Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene (OPRM1) promoter methylation, play a role in this dysfunction.
Using a repeated-measures design, 28 ME/CFS/FM patients and 26 matched healthy controls visited the hospital twice within four days. Assessments included blood sampling for epigenetic analysis, a clinical questionnaire battery, and quantitative sensory testing (QST). Global DNA (hydroxy)methylation was quantified via liquid chromatography–tandem mass spectrometry, and targeted pyrosequencing was performed on promoter regions of OPRM1, COMT, and BDNF. ME/CFS/FM patients reported significantly worse symptom outcomes.
No differences in global (hydroxy)methylation were found. Patients showed significantly higher OPRM1 promoter methylation, which remained after adjusting for symptom severity and QST findings. Across timepoints, OPRM1 methylation consistently correlated with BDNF Promoter I and Exon III methylation. This is, to the best of our knowledge, the first study examining OPRM1 methylation in ME/CFS/FM. Increased OPRM1 methylation in patients, independent of symptoms or pain sensitivity measures, supports the hypothesis of dysregulated opioidergic signaling in these conditions.
Source: Wyns A, Hendrix J, Van Campenhout J, Buntinx Y, Xiong H-Y, De Bruyne E, Godderis L, Nijs J, Rice D, Chiang D, et al. Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. International Journal of Molecular Sciences. 2026; 27(2):826. https://doi.org/10.3390/ijms27020826  https://www.mdpi.com/1422-0067/27/2/826 (Full text)

Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder marked by persistent fatigue and cognitive impairments, often termed “brain fog.” Emerging evidence suggests that immunosenescence, age- or stress-related deterioration of immune function, plays a pivotal role in the pathogenesis of cognitive dysfunction in ME/CFS.

Immunosenescence induces chronic low-grade inflammation (inflammaging); alters T-, NK-, and B-cell function; and promotes the release of senescence-associated secretory phenotype (SASP) factors. These changes are proposed to cerebral blood flow (CBF) regulation, may impair endothelial nitric oxide production, and may contribute to blood-brain barrier (BBB) breakdown. Consequently, brain hypoperfusion and oxidative stress are associated with impaired neuronal energy metabolism and synaptic plasticity, particularly in memory-related networks such as the default mode and fronto-hippocampal systems. This results in reduced ATP availability, excitotoxicity, and neurotransmitter imbalance, contributing to cognitive decline.

The review proposes an “immune-vascular-cognitive axis” linking peripheral immune aging to central neural dysfunction. It further highlights therapeutic strategies-such as cytokine blockade, nitric oxide enhancement, immune modulation, and acupuncture-that may ameliorate neurovascular impairments and cognitive symptoms. Understanding this integrative mechanism may offer new pathways for targeted intervention in ME/CFS.

Source: Xu H, Luo Y, Wu X. Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective. Compr Physiol. 2026 Feb;16(1):e70098. doi: 10.1002/cph4.70098. PMID: 41527963. https://pubmed.ncbi.nlm.nih.gov/41527963/

Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy

Abstract:

Background: Post-COVID condition (PCCo) affects 5-10% of individuals following SARS-CoV-2 infection, with cognitive disturbances being a major feature. Central hypotheses regarding its pathophysiology include disturbed cell energy metabolism and oxidative stress pointing to mitochondrial dysfunction. However, brain energy metabolism remains unexplored.

Methods: We investigated cerebral high-energy phosphate metabolism in 27 PCCo patients and 23 fully recovered controls using whole-brain 31P-MRSI at 3T. ATP/PCr ratios were quantified throughout the brain and analyzed with voxel-based and regional statistics including correlations with neuropsychological performance (Montreal Cognitive Assessment and Trail Making Test Part B). Statistical analysis employed voxel-wise comparisons with age as covariate, followed by region-of-interest analysis of cingulate cortex subdivisions.

Results: PCCo patients showed a significant cluster of reduced ATP/PCr ratios centered on the cingulate cortex. Regional analysis revealed consistent reductions across anterior (ACC), mid- (MCC), and posterior (PCC) cingulate cortices. Lower ATP/PCr ratios in the ACC specifically correlated with poorer cognitive performance. Exploratory analyses revealed a trend toward higher intracellular pH in the MCC with significant negative correlation between pH and ATP/PCr observed only in patients, suggesting disease-specific alterations in pH regulation and bioenergetic homeostasis. Subgroup analysis showed similar metabolic alterations in PCCo patients meeting ME/CFS criteria.

