Pathological mechanisms underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Daniel Missailidis, Sarah Annesley, Paul Fisher in Preprints  [Published  online: 16 July 2019] doi: 10.20944/preprints201907.0196.v1


Review abstract

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems.

This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems.

Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition.

Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.


ME/CFS is a heterogeneous condition that may encompass scenarios where uncertain, and possibly varying, underlying insults trigger body-wide molecular and cellular perturbations perpetuated by alternative, stable homeostatic states. Diagnostic advancement and the development of tools which objectively and accurately phenotype patients is therefore paramount for the development of mechanistic insight and effective therapeutics.

It is likely that the inflammation and immune dysfunction classically studied in ME/CFS are entangled with dysfunctional energetics, gut health, or autonomic and adrenal dysregulation. The evidence for metabolic and mitochondrial dysfunction indicates inefficient respiration, impaired provision of TCA cycle substrate, and metabolic shifts towards the utilization of alternative metabolites.

Immune effector cell dysfunction, chronic inflammation, defective signalling and elevated oxidative stress may interact with not only the dysfunctional energetics but also with abnormal gut physiology and microbiota composition. These effects on the gut may also tie back to mitochondrial function and vice versa.

The reciprocal interactions between these affected systems and the varied clinical presentation of relevant symptoms between individuals make it difficult to postulate cause-effect relationships with confidence. Furthermore, while disturbances to this range of interconnected systems across the body have been demonstrated, in some cases concurrently, this body of research has historically relied upon correlations, which creates the urgent need for research utilising direct experimental investigation of cause-effect relationships.

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