Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Fluge, Øystein; Tronstad, Karl Johan; Mella, Olav

doi:10.1172/jci150377

Cited by 36 publications

(54 citation statements)

References 29 publications

(27 reference statements)

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“…The observed metabolic effects may be associated with tissue hypoxia caused by an underlying pathology related to an autoimmune mechanism ( 13 ). An autoantibody-mediated mechanism may influence, indirectly or directly, the fine-tuned autoregulation of blood flow required to meet the metabolic demands of tissues.…”

Section: Discussionmentioning

confidence: 99%

“…ME/CFS has been suggested to be triggered by an aberrant immune response, with possible roles for autoimmunity, immune dysregulation, and inflammation ( 8 – 13 ). Pathological effects reported in the patients include neuroinflammation, neuroendocrine abnormalities, autonomic nervous system abnormalities, disturbed energy metabolism, and immunological changes ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

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A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Hoel¹,

Hoel²,

Pettersen³

et al. 2021

JCI Insight

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Hoel¹,

Hoel²,

Pettersen³

et al. 2021

JCI Insight

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“…Akin to heat stroke, several new hypotheses of ME/CFS suggest that vasoconstriction and hypoxia are central to its pathology—respectively focused on the consequence of ß2 adrenergic and M3 acetylcholine receptor autoantibodies ( 41 , 42 ), a potential reduction of ACE2 expression ( 43 ), and an abnormal immune response with a concomitant impact on endothelial function ( 44 ). In addition, postural orthostatic tachycardia syndrome (POTS) is a common comorbidity of ME/CFS ( 45 ), which is a complex disorder of the vascular system also associated with gastrointestinal dysfunctions ( 46 , 47 ).…”

Section: Pathophysiological Mechanismsmentioning

confidence: 99%

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

et al. 2021

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We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS. Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences - and despite heat stroke being an acute condition - the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.

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“…In our observational longitudinal PA-COVID Fatigue study of PCS patients with persistent moderate to severe fatigue and exertion intolerance for more than six months after mild to moderate COVID-19, we found that approximately 50% of patients fulfilled the diagnostic criteria of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but many PCS patients not fulfilling these criteria were equally impaired [ 4 ]. ME/CFS is a complex disease frequently triggered by an infection with Epstein-Barr virus (EBV) or parvovirus B19, but several other viral and nonviral triggers have been described [ 5 – 7 ]. Postexertional malaise (PEM), which describes a disproportional aggravation of symptoms typically lasting for more than 14 h up to several days following a mild mental or physical exertion is a key symptom of ME/CFS [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…The pathomechanism of ME/CFS is not well understood, but there is ample evidence for impaired perfusion and endothelial dysfunction (ED) [ 7 , 9 – 12 ]. ED is characterised by a diminished bioavailability of vasodilators, while on the other hand, endothelium-derived vasoconstrictors are increased, leading to impaired endothelium-dependent vasodilation [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

et al. 2022

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Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

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Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Cited by 36 publications

References 29 publications

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

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