Conclusions: Our study provides first in vivo evidence of impaired brain energy metabolism in PCCo, with anterior cingulate dysfunction directly linked to cognitive impairment. The observed pH-ATP/PCr relationship suggests broader disruption of cellular bioenergetic regulation. These findings support mitochondrial dysfunction as a key pathophysiological mechanism and may inform targeted therapeutic strategies.

Source: Weber-Fahr W, Dommke S, Sack M, Alzein N, Becker R, Demirakca T, Ende G, Schilling C. Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy. Biol Psychiatry. 2026 Jan 10:S0006-3223(26)00021-1. doi: 10.1016/j.biopsych.2026.01.004. Epub ahead of print. PMID: 41525818.  https://www.biologicalpsychiatryjournal.com/article/S0006-3223(26)00021-1/fulltext (Full text)

Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, whose hallmark characteristic is post-exertional malaise (PEM). It can affect many organs and systems, leading to severe impairment of patients’ quality of life. Although numerous post-infectious, immunological, neurological, metabolic, and endocrine alterations have been documented, neither a definitive diagnostic marker nor approved treatments are available. The etiology and pathophysiology remain incompletely understood; however, emerging evidence suggests that the gut microbiome plays a role in immune responses and the development of ME/CFS.

It is hypothesized that specific disturbances in gut microbiome composition, known as dysbiosis, may compromise the integrity of the intestinal barrier. This consequently leads to translocation of microbial components, which further triggers an immune response and systemic inflammation complicating the clinical presentation of ME/CFS. Furthermore, in terms of the so-called gut-brain axis, microbiome changes may lead to distinct neurocognitive impairments observed in ME/CFS patients.

This review offers the readers a broad perspective on the topic on ME/CFS, with a particular emphasis on the interplay between the gut microbiome and disease mechanisms. Last but not least, recent data on potential treatment strategies for intestinal dysbiosis in ME/CFS patients have been included.

Source: Nikolova R, Donchev D, Vaseva K, Ivanov IN. Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms. Int J Mol Sci. 2025 Dec 31;27(1):425. doi: 10.3390/ijms27010425. PMID: 41516296; PMCID: PMC12785659. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785659/ (Full text)

Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities.

Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component.

Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut-brain axis. Neuroendocrine findings such as hypothalamic-pituitary-adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities.

Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise.

Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance.

Source: Dudova D, Bozhkova M, Petrov S, Nikolova R, Kalfova T, Ivanovska M, Vaseva K, Nikolova M, Ivanov IN. Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Dec 26;27(1):268. doi: 10.3390/ijms27010268. PMID: 41516145; PMCID: PMC12785471. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785471/ (Full text)

Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.

The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.

Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Source: Nunes M, Kell L, Slaghekke A, Wüst RC, Fielding BC, Kell DB, Pretorius E. Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system. Cell Death Dis. 2026 Jan 9;17(1):16. doi: 10.1038/s41419-025-08162-2. PMID: 41513611; PMCID: PMC12789617. https://pmc.ncbi.nlm.nih.gov/articles/PMC12789617/ (Full text)

Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers

Abstract:

Background: Postacute sequelae of COVID-19 (PASC), also known as long COVID, and postacute COVID-19 vaccination syndrome (PACVS) present overlapping but distinct clinical challenges. We hypothesize that PASC and PACVS share clinical features but differ in symptom patterns and biomarker profiles. This study aims to identify differences in presentation and distinguish immunologic biomarkers relevant to general clinical practice.

Methods: This cross-sectional study analyzed 181 patients from a PASC clinic at Columbia University Irving Medical Center. Patients were divided into PASC with myalgic encephalomyelitis/chronic fatigue syndrome (MECFS), PASC without MECFS (LC), and PACVS groups. Prevalence and severity of self-reported symptoms, as well as immunologic abnormalities, were compared across groups.

