-sustaining vicious cycle.

This paper provides one of the most comprehensive explanatory models to date for why ME/CFS and Long COVID cause such persistent symptoms. Particularly significant is the description of neural circuits as a therapeutically targetable symptom generator, as well as the finding that biological abnormalities mutually reinforce one another – which explains why those affected do not simply 'recover' without targeted treatment. The paper directly connects basic research with therapeutic starting points and affects 60–400 million people worldwide.

The study analyzed the activation patterns of so-called human endogenous retroviruses (HERVs) – ancient viral remnants in the human genome – in blood immune cells from patients with ME/CFS, fibromyalgia, or both conditions. All 43 participants could be accurately assigned to one of four groups (ME/CFS, FM, co-diagnosis, healthy) based on their HERV profiles. Specific immune changes were found for ME/CFS (fewer γδ T cells, more memory T cells), which correlated with symptom severity, as well as an epigenetic mechanism involving the proteins SETDB1 and TRIM28 that could explain HERV activation. Surprisingly, patients with a co-diagnosis showed a largely unremarkable HERV pattern, suggesting a distinct, new disease entity.

This study provides, for the first time, molecular signatures that objectively and distinctly differentiate ME/CFS from fibromyalgia – a clinically urgently needed distinction, as both conditions are frequently confused or diagnosed in combination. The identification of HERV expression profiles as potential biomarkers could fundamentally improve the diagnostic situation and simultaneously opens up new approaches for researching epigenetic treatment strategies.

Researchers examined blood cells from 27 ME/CFS patients, 20 Long COVID patients, and 25 healthy controls, finding elevated reactive oxygen species (ROS) in both conditions as well as disruptions in the body's own protective mechanisms against them – particularly in memory T cells. Interestingly, women showed more markedly elevated ROS levels with excessive T cell proliferation, while men predominantly exhibited mitochondrial lipid damage. The already approved medication metformin was able to suppress excessive T cell activity in laboratory tests, making it an interesting potential therapeutic approach.

This study provides, for the first time, a direct molecular comparison between ME/CFS and Long COVID at the cellular level, demonstrating that both conditions are underpinned by similar biochemical disruptions. Particularly significant is the finding of sex-specific differences, which could explain why women and men become ill to differing degrees of severity and may potentially respond differently to treatments. Since the changes are measurable in the blood, this prospectively opens up the possibility of a biomarker as well as individualized therapeutic approaches.

In this study, 3,925 affected individuals were surveyed about their experiences with over 150 treatments. The core symptoms of both conditions overlap significantly – with 89.7% of ME/CFS and 79.4% of Long COVID patients reporting post-exertional malaise (PEM). The treatment experiences of both groups correlated strongly with each other (R²=0.68), suggesting shared disease mechanisms. Furthermore, identifiable patient subgroups benefited from specific therapeutic approaches: individuals with pronounced POTS responded better to medications for regulating the nervous system, while patients with severe cognitive impairment reported benefits from CNS stimulants.

Since there are currently no approved therapies for ME/CFS or Long COVID, patient-reported experiences on a large scale provide valuable guidance for clinical practice and future studies. The study also scientifically confirms what those affected have long described: ME/CFS and Long COVID are closely related in terms of symptoms and treatment, which justifies their joint research and management. The identification of patient subgroups with different treatment responses is particularly significant for the development of personalized therapeutic strategies.

Using invasive exercise testing (ergospirometry with cardiac catheterization), six components of oxygen transport were simultaneously measured in 15 Long COVID patients, 11 ME/CFS patients, and 11 healthy controls. The most striking finding: the diffusion capacity of skeletal muscles (DM) – that is, the ability to transport oxygen from the blood vessels into the muscle tissue – was most severely impaired in both disease groups. If this value alone were corrected to normal levels, maximum oxygen uptake would increase by 66% in Long COVID and by almost 35% in ME/CFS, indicating a key therapeutic target.

This study provides one of the most direct pieces of evidence to date that the physical exhaustion in ME/CFS and Long COVID has no psychogenic or deconditioning-related cause, but is instead based on a measurable, peripheral disorder of oxygen utilization in muscle tissue. The shared pathophysiology of both conditions strengthens the biological credibility of ME/CFS and opens up concrete research directions for targeted therapies – such as improving microcirculation or mitochondrial function in muscle.

The AI framework HEAL2 analyzed whole genome sequences from ME/CFS patients across multiple sites and identified 115 risk genes that are particularly sensitive to genetic loss-of-function mutations. These genes are active in immune cells – particularly cytotoxic CD4 T cells and B cells – as well as in the central nervous system, and show reduced gene expression in ME/CFS patients. The analysis also reveals genetic overlaps with depression and Long COVID, suggesting shared biological foundations.

This study provides for the first time an AI-based approach to the genetic characterization of ME/CFS and demonstrates that the disease has a clear biological, genetically verifiable basis. The identification of specific risk genes opens up new avenues for diagnostic tests and targeted therapeutic approaches. The genetic connection to Long COVID also supports the scientific recognition of both diseases as biologically related.

The authors analyze how two central disease mechanisms in ME/CFS are interconnected: mitochondrial dysfunction, which leads to energy deficiency, and immune alterations in the form of "immune senescence" (premature aging of immune cells) and "immune exhaustion" (chronically overactivated, functionally impaired immune cells). The central thesis is that an energy deficit directly impairs the immune system, as immune cells require enormous amounts of energy to function – a cycle that could perpetuate PEM and chronic fatigue. From this, the authors derive possible therapeutic approaches that simultaneously address energy metabolism and immune regulation.

This review is important because it systematically links two research fields that have mostly been considered separately until now – mitochondrial dysfunction and immunopathology. The concepts of 'immunosenescence' and 'immune exhaustion' are poorly researched in ME/CFS, but could explain why those affected respond poorly to infections while also displaying persistent inflammatory symptoms. The paper establishes a conceptual foundation for new therapeutic approaches that aim to break not just a single symptom, but the underlying metabolic-immunological vicious cycle.

Mitochondria are responsible for energy production in the body's cells. In ME/CFS, there is evidence that these organelles no longer function properly, which could explain why those affected fall into severe exhaustion even after minimal exertion (post-exertional malaise). The authors highlight parallels to Long COVID and evaluate existing research findings on mitochondrial dysfunction as a possible shared disease mechanism in both conditions.

This review article systematically summarizes the current state of research on mitochondrial dysfunction in ME/CFS and builds a biological bridge to Long COVID. It thereby provides an important conceptual foundation for the development of targeted therapies aimed at the energy metabolism disorder, and supports the recognition of ME/CFS as a physical illness with a measurable biological substrate.

Healthy brains optimize their energy consumption during repeated tasks: brain activity (measured as the BOLD signal) decreases over time – a sign of efficient adaptation. In people with ME/CFS, this adaptation is completely absent; instead, brain activity in motor, sensory, and cognitive areas actually increases. This elevated and inefficient brain activity also correlated significantly with the subjectively perceived severity of fatigue in those affected, suggesting a direct connection between the neurological finding and the experience of illness.

This study provides, for the first time, objective neuroimaging evidence that the brain in ME/CFS responds fundamentally differently to cognitive load than in healthy individuals. The absence of BOLD adaptation could explain why even mild mental activities lead to exhaustion and Post-Exertional Malaise (PEM) in those affected: the brain is unable to regulate energy efficiently. This strengthens the biological basis of the disease and refutes explanatory models that reduce ME/CFS to psychological factors.

The study summarizes that in ME/CFS, multiple body systems are simultaneously disrupted: the immune system shows weakened killer cells, exhausted T-cells, and autoantibodies; the gut exhibits an altered microbiome composition and increased permeability, which promotes inflammation and brain fog symptoms. Mitochondrial dysfunction leads to impaired ATP production and explains post-exertional malaise (PEM), while disruptions of the stress hormone systems (HPA axis) and vascular walls exacerbate symptoms such as orthostatic intolerance. All these mechanisms together form a self-sustaining cycle of chronic inflammation, energy deficiency, and neuroimmunological imbalance.

This paper provides a current and comprehensive overview of the most important biological disease mechanisms in ME/CFS and illustrates why ME/CFS is not a psychosomatic condition, but rather a complex, multisystemic biological process. For those affected, it offers a scientific basis for understanding the diverse symptoms; for research, it underscores the necessity of integrative therapeutic approaches.

In people with ME/CFS, oxygen uptake (VO2 peak), performance at the ventilatory threshold, and maximum heart rate drop significantly during a second exercise test following an initial stress test – a pattern that does not occur in healthy individuals. This chronotropic intolerance and reduced aerobic capacity on repeat testing provide objective, measurable evidence that the physiological systems of those affected are persistently impaired by exertion. The protocol is considered an important diagnostic tool for scientifically demonstrating post-exertional malaise and distinguishing it from other conditions.

The 2-day CPET protocol is one of the few objective methods that measures and reproducibly documents Post-Exertional Malaise – the cardinal symptom of ME/CFS. It refutes narratives about purely psychological causes and has direct relevance for diagnostic confirmation, recognition under social law, as well as the departure from exertion-increasing therapeutic approaches such as GET (Graded Exercise Therapy).

In this Swedish study involving 40 ME/CFS patients and 41 healthy controls, blood plasma and cerebrospinal fluid (CSF) were comprehensively analyzed – including cytokines, hormones, matrix metalloproteinases (MMPs), autoantibodies, and pathogen exposures. Analysis of the CSF samples revealed two distinct patient clusters based on MMP profiles, which differed in their inflammatory patterns and history of pathogen exposure, despite comparable clinical symptoms. Additionally, altered interaction patterns between biological factors were observed in the blood plasma of ME/CFS patients.

This study provides, for the first time, cerebrospinal fluid-based evidence that ME/CFS is not a uniform disease, but encompasses at least two biologically distinguishable subgroups. This is significant because it could explain why existing treatment approaches have such varying effects, and suggests that future therapies will need to be tailored to the respective immune type. The use of cerebrospinal fluid – the closest possible approximation to the central nervous system without direct brain biopsy – lends the findings particular significance with regard to neuroinflammatory processes in ME/CFS.

This review article summarizes studies that document subtle but detectable changes in the brains of ME/CFS patients using modern imaging technologies (MRI, PET, SPECT). The examined changes include structural abnormalities, disrupted brain activity, neurochemical deviations, and changes in tissue microstructure. These objective findings provide important biological evidence that ME/CFS is an organic disease with measurable brain changes.

This review is significant because it documents the neurobiological basis of ME/CFS through imaging techniques, thereby countering the common misconception that the disease is psychosomatic. The summary of various neuroimaging findings strengthens the scientific basis for the recognition of ME/CFS as a neurological disease and can guide future diagnostic approaches and treatment developments.

This systematic review and meta-analysis evaluated 13 studies with over 2,261 participants and demonstrated that women with endometriosis are 2.79 times more likely to also develop ME/CFS. Conversely, individuals affected by ME/CFS have a 2.52 times higher risk of endometriosis. Both conditions share central mechanisms such as chronic inflammatory processes and dysregulated immune regulation, which may explain the strong statistical overlap.

