Category: Pathophysiology

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)

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)

Low vasopressin in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objective: The complex clinical picture of ME/CFS includes orthostatic intolerance with symptoms and signs suggesting abnormal water homeostasis and hypovolemia. Since many ME/CFS patients report polyuria-polydipsia, we conducted an observational study based on series of plasma and urine osmolality (P-Osm and U-Osm) as well as plasma levels of vasopressin (P-VP) or copeptin in consecutive patients diagnosed with ME/CFS according to the International Consensus Criteria.

Methods: P-VP as well as P-Osm and U-Osm were measured in 111 patients after 10 hour overnight fasting and fluid deprivation. Additional 13 patients were assessed for copeptin, when P-VP measurements were no longer available. The clinical routine also included brain MRI and blood chemistry.

Results: P-Osm was abnormally high (>292 mOsm/kg) in 71/124 (57.3 %) and U-Osm below the reference interval (< 750 mOsm/kg) in 82/124 (66.1%) patients. P-VP was below the level of detection (<1.6 pg/mL) in 91/111 (82.0 %) patients. A normal P-VP level compared with their P-Osm was found in 11/111 (9.9 %) patients. Copeptin levels were all within the given reference range, albeit in the lower end in most patients. No indication of relevant pathology in either hypothalamus or hypophysis was present.

Conclusions: Our findings suggest that chronic down-regulation of VP mimicking central diabetes insipidus is an important measurable part of the disease mechanism that potentially contributes to criterial symptoms of ME/CFS.

Source: Huhmar HM, Soinne LS, Bertilson BC, Ghatan PH, Bragée BA, Polo OJ. LOW VASOPRESSIN IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. Endocr Pract. 2025 Dec 29:S1530-891X(25)01349-7. doi: 10.1016/j.eprac.2025.12.020. Epub ahead of print. PMID: 41475665. https://www.endocrinepractice.org/article/S1530-891X(25)01349-7/fulltext (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 undefined mechanisms, no diagnostic tools and treatments. To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multimodal analysis of energy metabolism, immune profiles, and plasma proteomics.

Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing toward less mature effector subsets of CD4+, CD8+, and γδ T cells, with reduced CD1c+CD141– conventional DC type 2 and CD56lowCD16+ terminal natural killer cells.

Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and regression tree modeling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng B, Gunasegaran B, Krishnamurthy S, Bustamante S, Pires AS, Chow S, Ahn SB, Paul-Heng M, Maciver Y, Smith K, Tran DP, Howley PP, Bilgin AA, Sharland A, Schloeffel R, Guillemin GJ. Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction. Cell Rep Med. 2025 Dec 16;6(12):102514. doi: 10.1016/j.xcrm.2025.102514. PMID: 41406947. https://www.sciencedirect.com/science/article/pii/S2666379125005877 (Full text)

Alterations in gut microbiota and associated metabolites in patients with chronic fatigue syndrome

Abstract:

To investigate differences in gut microbiota composition and short-chain fatty acids (SCFAs) metabolism between patients with Chronic Fatigue Syndrome (CFS) and Healthy Controls (HC), and to explore their associations with the CFS pathogenesis. This case-control study included 80 subjects, comprising 40 patients with CFS and 40 age- and sex-matched HC.

Fecal microbial community structure was analyzed using 16S rRNA gene high-throughput sequencing. Fecal SCFAs concentrations were quantified using Gas Chromatography-Mass Spectrometry (GC-MS). Spearman correlation analysis with false discovery rate (FDR) adjustment was performed to elucidate associations among gut microbiota, SCFAs, and clinical scores.

Compared to the HC group, the CFS group exhibited reduced gut microbiota α-diversity (e.g., ACE, Chao1, Shannon indices, all P < 0.01) and significantly altered β-diversity (ADONIS, P = 0.006). After FDR adjustment, fecal levels of acetate, butyrate, isobutyrate, and isovalerate remained significantly lower in the CFS group (all q < 0.05). Differential abundance analysis revealed a significant reduction in key taxa including the phylum Firmicutes (q = 0.010), class Verrucomicrobiae (q = 0.038), order Clostridiales (q = 0.043), and families Rikenellaceae (q = 0.011) and Ruminococcaceae (q = 0.049). Spearman correlation analysis solidified functional connections: key SCFA-producing taxa (e.g., Faecalibacterium, Subdoligranulum, Ruminococcaceae) were positively correlated with butyrate levels (r = 0.52-0.56, all q < 0.05).

Furthermore, reduced abundances of Rikenellaceae and Alistipes were associated with lower SF-36 scores (r = 0.26, q = 0.032) and higher fatigue scores (FSS/FS-14, r = – 0.28 to – 0.30, q < 0.05). Isovalerate levels were negatively correlated with FS-14 scores (r = – 0.307, q = 0.014). Among CFS patients, those with higher dietary fiber intake had significantly higher levels of acetate and isovalerate than those with lower intake (both q < 0.05).

