Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease's multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS's pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease's complexity and the multifaceted approach required for its study and management.

Keywords: diagnostic criteria; myalgic encephalomyelitis/chronic fatigue syndrome; pathology; pathophysiology; treatment.

Figure 1

Overview review article of ME/CFS as a complex and multifactorial condition (Created with Biorender.com).

Figure 2

Summary of the common symptoms of ME/CFS (, , –26). PoTS, postural orthostatic tachycardia syndrome. Created with Biorender.com.

Figure 3

Different diagnostic criteria available for ME/CFS with a concise history of timelines (, , , , , , –54). Created with Biorender.com. GET, graded exercise therapy; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; PEM, post-exertional malaise.

Figure 4

Infectious pathogens thought to promote the development of ME/CFS including viruses, bacteria, fungi, and parasites (, , , , –126). Created with Biorender.com.

Figure 5

The effects of the altered gut composition in ME/CFS (, , –, , –, –218). Created with Biorender.com. MAMP, microbe-associated molecular pattern; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Figure 6

Examples of how dysregulated inflammatory molecules could play a pathological role in ME/CFS (, , , , –247). Molecules highlighted in red represent pro-inflammatory molecules, whereas those written in green represent anti-inflammatory molecules. Created with Biorender.com. COX-2, cyclooxygenase-2; IL, interleukin; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NK, natural killer; PBMC, peripheral blood mononuclear cell; PGE2, prostaglandin-endoperoxide synthase 2; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

Figure 7

Elevated MicroRNAs in ME/CFS and how they influence endothelial cell functioning (, , –328). Created with Biorender.com. ED, endothelial dysfunction; eNOS, endothelial nitric oxide synthase; Fox3, transcription factor forkhead box protein 3; IL, interleukin; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; miRNA, micro ribonucleic acid; NF-κB, nuclear factor kappa B; NO, nitric oxide; Sirt1, silent information regulator 1; TGF-β, transforming growth factor beta; TNF-α, tumour necrosis factor alpha; Treg, regulatory T cell.

Figure 8

Vasoconstriction and hypoxia mechanisms in ME/CFS and an example of the potential effect of the local vasodilator bradykinin in ME/CFS (illustrated in the purple box) (, , , , –348). Created with Biorender.com. B2AdR, beta-2 adrenergic receptor; ED, endothelial dysfunction; HRV, heart-rate variability; HSP, heat shock protein; IL, interleukin; KKS, kallikrein-kinin system; M3, muscarinic acetylcholine receptor M3; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; MMA, muscle metaboreflex activation; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; SV, stroke volume; TNF, tumour necrosis factor.

Figure 9

Pathological alterations in the coagulation cascade present in ME/CFS (, , , –353). Created with Biorender.com. α (2)-AP, alpha-2-antiplasmin; CRP, C-reactive protein; IL, interleukin; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NK, natural killer; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; PBMC, peripheral blood mononuclear cell; PGE₂, prostaglandin-endoperoxide synthase 2; SAA, serum amyloid A; TF, tissue factor; TGF-β, transforming growth factor beta; TNF-α, tumour necrosis factor alpha; tPA, tissue plasminogen activator; VEGF, vascular endothelial growth factor.

Figure 10

Disruption of the blood-brain barrier, the translocation of pro-inflammatory cytokines, and chronic activation of various non-neuronal cells contribute to neuroinflammatory mechanisms in ME/CFS (45, 47, 52, 201, 251, 354, 355). Created with Biorender.com. BBB, blood-brain barrier; IL, interleukin; iNOS, inducible nitric oxide synthase; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NMDA, N-methyl-D-aspartate; TNF-α, tumour necrosis factor alpha.

Figure 11

Changes in the adaptive immune system in ME/CFS (, , , , –, –, , –485). Created with Biorender.com. BCR, B cell receptor; EBV, Epstein-Barr virus; HLA-DR, human leukocyte antigen- DR isotype; IL, interleukin; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; MHC, major histocompatibility complex; TCR, T cell receptor; TGF-β, transforming growth factor-β; Treg, regulatory T cell.

Figure 12

Pharmacological and non-pharmacological treatments currently available for ME/CFS (11, 23, 60, 532). Created with Biorender.com. GI, gastrointestinal; PEM, post-exertional malaise.

Figure 13

Potential therapies that could be beneficial in the treatment of ME/CFS (, , , , , , , –580). Created with Biorender.com. IgG, immunoglobulin G; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NK, natural killer; NO, nitric oxide; PPAR, peroxisome proliferator-activated receptor; TLR3, toll-like receptor 3; VDR, vitamin D receptor.