This study provides, for the first time, robust epidemiological evidence for a bidirectional link between endometriosis and ME/CFS. Since both conditions are frequently underdiagnosed and underestimated by medicine, the demonstration of shared pathomechanisms – particularly immune dysregulation – has direct relevance for diagnosis and treatment. For those affected, this means that the presence of one condition should prompt active screening for the other. Furthermore, the study strengthens the biological basis of ME/CFS as a systemic inflammatory disease.

The protein mTORC1 acts as a central switch in metabolism and regulates cell growth, energy balance, and immune response. The authors argue that chronic misactivation of mTORC1 – referred to as 'TorS' (mTORC1 Syndrome) – can explain the diverse symptoms of ME/CFS, Long COVID (PASC), and other post-infectious syndromes, including fatigue, PEM, cognitive impairment, and autonomic dysfunction. This framework could also explain why certain at-risk groups are more susceptible to chronic disease courses, and opens up possible therapeutic approaches, for example through known mTORC1 inhibitors such as rapamycin.

This paper is significant because it proposes, for the first time, an overarching molecular mechanism that unites ME/CFS, Long COVID, and related syndromes under a common pathophysiological framework. The mTORC1 axis is a well-researched metabolic pathway with already existing pharmacological inhibitors, which has direct therapeutic implications. At the same time, the work remains a theoretical synthesis (not a clinical experiment), meaning the hypothesis must first be validated through targeted studies.

Approximately 9–13% of individuals who contract infectious mononucleosis (glandular fever) develop ME/CFS within 6–12 months. The study is particularly valuable because blood samples and health data were collected prior to infection, making it possible to distinguish genuine predisposing factors from reactive changes. The research group analysed risk factors across three phases: before the illness, during the acute infection, and six months afterwards – and is now also examining long-term trajectories over seven years as well as parallels to Long COVID.

This paper is methodologically particularly strong because it uses one of the few prospective study designs that collects baseline data prior to the triggering infection. This allows genuine predispositions to be distinguished from mere consequences of the disease. The findings help to understand why only a proportion of those infected develop ME/CFS, and provide potential starting points for early interventions as well as parallels to Long COVID.

The study examined blood parameters in individuals with Post-COVID-19, ME/CFS, fibromyalgia, as well as mixed forms, and found that certain combinations of antibody isotypes against SARS-CoV-2, cytokines (IL-6, IL-8, IL-10, IFN-γ, TNF-α), and the nerve damage marker NfL enable reliable differentiation of Post-COVID from the other groups. Of particular relevance is the detection of the endogenous retrovirus protein HERV-W ENV not only in Post-COVID, but also in pre-pandemic ME/CFS and fibromyalgia cases, suggesting viral involvement in these chronic conditions. The identified markers also show moderate to strong correlations with patients' symptom severity scores and open up possible new therapeutic approaches.

This paper provides, for the first time, a concrete approach to laboratory-based differential diagnosis between Post-COVID, ME/CFS, and fibromyalgia – conditions that show substantial clinical overlap and have previously lacked reliable biomarkers. The detection of HERV-W ENV in pre-pandemic ME/CFS cases supports the hypothesis that viral triggers play a central role in the development of these conditions, and links ME/CFS research with current Post-COVID findings.

The study presents a methodological protocol that utilizes fibroblasts (connective tissue cells from skin biopsies) and peripheral blood immune cells (PBMCs) from ME/CFS patients to investigate mitochondrial dysfunction. Fluorescent dyes are employed to measure mitochondrial mass, membrane potential, and reactive oxygen species (oxidative stress), supplemented by measurements of energy metabolism via NAD/NADH ratios as well as the activity of the energy regulators TORC1 and AMPK. These methods make it possible to systematically identify specific biochemical abnormalities in the energy metabolism of individuals with ME/CFS.

This paper provides standardized, reproducible measurement methods for mitochondrial dysfunction in ME/CFS – a central step toward making findings from different laboratories around the world comparable and scientifically substantiating the biological basis of the disease (energy deficiency at the cellular level).

In people with ME/CFS, specific changes in the composition of gut bacteria have been identified, which can make the protective barrier of the intestine more permeable – a phenomenon known as 'leaky gut'. This allows microbial components to enter the bloodstream and persistently activate the immune system, which promotes systemic inflammation and the worsening of ME/CFS symptoms. Through the so-called gut-brain axis, these microbiome changes could also directly contribute to the cognitive impairments such as brain fog that many affected individuals experience.

This review comprehensively summarizes the current state of research on the role of the gut microbiome in ME/CFS, thereby providing an important piece of the puzzle in understanding the complex disease mechanisms. Particularly significant is the indication of possible treatment approaches targeting gut dysbiosis, which could open up new therapeutic avenues for those affected, for whom no approved therapies have existed to date.

HLA genes determine how the immune system recognizes and combats pathogens. This computer simulation study shows that certain HLA variants (C*07:04 and DQB1*03:03), which are associated with increased ME/CFS risk, bind antigens of all 9 known herpesviruses significantly less effectively than protective HLA variants (B*08:01 and DPB1*02:01). The same pattern was also found for SARS-CoV-2 (Long COVID) and Borrelia burgdorferi (Post-Lyme syndrome), suggesting that persisting pathogen antigens due to a genetically determined immune deficiency could be a common feature of these post-infectious diseases.

This study provides a plausible molecular mechanism that could explain why not every person develops ME/CFS following a herpesvirus infection. The genetically determined weaker antigen binding would lead to a persistence of viral antigens, which could trigger chronic immune activation and the typical ME/CFS symptoms. Particularly significant is the applicability of this model to Long COVID and post-Lyme syndrome, which suggests a common pathomechanism of post-infectious diseases and could influence future diagnostic as well as therapeutic approaches.

Using Mendelian randomization – a method that uses genetic data to separate genuine cause-and-effect relationships from mere correlations – 91 inflammatory cytokines and 731 immune cell characteristics were examined for their causal influence on ME/CFS. In the process, elevated levels of the signaling molecules CXCL5 and CCL20 were identified as increasing risk, while high TNF levels were surprisingly associated with a lower risk of ME/CFS. A total of 13 specific immune cell properties showed significant causal connections to the development of ME/CFS.

This paper is significant because it uses Mendelian randomization to provide a methodologically more robust statement on causality than classical observational studies – a frequent point of criticism in ME/CFS research. The identification of specific cytokines such as CXCL5 and CCL20 as causal risk factors opens up concrete starting points for biomarker development and targeted therapies. At the same time, the inverse TNF finding raises interesting questions about the complexity of immune regulation in ME/CFS.

In this study, saliva samples from 13 ME/CFS patients and 16 control subjects were examined for multiple viruses as well as for autoantibodies against type I interferons (important mediators of antiviral defense). ME/CFS patients showed a significantly elevated EBV viral load, while HHV6 was equally detectable in approximately half of all participants. Autoantibodies against type I interferon could not explain the impaired immune response in most patients, suggesting other mechanisms such as viral evasion of the interferon system.

The study provides further evidence that EBV reactivation is a relevant factor in ME/CFS and supports the hypothesis of a chronically exhausted antiviral immune response. At the same time, it demonstrates that autoantibodies against interferons – as observed in severe COVID-19 – do not offer a general explanation for ME/CFS, and opens up new research questions regarding viral immune evasion, such as through the degradation of interferon receptors.

The study examined two Austrian patient cohorts (totaling over 1,000 individuals) and found that up to 25.3% of ME/CFS patients meet the criteria for mast cell activation syndrome (MCAS), with the proportion increasing over the course of the disease. Patients with MCAS and orthostatic intolerance reported significantly more frequent symptom improvements through mast cell-targeted therapies than those without MCAS. Furthermore, orthostatic intolerance – particularly POTS syndrome – was significantly more prevalent in the MCAS group, suggesting a pathophysiological link between these two mechanisms.

This study provides important indications that ME/CFS is not a homogeneous disease, but can be divided into subgroups. The identification of MCAS as a treatable comorbidity opens up concrete therapeutic approaches for a substantial proportion of those affected. Particularly significant from a clinical standpoint is the connection between mast cell activation and orthostatic intolerance (POTS), as both conditions are often overlooked and can be specifically treated.

Trained immunity describes a state in which innate immune cells (such as monocytes and macrophages) become epigenetically reprogrammed following an infection and remain permanently hyperreactive. This hyperreactivity can spread to stem cells in the bone marrow, allowing it to persist long-term. The authors argue that this sustained hyperreactivity of the immune system could erroneously activate various immune pathways, thereby explaining core ME/CFS symptoms such as post-exertional malaise, chronic fatigue, and signs of inflammation.

This review offers a novel mechanistic explanatory approach for why in approximately 60% of ME/CFS patients an infection precedes the disease. The concept of trained immunity connects epigenetics, immunology, and metabolic changes, and could explain why ME/CFS develops following post-COVID, EBV, or other infections – and why the disease becomes chronic rather than resolving after the infection.

The glymphatic system is a recently discovered cleansing network of the brain that removes toxic metabolic waste products – primarily during sleep. The authors argue that a dysfunction of this system could explain the typical ME/CFS symptoms such as brain fog, sleep disorders, and post-exertional malaise (PEM), as harmful metabolic products would accumulate in the brain. Since a connection between glymphatic dysfunction and Alzheimer's disease has already been demonstrated, the authors call on the ME/CFS research community to seriously investigate this mechanism and to develop therapies that improve glymphatic function.

This paper opens up a novel explanatory approach for core ME/CFS symptoms such as brain fog and sleep disorders through the mechanism of glymphatic dysfunction. Since neither effective treatments nor simple diagnostic procedures for ME/CFS currently exist and approximately 90% of those affected remain undiagnosed, the identification of new pathophysiological pathways is of great importance. The approach connects ME/CFS with already established research on neurodegenerative diseases and could point to new therapeutic targets.

Previous studies have primarily searched for viruses in the blood of ME/CFS patients, even though mucous membranes (e.g., mouth, throat, intestine) are the main entry points for pathogens and can serve as a reservoir for persistent infections. The authors argue that latent viruses in these tissues are periodically reactivated, thereby triggering chronic inflammatory processes and immune disorders that could explain the core symptoms of ME/CFS. Initial data from saliva samples of affected individuals support this hypothesis and indicate reactivations of known herpesviruses.

The paper identifies a systematic blind spot in ME/CFS research: because mucosal tissues have rarely been examined, persistent viral reservoirs and their influence on the immune system may have been massively underestimated until now. This approach could explain why blood tests often fail to provide clear evidence of viruses, and opens up new avenues for diagnostics and future therapeutic approaches.

Researchers analyzed the entire exome (protein-coding portion of the genome) of 77 Australian ME/CFS patients and compared it with a healthy reference population. They found significant genetic variants in the so-called Neuroblastoma Breakpoint Family (NBPF), a gene family that encodes so-called Olduvai domains and is associated with the development of the cerebrum as well as with neurological disorders such as schizophrenia and autism. The results were partially confirmed in an independent US cohort, which strengthens the validity of the findings.

This study provides first concrete evidence of genetic risk factors in ME/CFS that lie in the area of brain development and neurogenesis – thereby establishing a biological bridge to other neuropsychiatric disorders. This supports the hypothesis that ME/CFS has a neurobiological basis and cannot be reduced to psychosomatic causes. The partial replication in a second, independent cohort considerably increases the credibility of the findings.

