Category: Pathophysiology

Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort

Abstract:

Background: Shared symptoms and biological abnormalities between post-acute sequelae of SARS-CoV-2 infection (PASC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could suggest common pathophysiological bases and would support coordinated treatment efforts. Empirical studies comparing these syndromes are needed to better understand their commonalities and differences.

Methods: We analyzed electronic health record data from 6.5 million adult patients from the National COVID Cohort Collaborative. PASC and ME/CFS diagnostic groups were defined based on recorded diagnoses, and other recorded conditions within the two groups were used to train separate machine learning-driven computable phenotypes (CPs). The most predictive conditions for each CP were examined and compared, and the overlap of patients labeled by each CP was examined. Condition records from the diagnostic groups were also used to statistically derive condition clusters. Rates of subphenotypes based on these clusters were compared between PASC and ME/CFS groups.

Results: Approximately half of patients labeled by one CP are also labeled by the other. Dyspnea, fatigue, and cognitive impairment are the most-predictive conditions shared by both CPs, whereas other most-predictive conditions are specific to one CP. Recorded conditions separate into cardiopulmonary, neurological, and comorbidity clusters, with the cardiopulmonary cluster showing partial specificity for the PASC groups.

Conclusions: Data-driven approaches indicate substantial overlap in the condition records associated with PASC and ME/CFS diagnoses. Nevertheless, cardiopulmonary conditions are somewhat more commonly associated with PASC diagnosis, whereas other conditions, such as pain and sleep disturbances, are more associated with ME/CFS diagnosis. These findings suggest that symptom management approaches to these illnesses could overlap.

Source: Powers JP, McIntee TJ, Bhatia A, Madlock-Brown CR, Seltzer J, Sekar A, Jain N, Hornig M, Seibert E, Leese PJ, Haendel M, Moffitt R, Pfaff ER; N3C Consortium and RECOVER-EHR. Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort. Commun Med (Lond). 2025 Apr 11;5(1):109. doi: 10.1038/s43856-025-00827-5. PMID: 40210986. https://www.nature.com/articles/s43856-025-00827-5 (Full text)

Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available. Approximately 60% of patients develop ME/CFS following an acute infection.

Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype. Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity. While trained immunity is beneficial to combat infections, a disproportionate response may cause disease.

We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS. In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.

Source: Humer B, Dik WA, Versnel MA. Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review. Front Immunol. 2025 Mar 25;16:1483764. doi: 10.3389/fimmu.2025.1483764. PMID: 40201181; PMCID: PMC11975576. https://pmc.ncbi.nlm.nih.gov/articles/PMC11975576/ (Full text)

Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the etiology of these illnesses remains largely unknown. Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients.

The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases. Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterization of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unraveling the metabolic phenotypes associated with these complex diseases.

Emerging evidence suggests that ME/CFS, GWS, and FM are all characterized by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention.

Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.

Source: Davis L, Higgs M, Snaith A, Lodge TA, Strong J, Espejo-Oltra JA, Kujawski S, Zalewski P, Pretorius E, Hoerger M, Morten KJ. Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front Neurosci. 2025 Mar 10;19:1498981. doi: 10.3389/fnins.2025.1498981. PMID: 40129725; PMCID: PMC11931034. https://pmc.ncbi.nlm.nih.gov/articles/PMC11931034/ (Full text)

mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS

Abstract:

Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined.

In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. ‘mTORC1 Syndrome’ (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

Source: Bar-Tana J. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS. J Transl Med. 2025 Mar 10;23(1):297. doi: 10.1186/s12967-025-06220-z. PMID: 40059164. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06220-z (Full text)

Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS)

Abstract:

We proposed that cerebrospinal fluid would provide objective evidence for disrupted brain metabolism in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). The concept of postexertional malaise (PEM) with disabling symptom exacerbation after limited exertion that does not respond to rest is a diagnostic criterion for ME/CFS. We proposed that submaximal exercise provocation would cause additional metabolic perturbations.

The metabolomic and lipidomic constituents of cerebrospinal fluid from separate nonexercise and postexercise cohorts of ME/CFS and sedentary control subjects were contrasted using targeted mass spectrometry (Biocrates) and frequentist multivariate general linear regression analysis with diagnosis, exercise, gender, age and body mass index as independent variables. ME/CFS diagnosis was associated with elevated serine but reduced 5-methyltetrahydrofolate (5MTHF).

One carbon pathways were disrupted. Methylation of glycine led to elevated sarcosine but further methylation to dimethylglycine and choline was decreased. Creatine and purine intermediates were elevated. Transaconitate from the tricarboxylic acid cycle was elevated in ME/CFS along with essential aromatic amino acids, lysine, purine, pyrimidine and microbiome metabolites. Serine is a precursor of phospholipids and sphingomyelins that were also elevated in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls.

The findings differ from prior hypometabolic findings in ME/CFS plasma. The novel findings generate new hypotheses regarding serine-folate-glycine one carbon and serine-phospholipid metabolism, elevation of end products of catabolic pathways, shifts in folate, thiamine and other vitamins with exercise, and changes in sphingomyelins that may indicate myelin and white matter dysfunction in ME/CFS.