Patients with CFS exhibit significant gut dysbiosis and abnormal SCFA metabolism. The reduction in key SCFA-producing taxa, their positive correlations with SCFAs levels, and the negative correlations of both with fatigue severity solidify a functional link between gut microbial depletion, reduced SCFAs, and clinical symptoms in CFS. Higher dietary fiber intake may partially ameliorate SCFAs metabolic disturbances in CFS patients.

Source: Cheng X, Wang W, Xu T, Wang Y, Zhen X, Man W, Gao S, Yin Y. Alterations in gut microbiota and associated metabolites in patients with chronic fatigue syndrome. Sci Rep. 2025 Dec 12;15(1):43681. doi: 10.1038/s41598-025-27564-y. PMID: 41387992; PMCID: PMC12700865. https://pmc.ncbi.nlm.nih.gov/articles/PMC12700865/ (Full text)

Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Defined by the World Health Organization as a neurological disorder, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness, affecting millions of people worldwide. First reported in the early nineteenth century, ME/CFS is uniquely characterized by a wide array of symptoms, including fatigue, brain fog, post-exertional malaise (PEM), sleep dysfunction, and orthostatic intolerance (OI). Despite decades of extensive research, there are no effective medical treatments or simple diagnostics for ME/CFS, with an estimated 90% of patients remaining undiagnosed.

The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep. A link between glymphatic dysfunction and some neurological disorders such as Alzheimer’s disease has already been established, raising the possibility of its involvement in ME/CFS. Accordingly, we believe the ME/CFS medical/scientific community will be interested in seriously considering GD an important contributor to its pathophysiology. If so, therapeutics that modulate glymphatic function may also benefit patients with ME/CFS.

Source: Nemat-Gorgani M, Jensen MA, Davis RW. Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Nov 27;26(23):11524. doi: 10.3390/ijms262311524. PMID: 41373677. https://www.mdpi.com/1422-0067/26/23/11524 (Full text)

Mucosal Viruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Missing Piece of the Puzzle?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition without a definitive aetiology, no reliable diagnostic test, and no proven effective treatment. Despite most patients reporting a post-viral onset of illness, findings to date are conflicting on whether a single virus or multiple viral triggers are involved. Most studies to date have focused on detecting viruses in blood and circulating immune cells with relatively few investigating the presence of viruses in mucosal sites.

In this review, we propose that this represents a critical gap in understanding the pathophysiology of ME/CFS knowledge, as mucosal tissues are primary entry points for most pathogens and often serve as reservoirs where viruses may persist. Consequently, they represent ideal niches for identifying persistent infections in ME/CFS. Emerging evidence from saliva and other mucosal samples in ME/CFS patients is consistent with this proposal and that latent viruses can persist and periodically reactivate in mucosal tissues from where they can potentially contribute to immune dysregulation, chronic inflammation, and increased symptom severity that defines ME/CFS.

Source: Perera KD, Cameron P, Sarwar T, Carding SR. Mucosal Viruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Missing Piece of the Puzzle? Int J Mol Sci. 2025 Nov 19;26(22):11161. doi: 10.3390/ijms262211161. PMID: 41303644; PMCID: PMC12652652. https://pmc.ncbi.nlm.nih.gov/articles/PMC12652652/ (Full text)

The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background/Objectives: Growing evidence suggests that mast cell activation (MCA) may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disorder characterized by persistent fatigue and post-exertional malaise (PEM). Particularly in relation to orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (POTS), this study aimed to investigate the prevalence and clinical relevance of MCA in an Austrian ME/CFS patient cohort.

Methods: Two data sets were analyzed. The CCCFS data set, a comprehensive, patient-centered online questionnaire consisting of 687 filled surveys, focuses on patient stratification. Self-reported clinical features, disease progression, and treatment responses were analyzed. Preliminary findings were validated in a second, retrospective study, analyzing data of 383 Austrian ME/CFS patients with regard to MCA involvement and OI.

Results: Among followed-up ME/CFS patients, MCA prevalence increased over the disease course, with up to 25.3% meeting the criteria for clinically relevant MCA. ME/CFS patients with Mast Cell Activation Syndrome (MCAS) and OI reported symptom alleviation significantly more often following mast cell-targeted treatment than those without MCAS (p < 0.0001). With regard to IF-channel inhibitors, ME/CFS patients diagnosed with MCAS responded more frequently than those without MCAS (p = 0.076), while no significant differences were observed in response to beta blockers (p = 0.637). In both cohorts, OI, particularly POTS, was significantly more common in patients with MCA involvement.

Conclusions: MCA appears to be a frequent and clinically relevant comorbidity in ME/CFS and is associated with a higher prevalence of OI, particularly POTS. Stratifying patients based on MCA involvement may support personalized treatment approaches and improve clinical outcomes.

Source: Rohrhofer J, Ebner L, Schweighardt J, Stingl M, Untersmayr E. The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics (Basel). 2025 Nov 7;15(22):2828. doi: 10.3390/diagnostics15222828. PMID: 41300853; PMCID: PMC12651186. https://pmc.ncbi.nlm.nih.gov/articles/PMC12651186/ (Full text)