This review article summarizes current findings from metabolic neuroimaging research: PET scans and MR spectroscopy reveal changes in cerebral glucose and oxygen consumption, neurotransmitter balance, and elevated oxidative stress in ME/CFS and Long COVID. Both conditions show overlapping disturbances in cerebral energy metabolism and neuroinflammatory processes, but also display distinct metabolite profiles, suggesting independent mechanisms. The authors emphasize that standardized diagnostic criteria and longitudinal studies are necessary to develop valid biomarkers for clinical diagnostics.

This paper is significant because it is the first to systematically summarize the state of metabolic brain imaging for both diseases, thereby pointing the way toward objective, measurable biomarkers – a decisive step away from a purely symptom-based diagnostic approach toward biologically grounded diagnostic and therapeutic possibilities.

ME/CFS is a highly heterogeneous disease, meaning that affected individuals exhibit very different biological profiles – classical diagnostic methods reach their limits here. The combination of machine learning (AI algorithms) and multi-omics approaches – that is, the simultaneous analysis of genes, proteins, metabolites, and gene activity – opens up the possibility of identifying hidden patterns in large datasets and detecting validated biomarkers. The authors emphasize the need for robust computational tools as well as international data-sharing initiatives in order to systematically decode the biological complexity of ME/CFS.

This review is important because it provides a methodological framework for future ME/CFS research: Instead of searching for a single biomarker, AI-supported multi-omics approaches could identify patient subgroups, thereby enabling individualized treatment strategies. In the long term, this could pave the way for objective diagnosis and targeted treatment.

Natural killer cells (NK cells) are important defensive cells of the immune system, whose impaired function in ME/CFS has been known for some time. This study examined, for the first time using high-resolution sequencing in a large cohort (418 patients, 473 controls), the precise gene variants (alleles) of the so-called KIR receptors, which regulate the activity of these NK cells. Five specific allele variants were identified that are significantly associated with ME/CFS – three occurred more frequently in patients, two less frequently – suggesting genetically determined dysregulation of NK cell function as a possible disease mechanism.

This study provides, with one of the largest cohorts to date, genetic evidence that changes in NK cell regulation in ME/CFS may be not only functional but also genetic in nature. The identification of specific KIR alleles as risk or protective factors could, in the long term, contribute to the development of biomarkers and to a better understanding of the immunological causes of ME/CFS.

Tetrahydrobiopterin (BH4) is an important cofactor involved in the regulation of blood vessels, neurotransmitters, and nitric oxide production. In ME/CFS patients with orthostatic intolerance (OI) – meaning dizziness or feelings of faintness upon standing – pronounced disruptions in BH4 metabolism are observed, which could lead to reduced cerebral blood flow. This review article summarizes current findings and presents a possible molecular explanatory approach for the severe circulatory symptoms in ME/CFS.

Orthostatic intolerance is one of the most common and debilitating symptoms in ME/CFS, and it has previously been unclear why affected patients exhibit such significantly reduced cerebral blood flow. The identification of BH4 metabolic disorders as a possible mechanism opens up new approaches for diagnostics and potentially also for targeted therapies, since BH4 can in principle be therapeutically influenced.

Herpesviruses such as EBV, HHV-6, or CMV classically exist in either an active (lytic) or dormant (latent) state. The authors propose the hypothesis that in ME/CFS a third state – known as abortive lytic replication – plays a decisive role: viruses begin to reactivate without completing the cycle fully, which can cause chronic immune activation and tissue damage. Since more than half of ME/CFS cases begin with a flu-like infection and no single virus has been identified as the sole trigger, the authors argue for a poly-herpesviral model in which multiple viruses act in concert.

This paper offers a conceptually new explanatory framework for why previous searches for a single viral trigger of ME/CFS have been unsuccessful. The model of abortive lytic replication could explain why standard virus tests often yield negative results, even though viruses are pathologically active – and has direct implications for future diagnostic and therapeutic approaches.

The authors present a comprehensive methods protocol ranging from blood collection through the isolation of natural killer cells (NK cells) to highly specialized measurement techniques such as calcium imaging and electrophysiology. The focus is on the ion channel TRPM3, which appears to be demonstrably altered in individuals with ME/CFS and may contribute to immune system dysfunction. The chapter serves as a reference for research laboratories seeking to reproduce and further develop these complex experiments.

TRPM3 research is one of the most promising approaches to identifying a measurable biological dysfunction in ME/CFS. Changes in this ion channel in NK cells could serve both as a biomarker for diagnosis and as a target for future therapies. This methods chapter is important because it enables the reproducibility of this research in other laboratories, thereby creating the foundation for larger studies.

The post-viral fatigue syndrome (PVFS), which the WHO classifies as a neurological disease, shows significant overlap with ME/CFS and is characterized by persistent exhaustion, cognitive impairments, and post-exertional malaise (PEM). New research findings suggest that disruptions in energy metabolism – particularly mitochondrial dysfunction and impaired creatine metabolism – are key disease drivers. The review article evaluates creatine both as a potential diagnostic marker and as a supplement for symptom relief, but emphasizes that robust clinical trials are still pending.

The paper is relevant because it further strengthens the bioenergetic perspective on ME/CFS and PVFS and brings creatine into focus as a readily available, well-tolerated substance. It is important for those affected to know that the current evidence is still based on narrative reviews and smaller studies – direct treatment recommendations cannot yet be derived from this. At the same time, the clear WHO classification of PVFS as a neurological disease (ICD-11) is a significant step towards recognition of the condition.

ME/CFS patients show disturbances in mitochondrial metabolism and in the electron transport chain, leading to an excess of reactive oxygen species (ROS) and thus to oxidative stress. In this study, protein modifications (known as protein carbonyls) in immune cells and plasma were measured before and after an exercise protocol – a method that proved to be feasible. The DNA damage marker 8-OHdG, which was also investigated, could not be reliably detected using the ELISA test employed, indicating limitations of the measurement method.

The search for objectively measurable biomarkers is one of the greatest challenges in ME/CFS research. This study demonstrates that protein carbonyls may serve as a stable and practically measurable marker for oxidative stress, and could potentially help to objectively document the course of the disease or the response to exertion (Post-Exertional Malaise). At the same time, it illustrates that not all measurement methods for oxidative stress are equally suitable.

The review article examines how metformin can intervene in the disrupted metabolic pathways in ME/CFS and Long COVID – including mitochondrial dysfunction, elevated inflammatory markers, disrupted gut flora, and impaired blood circulation. Metformin inhibits certain complexes of the respiratory chain (I and IV), which relieves the overburdened complex V and reduces the formation of harmful free radicals. Furthermore, metformin could improve energy metabolism via mTOR signaling pathways and exert anti-inflammatory as well as neuroprotective effects.

Metformin is a well-established, well-tolerated, and inexpensive medication that has been in use for decades and is now being discussed as a possible candidate for ME/CFS and Long COVID. Since both conditions currently have no approved therapies, the identification of repurposable agents with known safety profiles is of great practical importance. The article provides a systematic assessment of why metformin may be mechanistically relevant – even though clinical evidence from randomized trials is still largely lacking.

Both conditions share core symptoms such as persistent fatigue, post-exertional malaise (PEM), cognitive impairments, and autonomic dysfunction, with ME/CFS typically developing after various viral infections and Long COVID exclusively after SARS-CoV-2. Viral persistence, immune system disorders, vascular wall damage, and autoimmune processes are being discussed as shared disease mechanisms, although their precise interplay remains unclear. The authors emphasize the need for further research into immunopathology in order to develop targeted therapies and improved diagnostic procedures.

This review is relevant because it systematically summarizes the current state of knowledge regarding the similarities and differences between ME/CFS and Long COVID – an important point of reference for those affected and researchers alike, in order to understand to what extent findings on Long COVID can be transferred to ME/CFS and where independent research remains necessary. However, it should be noted critically that the positive mention of Cognitive Behavioral Therapy (CBT) and the uncritical classification of Graded Exercise Therapy (GET) contradicts the current consensus within the ME/CFS community and more recent guidelines, which do not recommend GET for ME/CFS due to the risk of PEM.

Salubrinal is a substance known for modulating stress responses in the so-called endoplasmic reticulum (ER) of the cell – a cellular component responsible, among other things, for protein folding. The authors argue that disrupted ER stress pathways could be a common mechanism in ME/CFS and Long COVID, and that salubrinal could thereby alleviate symptoms of both conditions. Since this is a purely review-based work without any own study data, clinical evidence is still lacking.

The paper demonstrates a biologically plausible connection between cellular stress and ME/CFS or Long COVID, and proposes a concrete pharmacological approach with salubrinal. This is relevant because ER stress is increasingly being discussed as part of the pathophysiology of ME/CFS – however, no clinical studies on salubrinal in humans have been conducted to date, which greatly limits the significance of the findings.

The so-called microbiota-gut-brain axis describes the bidirectional communication between gut bacteria and the central nervous system. In ME/CFS, changes in the composition of the gut flora (dysbiosis) have been observed, which may dysregulate immune responses, influence neurochemical messengers such as serotonin, and promote inflammatory processes in the brain. The authors conclude that targeted therapeutic interventions to correct dysbiosis – such as through probiotics or dietary interventions – could represent a promising approach to the treatment of ME/CFS.

This review summarizes the current state of research on the gut-brain connection in ME/CFS and provides patients as well as researchers with a structured overview of an increasingly significant mechanism. It connects immunological, neurological, and microbiome-related aspects of the disease and opens up potential new therapeutic targets beyond conventional symptom treatment.

The review analyzed clinical trials from multiple databases and found evidence that NADH, Coenzyme Q10 (CoQ10), wasabi extract, and probiotics can alleviate symptoms in people with ME/CFS. However, a central problem is that many studies use different measurement methods and do not utilize the standardized assessment instruments (Common Data Elements) recommended by the US National Institutes of Health (NIH), which makes direct comparison of results difficult. As long as uniform standards are not employed, the clinical utility of the findings remains limited.

Many ME/CFS patients resort to dietary supplements due to the lack of recognized therapies. This review provides a current overview of the existing evidence and highlights both promising approaches and methodological gaps – in particular the absence of standardized assessment tools, which prevents comparability between studies. The identification of NADH and CoQ10 as potentially effective substances is also consistent with well-known findings on mitochondrial dysfunction in ME/CFS.

An online survey with over 1,100 participants showed that the agreement between actually meeting the ME/CFS diagnostic criteria (according to CDC or IOM) and receiving a medical diagnosis was generally low. Particularly notable: White participants had an almost three times higher likelihood (odds ratio 2.94) of receiving the diagnosis than non-white participants, despite no differences in meeting the criteria. Furthermore, an ME/CFS diagnosis was associated with greater dissatisfaction with medical care.

This study shows that ME/CFS is not only underdiagnosed overall, but that ethnic minorities are particularly disadvantaged in this regard. This has direct implications for access to treatment, research, and social support. For the ME/CFS community, it highlights that structural barriers in the healthcare system are exacerbating the already difficult problem of diagnosis.