Results: Fatigue was the most common symptom (Total: 88.95%; MECFS: 100.00%; PACVS: 92.86%; LC: 78.05%). The MECFS group generally reported more symptoms across all organ systems. The PACVS group reported higher rates of atypical chief complaints such as peripheral neuropathy (17.9%), tinnitus (7.1%), and rash (10.7%) compared to the other groups (P = <.01). Functional impairment was comparable between the MECFS and PACVS groups and less severe in the LC group. All groups had high rates of autoantibody positivity and cytokine elevation. The PACVS group showed significantly higher rates of anticardiolipin IgM (PACVS 42.9%, LC 11.6%; P = .02) and anti-U1-RNP (PACVS 21.4%, LC 2.3%; P = .04) positivity compared to the LC group.

Conclusions: PASC and PACVS share symptom overlap but exhibit distinct biomarker patterns, particularly elevated autoantibody levels in PACVS. These findings suggest autoimmune involvement, warranting further investigation for targeted therapies.

Source: Purpura L, Heisler T, Palmer S, Shah J, Graham A, Seo GY, Sturiza A, Javier X, Pinto G, Rosa A, Bosco J, Reis K, Sobieszczyk ME, Yin MT. Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers. Clin Infect Dis. 2026 Jan 9:ciaf624. doi: 10.1093/cid/ciaf624. Epub ahead of print. PMID: 41510565. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf624/8417802 (Full text)

Multi-Strain Probiotic Improves Tryptophan Metabolism and Symptoms in Chronic Fatigue Syndrome Patients with Co-Occurring Irritable Bowel Syndrome: An Open-Label Pilot Study

Simple Summary:

Chronic Fatigue Syndrome (CFS) is a debilitating condition often accompanied by gut health issues, but effective treatments are scarce. Recent research suggests that an imbalance in gut bacteria (dysbiosis) may contribute to CFS symptoms by producing harmful substances that affect the nervous system. We investigated whether a specific multi-strain probiotic (CDS22-formula) could improve symptoms in women with CFS and co-occurring IBS. Over 12 weeks, patients took a high-dose probiotic supplement. We monitored their fatigue levels and analyzed urine samples to track changes in tryptophan metabolism—a key pathway linking the gut to the brain. The results showed that the probiotic intervention was associated with an improved gut bacteria profile. Importantly, this coincided with a reduction in neurotoxic metabolites and a significant decrease in fatigue severity. Our findings suggest that targeting the gut microbiome can be a valuable strategy for managing chronic fatigue, potentially by modulating the production of metabolites that affect brain function.
Abstract:

Background/Objectives: Gut dysbiosis in Chronic Fatigue Syndrome (CFS) drives low-grade inflammation and shifts tryptophan metabolism toward neurotoxic pathways. The causal link between bacterial translocation, kynurenine pathway dysregulation, and symptom severity remains under-defined. We evaluated the impact of a high-concentration multi-strain probiotic on the “gut-kynurenine axis” and clinical status in CFS patients with co-morbid IBS-U and confirmed dysbiosis.
Methods: Forty female patients with confirmed dysbiosis (GA-map™ Dysbiosis Index > 2) received the CDS22 formula (450 billion CFU/day) for 12 weeks. We compared urinary tryptophan metabolite profiles (LC-MS/MS), gut dysbiosis markers (3-indoxyl sulfate), and fatigue severity (FSS) against 40 age-matched healthy controls.
Results: Baseline analysis revealed profound metabolic perturbations: elevated bacterial proteolytic markers (3-IS), substrate depletion (low tryptophan), and a neurotoxic signature (high quinolinic acid [QA], low kynurenic acid [KYNA]). Following the intervention, fatigue scores declined by 40.3%, with 97.5% of patients reaching the remission threshold (FSS < 36). Biochemically, 3-IS levels decreased to the range observed in healthy controls and attenuated xanthurenic acid levels. Although absolute QA concentrations remained elevated compared to controls, the neuroprotective KYNA/QA ratio increased significantly (+45%). Increased systemic tryptophan availability correlated directly with clinical symptom reduction (Spearman’s rho = −0.36, p = 0.024).
Conclusions: The CDS22 formulation was associated with a restoration of intestinal eubiosis and functional tryptophan partitioning. Clinical remission coincides with a metabolic shift favoring neuroprotection (increased KYNA/QA ratio), validating the gut–kynurenine axis as a modifiable therapeutic target. Peripheral metabolic improvement relative to the healthy baseline appeared sufficient for symptom relief in this specific phenotype, despite incomplete clearance of neurotoxic metabolites.
Source:

Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study

Abstract:

Background: In recent years, evidence has indicated a metabolic shift towards increased demand for lipids in various lymphoid cell populations from people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We previously screened the mitochondrial function and gene expression of B cell-derived lymphoblastoid cell lines (LCLs) generated from the blood of people with ME/CFS to characterise a model for hypothesis discovery and testing, observing elevated expression of gene products facilitating amino acid and fatty acid degradation for energy.

Method: In this follow-up study we have expanded this characterisation by profiling the polar metabolomes and non-polar lipidomes of an all-female cohort of 17 healthy control and 15 ME/CFS LCLs, and we integrated this new data with the previously generated proteomic and transcriptomic data.

Results: In the polar metabolome we detected no significantly altered individual features, while integrated multi-omic analysis by MetaboAnalyst indicated 15 dysregulated pathways. Next, in the non-polar lipidome, we identified that PC(O-38:4) had significantly reduced levels in ME/CFS LCLs and was almost entirely discriminative of ME/CFS status. Among all detected classes of lipids we found that triradylglycerolipids (“triglycerides”), diradylglycerolipids and fatty acids were the most significantly affected and were elevated, and that most lipids exhibited average levels higher than in healthy controls. BioPAN pathway analysis of the lipidomic data predicted a more-active gene product that we confirmed to be significantly elevated in both our proteomic and transcriptomic data, this being phosphatidylserine synthase 1 (PTDSS1), plus 7 other gene products that were concordantly altered in expression in the transcriptomic data. We also found that ME/CFS LCLs exhibited a significant tendency towards more saturated lipid content.

Conclusions: LCLs generated from circulating B cells from people with ME/CFS show accumulation of lipids, skewed lipid profiles and altered activity of related metabolic enzymes such as PTDSS1. These findings will inform future hypothesis-driven studies of primary lymphoid cell populations from people with ME/CFS to dissect specific immunometabolic mechanisms that may be involved in the syndrome, particularly relating to intersections between lipid abnormalities and potential effects on immune cell effector functions.

Source: Missailidis D, Armstrong CW, Anderson D, Allan CY, Sanislav O, Smith PK, Esmaili T, Creek DJ, Annesley SJ, Fisher PR. Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study. J Transl Med. 2026 Jan 8. doi: 10.1186/s12967-025-07620-x. Epub ahead of print. PMID: 41508032. https://link.springer.com/article/10.1186/s12967-025-07620-x (Full text available as PDF file)

Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis

Abstract:

Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently report pronounced cognitive difficulties, yet the empirical literature has not fully characterised how discrete components of working memory are affected. Given that working memory serves as a foundational system supporting complex cognitive processes, differentiating performance across verbal and visual modalities provides critical insight into which higher-order functions may be most vulnerable. This systematic review/meta-analysis aimed to synthesise current research to investigate how ME/CFS impacts working memory systems.

Using PRISMA guidelines, a systematic search of 6 databases was undertaken (MEDLINE, CINAHL, Web of Science Core Collection, PubMed, EMBASE and PsycINFO). Initially, 10 574 papers were imported and following screening 34 studies of good to strong quality met the inclusion criteria. A series of random effects models were utilised to analyse working memory.

Results indicated a significant difference and large effect size between ME/CFS individuals and controls on verbal working memory tasks; however, no significant difference in visual working memory performance was found between the groups. Following the breakdown of these subsystems into span/attentional control tasks and object/spatial tasks, these results remained consistent.

These findings contribute to the body of ME/CFS research by articulating where specific working memory deficits lie. Specifically, they show that individuals with ME/CFS have impaired verbal memory performance. This knowledge can guide future research targeting higher-order verbal cognition and underscores the importance of recognising cognitive manifestations within ME/CFS clinical care.

Source: Penson M, Kelly K. Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis. Psychol Health Med. 2026 Jan 8:1-30. doi: 10.1080/13548506.2025.2606183. Epub ahead of print. PMID: 41504224. https://pubmed.ncbi.nlm.nih.gov/41504224/