Source: Baraniuk JN. Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). Sci Rep. 2025 Mar 3;15(1):7381. doi: 10.1038/s41598-025-91324-1. PMID: 40025157. https://www.nature.com/articles/s41598-025-91324-1 (Full text)

Unravelling the Connection Between Energy Metabolism and Immune Senescence/Exhaustion in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease, characterized by a diverse array of symptoms including post-exertional malaise (PEM), severe fatigue, and cognitive impairments, all of which drastically diminish the patients’ quality of life. Despite its impact, no curative treatments exist, largely due to the limited understanding of the disease’s underlying pathophysiology.
Mitochondrial dysfunction, leading to impaired energy production and utilization, is believed to play a key role in the onset of fatigue and PEM, positioning it as a potential key pathophysiological mechanism underlying ME/CFS. Additionally, the disorder shows similarities to chronic viral infections, with frequent reports of immune system alterations, suggesting a critical role for immune (dys)functioning. In particular, the roles of immune senescence and immune exhaustion—two fundamental immune states—remain poorly understood in ME/CFS.
This state-of-the-art review explores how metabolic dysfunction and immune dysfunction may be interconnected in ME/CFS, proposing that energy deficits may directly impair immune function. By examining this metabolic–immune interplay, this review highlights potential pathways for developing innovative therapeutic strategies that target both energy metabolism and immune regulation, offering hope for improving patient outcomes.
Source: Van Campenhout J, Buntinx Y, Xiong H-Y, Wyns A, Polli A, Nijs J, Aerts JL, Laeremans T, Hendrix J. Unravelling the Connection Between Energy Metabolism and Immune Senescence/Exhaustion in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomolecules. 2025; 15(3):357. https://doi.org/10.3390/biom15030357 https://www.mdpi.com/2218-273X/15/3/357 (Full text)

Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with no known underlying mechanisms, diagnostic tools, or treatments.  Multiple areas of dysfunction have been extensively studied, but rarely examined together. We recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal study examining energy metabolism, immune profiles and plasma protein levels.

Elevated levels of adenosine monophosphate (AMP) were detected in both plasma and immune cells. Additionally, immune cells showed higher levels of adenosine diphosphate (ADP) and a reduced adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio.

These findings imply decreased ATP generation and the presence of energy stress within the immune cell population. Adaptive immune cell populations were skewed towards less mature effector subsets of CD4+, CD8+ and gd T cells, and proportions of CD1c+CD141-conventional DC type 2 (cDC2) and CD56lowCD16+ terminal natural killer (NK) cells were also reduced. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Using Classification and Regression Tree (CART) modelling, we identified variables from each mode of investigation with strong predictive potential for ME/CFS. Together, this study provides new insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng, Ruiwen Benjamin and Gunasegaran, Bavani and Krishnamurthy, Shivani and Bustamante, Sonia and Staats, Ananda and Chow, Sharron and Ahn, Seong Beom and Paul-Heng, Moumita and Maciver, Yolande and Smith, Kirsten and Tran, Denise Phuong and Howley, Peter P. and Bilgin, Ayse Aysin and Sharland, Alexandra and Schloeffel, Richard and Guillemin, Gilles J. and Administrator, Sneak Peek, Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction. Available at SSRN: https://ssrn.com/abstract=5131664 or http://dx.doi.org/10.2139/ssrn.5131664  https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5131664 (Full text available as PDF file)

The Microbiota-Gut-Brain Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Narrative Review of an Emerging Field

Abstract:

The intricate relationship between gut microbiota and the brain has emerged as a pivotal area of research, particularly in understanding myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This complex condition is characterized by debilitating fatigue, cognitive dysfunction, and a wide array of systemic manifestations, posing significant challenges for diagnosis and treatment. Recent studies highlight the microbiota-gut-brain axis as a crucial pathway in ME/CFS pathophysiology, suggesting that alterations in gut microbial composition may impact immune responses, neurochemical signaling, and neuronal health.

This narrative review systematically explores English-language scholarly articles from January 1995 to January 2025, utilizing databases such as PubMed, Scopus, and Web of Science. The findings underscore the potential for targeted therapeutic interventions aimed at correcting gut dysbiosis. As research progresses, a deeper understanding of the microbiota-gut-brain connection could lead to innovative approaches for managing ME/CFS, ultimately enhancing the quality of life for affected individuals.

Source: El-Sehrawy AAMA, Ayoub II, Uthirapathy S, Ballal S, Gabble BC, Singh A, V K, Panigrahi R, Kamali M, Khosravi M. The Microbiota-Gut-Brain Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Narrative Review of an Emerging Field. Eur J Transl Myol. 2025 Feb 12. doi: 10.4081/ejtm.2025.13690. Epub ahead of print. PMID: 39937103. https://pubmed.ncbi.nlm.nih.gov/39937103/

Cerebral Blood Flow in Orthostatic Intolerance

Abstract:

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Source: Khan MS, Miller AJ, Ejaz A, Molinger J, Goyal P, MacLeod DB, Swavely A, Wilson E, Pergola M, Tandri H, Mills CF, Raj SR, Fudim M. Cerebral Blood Flow in Orthostatic Intolerance. J Am Heart Assoc. 2025 Feb 3:e036752. doi: 10.1161/JAHA.124.036752. Epub ahead of print. PMID: 39895557. https://www.ahajournals.org/doi/10.1161/JAHA.124.036752 (Full text)

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods.
Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies.
A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma.
The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.
Source: Baraniuk JN. Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2025; 26(3):1282. https://doi.org/10.3390/ijms26031282 https://www.mdpi.com/1422-0067/26/3/1282 (Full text)