Researchers compared the B-cell receptor (BCR) patterns of 61 ME/CFS patients (25 mild/moderate, 36 severe), 21 healthy controls, and 28 multiple sclerosis patients using high-throughput sequencing. No increased clonality or enhanced somatic hypermutation was found – both of which are typical signs of active immune responses in autoimmune diseases or infections. An interesting incidental finding was an altered IgM-to-IgG ratio in mildly/moderately affected patients, which could indicate a subtle disruption of B-cell maturation.

This paper is important because it directly examines a central hypothesis regarding the cause of ME/CFS – classical B-cell-mediated autoimmunity or persistent infection – using a modern sequencing approach, and is unable to confirm it in the cohort studied. Nevertheless, the partial replication of the IGHV3-30 finding from a preliminary study, as well as the new IgM/IgG finding, provide starting points for follow-up studies. The result limits certain autoimmune explanatory models and may direct research toward other immunological mechanisms.

The review analyzed 14 studies with a total of 809 participants and examined supplements such as L-carnitine, guanidinoacetic acid, oxaloacetate, CoQ10 in combination with selenium, as well as NADH alone and in combination with CoQ10. Some of these substances showed statistically significant reductions in fatigue, possibly through support of mitochondrial energy metabolism and reduction of oxidative stress. However, all included studies exhibited a high risk of bias — due to small sample sizes, missing data, and selection bias — meaning that robust conclusions cannot be drawn.

Dietary supplements are frequently used by people with ME/CFS on their own initiative, although the evidence base has so far hardly been systematically reviewed. This review provides, for the first time, a current overview of 30 years of research on this topic and identifies substances with a cautiously positive signal – in particular those that target energy metabolism. At the same time, it highlights the urgent need for methodologically rigorous, larger clinical trials with standardized diagnostic criteria.

The case study describes a patient with CFS present since childhood, in whom a novel mutation was identified in the ADCK1 gene, which is important for mitochondrial function. ADCK1 deficiencies have been associated with mitochondrial dysfunction, increased oxidative stress, and cell death. Following the introduction of oral 5-aminolevulinic acid with sodium ferrous citrate (5-ALA/SFC) as well as ubiquinone, the patient's daily activities, mobility, and psychosocial functioning improved considerably.

This paper supports the hypothesis that genetically determined mitochondrial dysfunction can contribute to the development of ME/CFS, and provides a concrete molecular starting point (ADCK1 mutation). At the same time, it demonstrates that targeted interventions to improve mitochondrial function (5-ALA/SFC, ubiquinone) could have therapeutic benefit – even though this involves only a single case.

Worldwide, an estimated 17–24 million people suffer from ME/CFS, with over 60 percent still undiagnosed. The article was created as part of a scholarship program of the New Jersey ME/CFS Association, which motivates medical students to engage with the disease. It sheds light on the biological mechanisms behind ME/CFS and provides practical recommendations for clinicians to improve the quality of life of those affected.

The paper is relevant because it shows that ME/CFS continues to be massively underdiagnosed despite decades of research, and that healthcare professionals receive insufficient training. The initiative to actively involve medical students in ME/CFS research communication is an important step toward improving the care situation. For those affected, it highlights the urgent need for better education within the healthcare system.

Blood cells (PBMCs) from ME/CFS patients were examined before and after a whole-body hyperthermia session. The results suggest that ME/CFS patients exhibit elevated levels of an autophagy marker (LC3-II) and altered mitochondrial function. Following heat treatment, LC3-II levels decreased to those of healthy controls, and mitochondrial parameters increased – suggesting a possible positive influence on these cellular processes.

The study provides initial cellular data on a previously little-researched therapeutic approach (whole-body hyperthermia) in ME/CFS and connects clinical treatment with measurements at the cellular and molecular level. The findings on autophagy dysregulation and mitochondrial function are consistent with other research results that consider these mechanisms to be central to ME/CFS. However, due to the very small sample size (n=9) and the pilot nature of the study, the results can only be regarded as hypothesis-generating.

Extracellular vesicles (EV) are microscopically small membrane-bound sacs that are released into the blood by nearly all cells in the body and carry information about the state of these cells. The microRNAs (miRNAs) contained within them are short RNA molecules that simultaneously regulate the activity of many genes and may be altered in complex diseases such as ME/CFS. The study describes a methodological approach for isolating these vesicles and analyzing their miRNA contents, which could in the future serve as a diagnostic fingerprint for ME/CFS.

ME/CFS has to this day suffered from the absence of validated biological markers, which complicates diagnosis and often leaves those affected in uncertainty for years. A blood-based biomarker derived from miRNAs in extracellular vesicles would represent a significant advancement, as it would be non-invasive, reproducible, and potentially disease-specific. The study provides a methodological foundation for larger follow-up investigations.

The study used single-cell RNA sequencing to compare the gene activity profile of individual immune cells in ME/CFS patients and healthy controls – both at rest and following a standardized exercise test. At rest, classical monocytes (an important type of immune cell) displayed defective maturation and migration patterns; notably, 'sick' and 'more normal' monocytes coexisted within the same patients, with the proportion of sick cells correlating with disease severity. Following physical exertion – which triggered post-exertional malaise (PEM) – additional signs of defective platelet activation were found, while other immune cells showed little change.

This study provides biological evidence, at a previously unique level of resolution (individual cells), for two central ME/CFS phenomena: a chronic immune disorder at rest and a specific biological mechanism that could explain PEM. The correlation of the proportion of 'sick' monocytes with disease severity also opens up the prospect of a potential biomarker. The platelet dysfunction following exertion is significant, as platelets influence inflammatory responses and blood coagulation, and could thereby contribute to a deterioration in blood flow and energy supply in tissues.

The study examined ME/CFS patients using strict inclusion criteria and found that the central problem is a disruption of the decision-making centers in the brain that regulate how much effort a person is willing to expend — possibly caused by a malfunction in the catecholaminergic system (dopamine/noradrenaline). At the same time, immune measurements showed evidence of chronic antigen stimulation with altered B-cell populations, suggesting persistent immune activation. Gene expression analyses of blood cells and metabolic studies confirmed these cellular changes and also revealed distinct differences between male and female patients.

This paper is one of the methodologically strongest of its kind, as it combines rigorous recruitment criteria, matched controls, and a broad spectrum of measurement methods (neuroimaging, immune phenotyping, gene expression, metabolomics). The finding that ME/CFS is primarily associated with altered effort preference due to brain dysfunction – rather than 'imagined' weakness or purely muscular fatigue – represents an important step toward destigmatization and the development of targeted treatment approaches.

Using state-of-the-art single-cell analyses, profound changes in CD8+ T cells have been demonstrated in ME/CFS patients: key transcription factors that regulate T cell exhaustion were upregulated, the DNA structure (chromatin) was remodeled, and cellular metabolism was pathologically altered. These findings were confirmed at both the gene and protein levels (flow cytometry) and were particularly pronounced following symptom provocation. The results suggest that ME/CFS immunologically resembles the state observed in chronic viral infections – thereby opening up new therapeutic approaches such as checkpoint inhibitors or antiviral therapies.

This paper provides, for the first time, multidimensional molecular evidence for T cell exhaustion as a central disease mechanism in ME/CFS. The combination of single-cell RNA sequencing, ATAC-seq, and proteomic analysis makes the findings particularly robust. Of special significance is the link to established therapeutic concepts (checkpoint blockade, antiviral strategies) that are already being used clinically in other diseases – this could considerably accelerate the development of targeted ME/CFS therapies.

ME/CFS and Long COVID show strong overlaps both clinically and biologically: Both conditions frequently begin after viral infections and display abnormalities in the immune system, energy metabolism, the nervous system, and the gut microbiome. Since ME/CFS generally has a longer disease duration than Long COVID, insights into the long-term course of ME/CFS can help predict how Long COVID might develop in some of those affected. The authors emphasize that a better understanding of these shared mechanisms is crucial for the development of effective therapies and diagnostic procedures.

This work is significant because it systematically summarizes the biological commonalities of both conditions and positions ME/CFS as a model disease for Long COVID. It strengthens the legitimacy of ME/CFS as a serious biological disease and can help ensure that research funding and attention generated by Long COVID also benefit ME/CFS research.

In ME/CFS patients, genes associated with interferon signaling pathways and antibody production were primarily downregulated, suggesting a form of immunosuppression. In Long COVID, on the other hand, disruptions in antigen presentation and immune activation were observed. Both conditions point to a dysregulation of both the innate and adaptive immune systems, bringing immune exhaustion to the forefront as a possible central disease mechanism.

This study is significant because it is the first to directly compare ME/CFS and Long COVID, revealing both commonalities and disease-specific differences in immune exhaustion. The use of a standardized gene expression panel (NanoString nCounter) increases comparability with other studies. The findings provide concrete molecular starting points for future therapies and confirm that ME/CFS is not a psychosomatic condition, but rather a biologically demonstrable disease with measurable immune alterations.

The authors analyze how ME/CFS arises from a complex interplay of genetic vulnerabilities and environmental triggers – particularly viral infections – leading to immune regulation disorders, chronic inflammation, gut microbiome alterations, and metabolic problems. Previous research approaches often examined these factors in isolation; this model connects them for the first time into a coherent overall picture of disease development. The paper emphasizes that neither standardized diagnostic criteria nor effective treatments currently exist, and advocates for a holistic research approach.

This paper is significant because it brings together the fragmented state of research on ME/CFS within a unified pathophysiological model, thereby initiating a paradigm shift in the scientific understanding of the disease. For those affected, it provides scientific confirmation that ME/CFS is a complex biological condition with measurable mechanisms – not a psychosomatic phenomenon. At the same time, it identifies concrete starting points for future therapy development.

The ion channel TRPM3, which is found in many body tissues and regulates, among other things, pain perception, immune defense, and the release of neurotransmitters in the brain, shows significantly reduced activity in natural killer cells (NK cells) in ME/CFS patients. This dysfunction leads to reduced calcium influx into the cells and could explain why viruses are not effectively combated and may persist. In laboratory and ex vivo experiments, naltrexone was able to restore TRPM3 function, which would provide a biological explanation for the observed clinical improvements under low-dose naltrexone (LDN).

This paper is significant because it proposes a concrete molecular mechanism that unites numerous ME/CFS symptoms – from pain and immune deficiency to neurological complaints – within a unified explanatory framework. At the same time, it provides a biological rationale for the clinical use of low-dose naltrexone, a medication that many patients are already trying. The overlap with post-COVID syndrome underscores the broader relevance of this research.

Using advanced MRI imaging, 25 adolescent ME/CFS patients were compared with 23 healthy controls. The study found evidence of an increased number of structural connections in anterior regions of the hypothalamus in ME/CFS patients, while connections in the posterior hypothalamus decreased with increasing disease duration. Additionally, a correlation was observed between connectivity strength in the middle hypothalamus and individual fatigue severity — a finding that was absent in healthy individuals.

The hypothalamus is a key structure for the regulation of sleep, energy metabolism, stress hormone axes (HPA axis) and the autonomic nervous system – areas that are typically dysregulated in ME/CFS. This study provides, for the first time, neuroanatomical imaging data specifically for adolescent individuals with ME/CFS and supports the hypothesis that ME/CFS is associated with measurable changes in the central nervous system. The correlation between connectivity changes and clinical parameters (fatigue, disease duration) strengthens the biological plausibility of the finding.

The study examined blood samples from ME/CFS patients and divided them into two groups based on their immune competence: patients with immunodeficiency showed decreased levels of the complement protein C4a, indicating impaired innate immune defense. Patients without classical immunodeficiency, on the other hand, showed elevated levels of lipopolysaccharide-binding protein (LBP), suggesting increased intestinal permeability ('leaky gut') and associated inflammatory processes. These findings indicate that ME/CFS is not a uniform clinical picture, but encompasses at least two pathophysiologically distinct subtypes.

The study provides an important contribution to the understanding of the heterogeneity of ME/CFS and underscores why previous treatment studies have often shown contradictory results: when different patient groups with different underlying mechanisms are studied together, the effects become obscured. Precise stratification by immune status could in the future help to develop more targeted and effective treatment approaches for each respective subgroup.

The review article analyzes clinical trials on pharmacological and nutritional treatment approaches targeting immunological, metabolic, neurological, and neuroendocrine disorders in ME/CFS. A central finding is that fewer than 5% of those affected ever regain their previous level of activity, which underscores the urgent need for robust clinical trials. The authors provide specific recommendations on appropriate outcome measures and study designs in order to develop evidence-based therapies in the future and establish them in clinical practice.

This paper provides a structured inventory of the entire clinical research field in ME/CFS and systematically identifies gaps in the existing body of studies. For those affected, it is important to understand why, despite years of research, barely any effective therapies exist, and what concrete steps are necessary to improve this situation. The practical recommendations for future study designs can considerably enhance the quality of future ME/CFS research.

This 2024 review article summarizes and critically evaluates the current state of research on changes in the gut microbiome in ME/CFS. Dysbiosis could lead to increased permeability of the intestinal barrier, allowing microbial components to enter the bloodstream and trigger oxidative stress and immune responses. However, the authors emphasize that existing studies only demonstrate associations and frequently exhibit methodological weaknesses — for example, through poorly defined patient groups that conflate ME/CFS with other conditions such as irritable bowel syndrome.

The gut microbiome is a promising but thus far insufficiently researched factor in ME/CFS. This review provides a sober assessment of the existing evidence while simultaneously highlighting concrete approaches for how targeted interventions in the microbiome — analogous to other gastrointestinal diseases — could be investigated as a future therapeutic option. Particularly relevant is the reference to Post-COVID as a PAIS, as this extends the research to a broader group of post-viral conditions.

The study examined how water-filtered infrared-A light (wIRA) at 39°C over 60 minutes affects cells from ME/CFS patients and healthy donors. Surprisingly, ME/CFS patients showed higher mitochondrial function than healthy individuals – which contradicts previous assumptions – and the heat treatment slightly reduced this function toward the healthy normal value. In addition, enhanced autophagy (cellular cleansing processes) as well as the activation of heat shock proteins and autophagy-related genes (MAP1LC3B, SIRT1) were observed in all cells.

This study is significant because it documents, for the first time, the cellular effects of a non-invasive heat treatment in ME/CFS at the molecular level. The surprising finding of increased mitochondrial function in ME/CFS patients (possibly a compensatory mechanism or methodological artifact), as well as the normalizing trend observed with wIRA treatment, generate new hypotheses. The activation of autophagy and heat shock proteins could explain why heat treatments have a symptom-relieving effect in some patients. However, the study should be regarded as a pilot study and requires larger clinical follow-up studies.

In 2021, the British National Institute for Health and Care Excellence (NICE) published a comprehensive guideline on the diagnosis and treatment of ME/CFS. A critique paper had objected to eight alleged errors in the guideline development process. The present authors refute these points of criticism and explain that the guideline – including its departure from therapies such as cognitive behavioural therapy and graded exercise training as primary treatments – is based on a methodologically sound evidence assessment.

This publication is significant for people with ME/CFS, as the 2021 NICE guideline marked a paradigm shift: for the first time, it recommended that therapies such as graded exercise training (GET) should no longer be used as standard practice, as these can worsen the condition of those affected. The defence of this guideline strengthens the scientific consensus that ME/CFS is a biologically based disease requiring evidence-based and patient-centred care.

ME/CFS is classified as a neurological disease in which several biological processes are simultaneously disrupted – including cellular energy production (mitochondria), excessive oxidative stress, as well as inflammatory and immune responses. The variety and diversity of symptoms such as fatigue, muscle pain, post-exertional malaise, and cognitive impairment make both diagnosis and treatment difficult. However, new technologies are opening up improved diagnostic possibilities, and the combination of several targeted agents is currently considered the most promising treatment approach.

The article provides a current comprehensive overview of the known disease mechanisms of ME/CFS and emphasizes that no single mechanism alone explains the condition – an important understanding for both those affected and treating clinicians alike. The classification as a neurological disease with biologically measurable disorders underscores the legitimacy of the symptoms and demonstrates why multimodal therapeutic approaches are necessary.

ME/CFS is a complex chronic disease characterized by persistent, debilitating fatigue that does not improve with rest and typically worsens with physical or mental exertion (post-exertional malaise). Diagnosis remains challenging, as clear biomarkers are lacking, symptoms overlap with other conditions, and uniform diagnostic criteria are not globally standardized. This review examines the disease mechanisms — including immune dysregulation, neuroinflammation, and mitochondrial dysfunction — as well as existing therapeutic approaches and future research directions.

This current review article from 2024 provides a structured summary of the present state of research on ME/CFS and is therefore valuable for those affected, their relatives, and medical professionals seeking a well-founded introduction to the topic. It illustrates why ME/CFS remains underdiagnosed and inadequately treated despite growing research activity, and identifies specific gaps that future studies need to address.

The authors systematically compare symptoms and pathophysiology of ME/CFS and Long COVID, finding extensive overlaps across nearly all body systems examined: the central and autonomic nervous system, heart, lungs, blood vessels, immune system, gut microbiome, as well as energy metabolism and oxidative stress are affected in similar ways in both conditions. The study highlights the strength of evidence for individual abnormalities in each case and serves as a comprehensive orientation map through the scientific literature on both diseases. The societal costs of both conditions are estimated at trillions of dollars for the United States alone.

This paper is one of the most significant review works in recent ME/CFS research, as it is the first to systematically and comprehensively document the biological commonalities between ME/CFS and Long COVID. It strengthens the scientific legitimacy of both conditions as clearly biologically justifiable states, highlights priorities for future research, and provides patients as well as physicians with reliable guidance within the growing body of literature.

The protein WASF3 has been detected in elevated amounts in the skeletal muscle tissue of ME/CFS patients and is associated with a malfunction of so-called respiratory supercomplexes in the mitochondria – those molecular machines that supply cells with energy. Transgenic mice with increased WASF3 expression showed a significantly reduced physical performance as well as diminished complex IV levels in muscle mitochondria. A key trigger appears to be endoplasmic reticulum (ER) stress: when this ER stress is pharmacologically inhibited, mitochondrial function in patient cells improves in a measurable way.

This paper provides, for the first time, a concrete molecular mechanism that can explain exercise intolerance and energy deficits in ME/CFS at the cellular level. Particularly significant is the identification of ER stress as a treatable trigger, and the finding that inhibition of ER stress improved mitochondrial function – this opens up potential therapeutic targets. The study was published in the prestigious Proceedings of the National Academy of Sciences (PNAS) and also links ME/CFS findings to Long COVID and other fatigue-associated conditions.

This review article summarizes the current state of research on cardiovascular and blood changes in ME/CFS, drawing parallels to Long COVID, where similar vascular damage, coagulation disorders, and endothelial dysfunction have been described. Particularly noteworthy are reduced cardiac output, diminished blood flow to the brain (cerebral hypoperfusion), as well as evidence of increased coagulation tendency and platelet activation – findings that cannot be explained by physical deconditioning, but rather point to involvement of the autonomic nervous system and possibly persisting herpesviruses. The authors argue that these vascular and hematological abnormalities could impair the supply of oxygen and nutrients to tissues, thereby directly contributing to the symptom burden in ME/CFS.

This review is important because it systematically demonstrates that ME/CFS is not only a disease of the immune system or energy metabolism, but also structurally affects the cardiovascular system and blood coagulation. The parallels to Long COVID strengthen the credibility of these findings and open up potential therapeutic approaches – for example through treatment of coagulation disorders or endothelial dysfunction. In addition, the role of persistent viruses (particularly herpesviruses) as a possible cause of these changes is discussed, which supports the research field of antiviral therapies for ME/CFS.

At the second international ME/CFS conference at the Charité, over 100 researchers discussed the current state of science. Central topics included the role of the immune system, disruptions of the vascular system and the autonomic nervous system, as well as the reactivation of viruses as possible causes of the disease. The authors emphasize that despite increased attention due to Long COVID, ME/CFS remains massively under-researched and urgently requires more research funding.

This report provides a comprehensive overview of the current state of research from 2023 and reflects the consensus of leading international ME/CFS researchers. It consolidates findings on pathomechanisms, diagnostics, and therapy, while also demonstrating how significantly Long COVID has increased the urgency of ME/CFS research – an important reference document for understanding the disease.

In this study, blood samples from 40 ME/CFS patients and 20 healthy controls were examined for eight selected microRNAs (short, non-coding RNA molecules). Five of these (miR-127-3p, miR-142-5p, miR-143-3p, miR-150-5p, and miR-448) were significantly elevated in patients, while one (miR-140-5p) was decreased – and these changes reflected the severity of the disease. Interestingly, no associations were found with inflammatory signaling molecules (cytokines) or the detection of herpesviruses (HHV-6A/6B), suggesting independent disease mechanisms.

ME/CFS continues to suffer from the lack of objective diagnostic biomarkers. MicroRNAs in blood plasma are stable, easily measurable molecules that reflect epigenetic regulatory processes. This paper provides initial evidence that a pattern of multiple miRNAs could distinguish patients from healthy individuals while simultaneously reflecting disease severity – both of which are fundamental requirements for a clinically useful biomarker. Furthermore, the identified miRNAs open up new insights into previously poorly understood disease pathways such as immune cell regulation and tissue remodeling.

ME/CFS is a chronic neurological disease that frequently occurs following an infection. The authors provide physicians with a practice-oriented overview of diagnostic criteria, diagnostic workup, and management strategies. Particular emphasis is placed on the close overlap with Long COVID, as multiple studies show that up to 50% of those affected by Long COVID meet the ME/CFS diagnostic criteria.

Since ME/CFS is frequently unrecognized or mistreated, this guide from the renowned Mayo Clinic addresses an important gap in care. The explicit link to Long COVID increases the visibility of the condition and can help ensure that more affected individuals receive a correct diagnosis and appropriate care. For those affected, this is relevant because it demonstrates that ME/CFS is increasingly being recognized in mainstream medical literature.

A reanalysis of symptom comparison data shows a correlation of 0.902 between the symptom profiles of ME/CFS and PASC patients – an exceptionally high value. The authors propose that both conditions are underpinned by a chronic dysfunction of the so-called 'Central Homeostasis Network', in which the interaction between the autonomic nervous system, central nervous system, and brainstem becomes permanently dysregulated. Comparable to a faulty thermostat that can no longer maintain a stable set point, this model explains the unpredictable, fluctuating symptom patterns seen in both conditions.

This paper is important because it is the first to document, with concrete statistical data, how strongly ME/CFS and Long COVID overlap symptomatically – and from this derives a unified explanatory hypothesis. The dyshomeostasis model connects endocrinological, immunological, and metabolic findings into an overarching framework that could explain why symptoms fluctuate so unpredictably. For those affected, it confirms that their complaints are biologically justifiable and not psychosomatic.

The study examined 33 different natural autoantibodies against neural and tissue antigens in ME/CFS patients (with and without fibromyalgia) compared to healthy individuals. Both patient groups more frequently showed elevated autoantibodies against GABA receptors, which are important for signal transmission in the nervous system. Particularly notable was the fact that it was not individual autoantibody levels, but rather the overall interaction patterns (correlation signatures) that differed significantly between patients and healthy individuals – and these patterns correlated with clinical symptoms such as fatigue, pain, and quality of life.

The study provides initial evidence that in ME/CFS, not only individual autoantibodies are elevated, but that the entire natural autoimmune network may be disrupted in its balance. The finding regarding GABA receptor autoantibodies is particularly interesting, as GABA signaling pathways regulate sleep, pain perception, and neuropsychiatric symptoms – areas that are typically affected in ME/CFS. However, this is a very small pilot study (11 persons per group), which is why the results should be interpreted with caution.

The analysis objectively demonstrates measurable deficits in visuospatial short-term memory performance, reading speed, and graphomotor function. Episodic memory (encoding, retrieval, recognition) and attentional processes are also impaired, while executive functions such as planning and problem-solving appear to be less affected. The results emphasize that the so-called 'brain fog' in ME/CFS is not a subjective perception, but rather is demonstrable and quantifiable through neuropsychological testing.

This study provides, for the first time, a comprehensive, statistically validated mapping of the cognitive impairment profile in ME/CFS, based on more than three decades of research literature. It is important because it objectifies 'brain fog', thereby giving those affected a scientific basis for communicating their symptoms to doctors and expert assessors. Furthermore, the precise profile helps to develop future diagnostic tests and therapeutic approaches in a more targeted manner.

The analysis of 71 COVID-19 and 26 ME/CFS studies revealed that six genes – including ACE, several HLA genes, and TYK2 – are significantly altered in both diseases. The metabolic pathway analysis shows that inflammatory processes involving chemokines and cytokines, T-cell activation, and Toll-like receptor signaling pathways are particularly implicated in both conditions. These findings support the hypothesis that immune dysfunction represents a central common element of COVID-19 and ME/CFS.

This paper is important because it systematically identifies genetic commonalities between COVID-19 and ME/CFS for the first time, thereby building a biological bridge between Post-COVID and classic ME/CFS. In particular, the overlaps in HLA genes (which are crucial for immune recognition) and the TYK2 gene (a regulator of immune responses) provide clues as to why some people may be more susceptible to ME/CFS-like conditions following viral infections. This provides potential targets for future therapies.

Tryptophan is broken down in the body primarily via the so-called kynurenine pathway, which produces both neuroprotective and neurotoxic substances and generates the energy carrier NAD+. In ME/CFS, this pathway appears to be overactivated, which on one hand leads to an accumulation of neurotoxic substances and on the other hand paradoxically depletes NAD+ production. The authors propose that targeted supplementation with NAD+ precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) could alleviate symptoms and improve the quality of life of those affected.

This review provides a plausible biochemical explanatory framework that links energy deficits, neurological symptoms, and gastrointestinal complaints in ME/CFS through a common metabolic pathway. Particularly significant is the reference to NAD+ supplementation as a potentially accessible therapeutic strategy, which is already being investigated in other diseases and is available with a relatively good safety profile. Furthermore, the work integrates the role of the gut microbiome, which sheds light on the connection between gastrointestinal symptoms and systemic exhaustion in ME/CFS.

The British health authority NICE concludes in its revised guideline that ME/CFS is a complex multisystem disease in which Graded Exercise Therapy should not be used and cognitive behavioural therapy (CBT) is considered only as a supportive measure – not as a cure or causal treatment. Particularly significant is the finding that subjective outcome measures in unblinded studies are fundamentally unreliable, which calls into question earlier positive study results for GET and CBT. The authors call for high-quality, randomised controlled trials with objective measurement parameters in order to develop effective pharmacological treatments.

This paper is of great importance for those affected, as it summarizes the scientific reassessment of the long-dominant biopsychosocial treatment approaches (GET and CBT) and identifies methodological weaknesses in earlier studies. It marks a paradigm shift in official treatment recommendations and lays the foundation for biomedically oriented research with objective outcome measurements.

The analysis examined studies on graded exercise therapy (GET) and cognitive behavioral therapy (CBT) in ME/CFS that used work capacity as a outcome measure. The results are alarming: following these treatments, a greater proportion of patients were unable to work than before the start of treatment, indicating a deterioration in their condition. The study thus confirms the conclusions of the 2021 British NICE guidelines, which no longer recommends GET and CBT as treatments for ME/CFS, and explicitly warns against their application to Long COVID patients.

This paper is significant because it directly refutes, using employment capacity data, the decades-long practice of treating ME/CFS patients with GET and CBT and of questioning their recovery behavior. It provides an important foundation for the rehabilitation of the patient perspective and supports the move away from a purely psychosocial disease model. For those affected by Long COVID, it serves as an early warning against the uncritical transfer of outdated therapeutic concepts.

The publication summarizes the consensus recommendations of 21 clinically experienced ME/CFS experts and is aimed at general practitioners as well as specialists. It is based on the diagnostic criteria published in 2015 by the US National Academy of Medicine and emphasizes that therapies such as Graded Exercise Therapy (GET) and cognitive behavioral therapy (CBT) have been withdrawn as first-line treatments. Particular emphasis is placed on the relevance to post-COVID conditions, as a significant proportion of those affected develop a clinical picture similar to ME/CFS.

This paper is of high practical significance, as it consolidates the current clinical consensus on ME/CFS care while clearly rejecting outdated, potentially harmful treatment approaches. It directly addresses the massive diagnostic deficit (up to 91% of affected individuals in the US remaining undiagnosed) and builds a bridge to Post-COVID, which underscores its relevance for a growing patient population. For those affected, it is an important document for having informed conversations with physicians.

Autoantibodies against β2-adrenoceptors not only disrupt blood vessel regulation, but also inhibit an important sodium pump (Na+/K+-ATPase) in the musculature. This causes too much sodium to flow into the muscle cells, which in turn triggers a dangerous calcium influx via an exchanger – a process known from cardiac research as ischemia-reperfusion injury. The resulting calcium overload damages the mitochondria and energy metabolism, and explains why even minor exertions in daily life can repeatedly trigger flare-ups of the disease (post-exertional malaise).

This work provides a detailed, mechanistically coherent model that traces several core phenomena of ME/CFS – exercise intolerance, post-exertional malaise, hypovolemia, and chronification – back to a common causal chain. Particularly important is the explained vicious cycle: a once-triggered calcium overload lowers the threshold for future damage, which explains why affected individuals react to increasingly lower levels of exertion over time. The model connects autoimmune, vascular, and muscle physiology and opens up potential therapeutic approaches such as NHE1 inhibitors or calcium channel blockers.

Using proteome and transcriptome analyses of cell lines from up to 34 ME/CFS patients and 31 healthy controls, elevated levels of enzymes involved in the citric acid cycle, fatty acid oxidation, and amino acid breakdown were detected – while the enzymes of normal glucose metabolism remained unchanged. This suggests that mitochondria in ME/CFS are under chronic energy stress and therefore must resort to alternative, less efficient fuels. The cellular energy stress sensor AMPK was elevated, but did not reach statistical significance.

This study provides molecular evidence that ME/CFS is associated with a fundamental disruption of cellular energy metabolism. The systematic dysregulation of multiple metabolic pathways – not just individual enzymes – supports the hypothesis that ME/CFS is a measurable, biologically demonstrable disease and opens up possible starting points for targeted therapies.

The authors derive specific disease mechanisms from existing evidence on endothelial dysfunction and reduced cerebral blood flow in ME/CFS. They describe how elevated intracranial pressure and an overactive adrenergic stress response of the nervous system interact, thereby causing the broad spectrum of neurocognitive symptoms. The model connects vascular, neurological, and autonomic dysfunctions into a coherent explanatory framework for ME/CFS.

This paper provides an important theoretical framework that traces many of the previously difficult-to-explain neurological ME/CFS symptoms back to measurable physiological processes. It strengthens the biological basis of the disease and could identify potential starting points for future therapies targeting cerebral hypoperfusion and autonomic dysfunction.

The EUROMENE network, funded by the European COST programme (2016–2020), has examined the current state of ME/CFS care in Europe and developed standardised recommendations on this basis. Clinicians and researchers from 22 European countries have formulated guidelines for diagnosis, healthcare, and care with the involvement of those affected. The aim is more coordinated and higher-quality care for ME/CFS patients throughout Europe.

This consensus document is groundbreaking because it creates, for the first time, a Europe-wide, coordinated foundation for ME/CFS diagnosis and care. It strengthens the recognition of the disease at an institutional level, standardizes diagnostic criteria, and can serve as a reference document for those affected in Europe to advocate for better medical care.

The paper systematically compares what is known about the mechanisms underlying ME/CFS with the clinical picture of Post-COVID-19 ('Long COVID') and identifies striking overlaps. The authors propose specific molecular mechanisms – including immune dysregulation, autoantibodies, autonomic nervous system dysfunction, and impaired energy metabolism – that could explain both the fatigue and accompanying symptoms in both conditions. At the same time, they outline a research agenda to address open questions relating to both syndromes jointly and more efficiently.

This paper is significant because it embeds ME/CFS in the mainstream scientific discourse around Long COVID, thereby elevating the decades-long marginalized research on ME/CFS. The parallel examination of both conditions strengthens the argument that ME/CFS is a biologically real, post-infectious disease, and opens up the possibility of finally deciphering ME/CFS mechanisms more thoroughly through Long COVID research – with potentially shared therapeutic approaches.

The paper develops a conceptual framework that divides the natural course of ME/CFS – particularly following infections – into clearly distinguishable stages. In the early stages, preventive strategies such as adequate rest, reduced activity, and pacing are emphasized in order to prevent chronification. Later stages require a more comprehensive, individually tailored treatment approach targeting the various body systems. Furthermore, a stricter and more consistent application of case definitions in research is called for.

This paper is important because it proposes a paradigm shift in ME/CFS research and care: away from a purely symptom-based classification toward a stage-oriented model. For those affected, this means that interventions – particularly early recognition and consistent pacing following a viral illness – could potentially prevent chronification. The framework is also highly relevant for those with Long COVID, as post-viral trajectories are explicitly included.

The authors summarize that ME/CFS, despite a prevalence of 0.5–1.5% in the United States, remains largely untreatable — current therapies only alleviate symptoms. Immune dysregulation and mitochondrial dysfunction are highlighted as central disease mechanisms, although the exact origin of the condition is not yet fully understood. The study also provides an outlook on possible pharmacological targets and emphasizes that the COVID-19 pandemic could significantly increase the prevalence of ME/CFS through post-viral developments.

This review provides a systematic inventory of past clinical trials and identifies specific molecular targets for new drugs – thus providing important guidance for future research and development priorities in the ME/CFS field.

Earlier studies on herpesviruses such as EBV and ME/CFS yielded contradictory results, which is why their role was long underestimated. More modern analytical methods now show that specific EBV-encoded proteins could explain the known immune and neurological abnormalities in a subset of ME/CFS patients. These findings open up new avenues for the development of biomarkers and targeted therapies.

The paper rehabilitates the herpesvirus hypothesis in ME/CFS on the basis of new scientific methods and provides a mechanistic explanatory approach for how a past EBV infection can cause long-lasting immune and nervous system disorders – particularly relevant in the context of post-viral syndromes such as Long COVID.

In this randomized crossover study involving 16 ME/CFS patients, dramatic drops in cardiac output (−27%) and cerebral blood flow (−25%) were measured during tilt table examinations without stockings — and this occurred without classic changes in heart rate or blood pressure. Wearing knee-high compression stockings significantly reduced these drops to approximately half (−15% and −14%, respectively). The results objectively confirm for the first time what patients had reported subjectively, and demonstrate that orthostatic dysfunction in ME/CFS can be measured even without typical drops in blood pressure.

This study is important because it objectively demonstrates, using Doppler measurements, a frequently underestimated mechanism in ME/CFS – the drop in cerebral blood flow upon standing without classic vital sign changes. This explains why many affected individuals experience cognitive impairment and exhaustion while standing, even though their blood pressure remains unremarkable. At the same time, the study offers an easily accessible, safe, and cost-effective treatment option with measurable benefits, which is directly relevant to clinical practice.

The authors analyzed studies on brain imaging (MRI, PET) and dysautonomia tests in individuals with ME/CFS. Structural, metabolic, and functional changes in the brain were found, however these alone do not allow for a definitive diagnosis. More promising are investigations of the autonomic nervous system: heart rate variability, the tilt table test, as well as autoantibodies against adrenergic, cholinergic, and serotonin receptors could potentially serve as biomarkers in the future to identify patient subgroups.

This review paper supports the classification of ME/CFS as a neurobiological disease (ICD-11: 8E49) and provides a structured overview of diagnostically useful biomarkers. In particular, dysautonomia research involving the detection of autoantibodies shows concrete approaches for subgroup diagnoses, which is relevant both for clinical practice and for understanding the disease mechanisms.

The review article summarizes the current state of research on the relationship between the gut microbiome and ME/CFS. Central mechanisms include dysbiosis (imbalance of gut bacteria), increased intestinal permeability with translocation of bacterial components into the bloodstream, altered production of short-chain fatty acids, and disrupted tryptophan metabolism – all of which can promote inflammatory responses, mitochondrial dysfunction, and neurocognitive impairments. The authors also emphasize that early childhood antibiotic use could alter the composition of the gut microbiome in the long term in such a way as to constitute a risk factor for the development of ME/CFS.

This review provides a systematic overview of plausible mechanisms linking the gut microbiome to central ME/CFS symptoms such as fatigue, cognitive impairment, and immune dysregulation. It identifies concrete starting points for future therapeutic studies — including probiotics, dietary interventions, and fecal microbiota transplantation — and calls for urgently needed longitudinal studies that jointly capture disease progression and microbiome changes.

The article highlights the various factors that may be involved in the development of ME/CFS: infections (including by SARS-CoV-2), genetic predispositions, hormonal changes, and disruptions of the gut microbiome. Particular emphasis is placed on the potential of so-called non-coding RNA (ncRNA) as future biomarkers for objective diagnosis. Since the disease presents very differently from patient to patient, there are currently neither uniform biomarkers nor standardized tests – the diagnosis continues to rely on clinical symptom criteria.

This paper provides an accessible general overview of the current state of research on ME/CFS and is particularly well suited as introductory reading. It connects well-known mechanisms (immune system, microbiome, hormones) with newer fields of research such as ncRNA and Long COVID, and illustrates why the disease is so difficult to diagnose and treat.

The authors analyze commonalities between EBV-associated autoimmune diseases, certain types of cancer, and ME/CFS – in particular a disrupted T-cell control over EBV-infected cells, an increased number of EBV-infected cells in the blood, and elevated anti-EBV antibodies. They propose that in a subgroup of ME/CFS patients with specific HLA alleles (DRB1 and DQB1), EBV-infected cells may escape the immune system and trigger a shifted immune response (Th2-dominant). In conclusion, the authors call for targeted clinical trials to investigate whether anti-EBV therapies could be effective in this patient subgroup.

The paper provides a structured overview of a plausible immunological mechanism linking EBV to ME/CFS, and identifies specific genetic risk markers (HLA alleles). In doing so, it offers a foundation for future subgroup research and potentially individualized therapeutic approaches – an important step away from viewing ME/CFS as a homogeneous disease.

The collected publication addresses fundamental questions about the nature of ME/CFS, including growing knowledge about pathological processes in the body as well as the persistent skepticism of many physicians toward the disease. A central proposal is the new category 'Post-Active Phase of Infection Syndromes' (PAPIS), which unites ME/CFS and Long COVID due to their strong overlaps. In addition, diagnostic and treatment recommendations from European experts, quality of life studies from several countries, and possibilities for early diagnosis as secondary prevention are presented.

The paper is important because it embeds ME/CFS in a broader context: it connects current research findings on biological mechanisms with the real-world care problems faced by those affected and proposes for the first time a overarching taxonomic category that encompasses ME/CFS and Long COVID. In doing so, it provides a conceptual foundation for future research and health policy.

The paper shows that in Post-Viral Fatigue Syndrome (PVFS), deviations in creatine metabolism can be detected at multiple levels: altered creatine levels in the brain (via MR spectroscopy), slowed phosphocreatine resynthesis in muscle tissue following exertion, and elevated creatine kinase levels in the blood. These findings are pathophysiologically significant, as phosphocreatine is considered an immediate energy buffer for ATP-dependent processes, and impaired resynthesis could explain the characteristic exercise intolerance (PEM). The review article also evaluates clinical studies on creatine supplementation, which — despite an overall heterogeneous body of data — demonstrate moderate improvements in fatigue-associated symptoms.

This paper is relevant because it discusses disruptions in creatine metabolism as a possible objective biomarker for ME/CFS, thereby representing a step toward diagnostic tests that have so far been lacking. At the same time, it provides a rational basis for why energy provision in the muscles and brain is impaired in those affected – which could mechanistically explain central symptoms such as PEM and cognitive limitations. The outlook on Post-COVID-19 also makes the work applicable to the understanding of current Long COVID phenomena.

Non-restorative sleep is one of the core symptoms of ME/CFS, but this review of 20 studies shows that objective sleep measurements such as polysomnography yield contradictory results — for example regarding deep sleep proportion, sleep apnea index, and sleep onset latency. The quality of the available studies was limited by small sample sizes, varying diagnostic criteria, and lack of replication, meaning that no consistent objective sleep profile for ME/CFS has been identified to date.

Non-restorative sleep is a core diagnostic feature of ME/CFS, and understanding the underlying sleep disorders could provide important insights into disease mechanisms. This first systematic review in the field makes clear that despite subjectively massively disturbed sleep, the objective measurement data have so far not produced a consistent picture – which points to both methodological gaps and the complexity of the symptom, and highlights an urgent need for research.

Researchers examined lymphocytes (immune cells) from 51 ME/CFS patients and found that the so-called Complex V – the central enzyme for producing cellular energy (ATP) – operates significantly less efficiently than in healthy control subjects. The cells attempt to compensate for this by upregulating their entire respiratory chain activity, which maintains normal ATP levels at rest. However, this constant overactivation means that the cells are no longer able to mobilise additional reserves when there is a sudden increased demand – such as during physical or mental exertion – which represents a biological mechanism for Post-Exertional Malaise (PEM).

This study provides one of the most concrete molecular explanations to date for PEM, the core symptom of ME/CFS. The demonstrated Complex V defect with exhausted compensatory reserves provides, for the first time, a biochemically plausible explanation for why exertion leads to a worsening of symptoms in those affected, rather than – as in healthy individuals – to adaptation. The use of 51 patient samples with a control group and several independent measurement methods (Seahorse analysis, proteomics, biochemical assays) makes the results particularly robust.

The review article analyzes existing studies on genetic risk factors in ME/CFS and finds that most candidate genes identified to date could not be confirmed in larger cohorts – particularly the UK Biobank. Several genome-wide association studies (GWAS) also failed to yield consistently significant genetic variants. At the same time, the authors emphasize that ME/CFS has a heritable component and call for larger, methodologically more robust GWAS studies in order to identify causal DNA variants and affected cell types.

This paper is important because it soberly and critically evaluates the current state of genetic ME/CFS research, while highlighting why previous approaches have failed. It establishes an important foundation for future studies and makes clear that ME/CFS, despite its high prevalence and societal burden, has been greatly neglected in genetic research compared to other complex diseases. Placing the research deficit in context helps to justify the need for greater investment and methodologically stronger studies.

The study illuminates a range of biological anomalies in individuals with ME/CFS, including immune system disorders, inflammatory markers, autonomic nervous system dysfunctions, and changes in energy metabolism. The aim is to make these findings usable as potential diagnostic biomarkers and to place the diagnosis of ME/CFS on a more objective, biomedical foundation. The authors emphasize that the current purely symptom-based diagnosis should be supplemented by measurable biological parameters.

ME/CFS is still diagnosed primarily on a clinical basis today, as established biomarkers are lacking. This review consolidates current biomedical findings and highlights which measurable biological changes could serve as diagnostic markers in the future – an important step toward a more objective diagnosis and better differentiation from other diseases.

The study examined blood cells (PBMCs) from ME/CFS patients of varying disease severity and found that in all those affected – including those with moderate illness – the mitochondria (the 'powerhouses' of the cells) function less efficiently than in healthy individuals. Severely affected patients additionally show impaired glycolysis, meaning the alternative energy pathway that can normally serve as a backup. Furthermore, severely ill patients produce more acid in their cells during respiration, which refines energy measurement and explains why their symptoms are significantly more pronounced.

This paper provides important evidence that ME/CFS is not solely a disease of the mitochondria, but that in severely affected patients the entire cellular energy system – both the mitochondrial and the glycolytic pathway – breaks down. This biologically explains why some patients are significantly more impaired than others, and supports the call for severity stratification in research and care. Also of methodological value is the consideration of respiratory acidification, which enables more precise measurements of glycolysis.

Five ME/CFS patients who had already benefited from a five-day immunoadsorption (IA) treatment in a previous study were retreated approximately two years later using a modified IA protocol. This removed 80–90% of total IgG as well as β2-adrenoceptor antibodies from the blood, resulting in rapid and lasting improvement of various symptoms in four of the five patients, persisting for up to 12 months. The findings support the hypothesis that ME/CFS is an autoimmune disease in a subset of those affected, in which misdirected antibodies against adrenergic receptors play a central role.

This study provides an important further indication of the autoimmune nature of ME/CFS and demonstrates that the targeted elimination of β2-adrenoceptor antibodies by means of immunoadsorption can have a repeatable therapeutic effect. It supports the theory that some cases of ME/CFS are caused by pathological autoantibodies – similar to other autoimmune diseases – and justifies the call for larger, controlled clinical trials of this therapeutic approach.

The article discusses ME/CFS as a rare disease with no known cure and examines therapy options targeting specific disease mechanisms: metformin and Momordica charantia extract are intended to correct insulin resistance, meldonium to improve glucose transport into the mitochondria, sodium dichloroacetate (DCA) to activate the enzyme pyruvate dehydrogenase and thereby enhance mitochondrial energy production. Additionally, the importance of comorbidities is emphasized, as their independent treatment can significantly influence the overall symptomatology.

The paper provides a practice-oriented overview of metabolically targeted therapeutic concepts and connects known pathomechanisms (mitochondrial dysfunction, insulin resistance, oxidative stress) with specific substances. For those affected, the emphasis on comorbidities is particularly important, as their recognition and treatment can improve quality of life. However, the recommendations are predominantly based on small studies or theoretical considerations, meaning that the clinical evidence is still limited.

The analysis of 32 studies shows that ME/CFS patients consume an average of 5.2 ml of oxygen per kilogram of body weight per minute less than healthy controls during exercise testing – a clinically significant difference. There is an 88% probability that this effect exceeds the threshold for clinical relevance. This reduction in peak oxygen uptake (VO2peak) is considered an objective marker of impaired physical capacity and is independent of subjective symptom reports.

This meta-analysis is significant because it objectively demonstrates, with high statistical power and on the basis of 32 studies, that the fatigue in ME/CFS is not a purely subjective perception, but is reflected in measurable physiological parameters. The reduced VO2peak is a central finding that distinguishes the condition from psychosomatic explanatory models and at the same time points to disturbances in energy metabolism – possibly at the level of the mitochondria or oxygen utilization. The result strengthens the legitimacy of ME/CFS as a physical illness and provides an important foundation for further research into exertion limits and post-exertional malaise (PEM).

Chronotropic intolerance (CI) describes the inability of the heart to sufficiently increase heart rate during physical exertion, resulting in impaired cardiac output. Through systematic evaluation of studies using standardized exercise tests (CPET), this review demonstrates that individuals with ME/CFS consistently exhibit an attenuated heart rate response. This may represent a central physiological mechanism underlying post-exertional malaise (PEM) and has direct implications for the investigation of causes as well as for clinical management.

This review article with meta-analysis provides measurable, objective evidence that ME/CFS is not a purely subjective condition, but is associated with demonstrable cardiovascular dysfunctions. Chronotropic intolerance explains, at a physiological level, why those affected reach their limits even with minimal exertion, and underscores why exercise-based therapies such as GET (Graded Exercise Therapy) can be harmful. Furthermore, the finding opens up new approaches for diagnostics and targeted therapeutic interventions.

ME/CFS manifests through extreme physical and mental exhaustion, pain, sleep disorders, cognitive impairments, autonomic dysfunction, and post-exertional malaise (PEM). The condition is frequently triggered by infections or severe physical or psychological stress. Decades of research have demonstrated measurable changes in mitochondria, the neuroendocrine system, the immune system, and metabolism, which forms the basis for the development of new biomarkers and treatment approaches.

This review article provides a structured summary of the biological findings established in ME/CFS up to 2019 and substantiates the disease status as an organic multisystem disorder. It is particularly valuable as introductory literature, as it consolidates central mechanisms such as mitochondrial dysfunction and immune dysregulation, and points the way toward targeted biomarker research and therapeutic development.

Using a special peptide microarray – a chip with thousands of randomly arranged protein fragments – the antibodies in the blood serum of ME/CFS patients from Canada, Norway, and the United States were analyzed. This revealed a characteristic pattern of 256 peptides that consistently distinguishes ME/CFS patients from healthy individuals. The results support the so-called 'hit-and-run' hypothesis, which proposes that an initial trigger (e.g., an infection) sets off a persistent immune dysregulation that continues even after the trigger has disappeared.

This paper is significant because ME/CFS to this day has no laboratory-diagnostically confirmed diagnosis and those affected often go through years-long odysseys through the healthcare system. A reproducible immunological biomarker based on antibody signatures could provide the foundation for an objective blood test. Furthermore, the international validation of the signature (Canada, Norway, USA) strengthens the significance of the findings and shows that the immunological profile of ME/CFS is consistent across cultures.

The model begins with a viral or bacterial infection that triggers a chronic inflammatory and stress response in genetically susceptible individuals. The central mechanisms are increased intestinal permeability (leaky gut), which allows the body's own bacterial components to enter the bloodstream, as well as the resulting neuroinflammation and mitochondrial exhaustion. Particularly interesting is the concept of 'endotoxin tolerance', in which the immune system switches to a throttled state and cells fall into a kind of 'hibernation' – which could explain many typical ME/CFS symptoms such as fatigue and cognitive problems.

This paper is significant because it brings together, for the first time, many isolated biological anomalies observed in ME/CFS into a coherent overall model. It connects findings from immunology, neurology, metabolic research, and microbiome research, thereby providing a theoretical foundation for future therapeutic approaches. The model has substantially influenced subsequent research into mitochondrial dysfunction and immune suppression in ME/CFS.

The authors summarize current research findings that demonstrate elevated inflammatory and immune activity, persistent neuroinflammation, and reduced mitochondrial function in individuals with ME/CFS. These findings provide possible molecular biomarkers that could potentially be used for an objective diagnostic test in the future. At the same time, it is emphasized that ME/CFS, in accordance with the Institute of Medicine report, is clearly to be classified as a physical – not psychiatric – illness.

This paper is important because it brings together the previously fragmented biological findings on ME/CFS in a comprehensive overview and concretely demonstrates which mechanisms – inflammation, immune activation, and energy metabolism disorders – could be used as measurable biomarkers for a more objective diagnosis. It strengthens the scientific legitimacy of the disease and marks an important step away from the purely exclusion-based diagnosis.

The authors demonstrate that ME/CFS is not a purely psychological phenomenon, but is characterized by measurable dysfunctions across multiple body systems – including inflammatory processes, autonomic nervous system dysfunction, abnormalities in muscle cells and mitochondria, as well as changes in the gut microbiome. The thesis is put forward that these various dysfunctions may be parts of a common, profound biological imbalance. Since those affected present with very different symptoms and ME/CFS can develop through various triggers (e.g., infections), the authors emphasize the need to better stratify patient groups for future research.

This paper provides an important overview of the current state of research on the biological basis of ME/CFS and makes clear that the condition is a complex, measurable disease entity. It underscores the urgency of developing biomarkers for diagnosis and provides patients as well as the general public with a scientifically sound foundation for understanding the legitimacy of the disease.

Using neurophysiological measurement methods, it has been demonstrated that ME/CFS patients exhibit both central fatigue (reduced signal transmission from the motor cortex) and peripheral fatigue (impaired electrical conductivity of the muscle membrane). Elevated oxidative stress has been identified as a possible cause of the muscle problems: lipid hydroperoxides damage the sarcolemmal membrane and disrupt ion transport, which impairs muscle excitability and potassium flow. Additionally, individuals with ME/CFS produce fewer heat shock proteins (HSPs) following exertion — proteins that normally protect muscle cells from reactive oxygen species — and this deficiency may perpetuate the cycle of oxidative stress and muscle failure.

This paper provides an important neurophysiological framework that explains why muscle fatigue in ME/CFS is not a psychological phenomenon, but has measurable biological causes on multiple levels. The combination of central and peripheral fatigue, along with the association with oxidative stress and HSP deficiency, opens up concrete starting points for future treatment strategies and supports the legitimacy of the physical complaints experienced by those affected.

This comprehensive review analyzes the current scientific status of cytokines – messenger substances of the immune system – in ME/CFS. The authors confirm that altered cytokine patterns can be detected both in the blood and in the cerebrospinal fluid (CSF), which are associated with the severity and course of the disease. Nevertheless, the methodological and biological challenges are currently still too great to use individual cytokines as reliable diagnostic markers or as therapeutic targets.

This study is important because it systematically demonstrates that ME/CFS has a measurable immunological basis and is not a purely psychosomatic illness. At the same time, it honestly highlights the current limitations of research – namely that the cytokine profile alone is not yet sufficient for diagnosis or therapy – and identifies concrete starting points for future research.

By means of repeated forced swimming, a ME/CFS-like condition was induced in mice, manifesting as progressive immobility and reduced activity. In the skeletal muscle of these animals, the activity of pyruvate dehydrogenase (PDH) – a key enzyme that establishes the link between glucose metabolism and cellular energy production – was significantly reduced. The administration of sodium dichloroacetate (DCA), a compound that activates PDH, was able to markedly improve the fatigue-like behaviour of the mice.

This study provides a concrete animal model for ME/CFS and supports the hypothesis that impaired mitochondrial energy production – specifically through reduced PDH activity – could be central to the development of ME/CFS symptoms. Since clinical studies in humans also indicate PDH dysfunction, this model substantiates the biological basis of the disease and suggests PDH as a potential therapeutic target.

The review article analyzes various pharmacological treatment approaches for ME/CFS, including antiviral agents, pain medications, antidepressants, and oncological compounds. The results of existing studies are predominantly inconclusive or contradictory, which can be attributed to methodological weaknesses and the pronounced heterogeneity of the disease. The authors conclude that combination therapies based on a systematic analysis of immune and hormonal system interactions may hold more promise than previous single interventions.

The paper provides an important overview of the current state of pharmacological treatment of ME/CFS and clarifies why previous therapeutic approaches have failed. The demand for precision medicine and combination therapies taking into account the immune and hormonal systems provides important impulses for future research directions and explains why there is still no approved therapy for ME/CFS to date.

The authors evaluated the current state of scientific research on post-bacterial fatigue syndromes, latent infections, and asymptomatic bacterial carriage. They conclude that there is no reliable evidence that subjective symptoms following a bacterial infection are caused by persisting or dormant bacteria. Instead, unknown microorganisms as well as psychological trauma resulting from the illness itself are discussed as possible causes, while continued antibiotic therapy — except in cases of latent syphilis and tuberculosis — is considered to be unjustified.

This paper is relevant to ME/CFS patients because it critically examines and refutes, based on the literature, a frequently discussed hypothesis – persistently active or dormant bacteria as a cause of ongoing symptoms. It clarifies that the causes of post-infectious fatigue syndromes remain largely unexplained even after bacterial triggers, and emphasizes the need for further research into other pathophysiological mechanisms beyond persisting pathogens.

The authors analyze three common research methods for investigating neuroinflammation in ME/CFS: PET imaging with TSPO radioligands, magnetic resonance spectroscopy (MRS), and cytokine measurements in blood and cerebrospinal fluid. In doing so, they note that most previous imaging studies have neglected a crucial area: the brainstem, which is likely to be particularly relevant to the autonomic symptoms of ME/CFS. Regarding cytokine profiles, the authors argue that, due to biological complexity and methodological variance, a reliable, reproducible diagnostic cytokine pattern will likely never be found.

This paper is important because it urges the research community to exercise greater methodological care: many contradictory study results in ME/CFS could be attributable to avoidable measurement errors. The criticism of the neglect of the brainstem provides important impetus for future study designs. At the same time, it tempers unrealistic expectations regarding cytokine biomarkers and helps to deploy research resources in a more targeted manner.