Summary of recent significant findings in M.E.

/cfs research – updated February 2019

Immune System & Cytokine studies.

Author(s) Title Journal & Link Description of findings

Mehalick et al Longitudinal associations of Fatigue Results indicated that higher proportions of naïve T cells and lower
lymphocyte subsets with clinical proportions of Natural Killer cells were associated with worse physical
2018 outcomes in Chronic Fatigue https://www.ncbi.nlm.nih.go functioning and vice versa.
Syndrome. v/pmc/articles/PMC6089525
Loebel et. al. Deficient EBV-Specific B- and T-Cell Plos One Taken together, these findings give evidence for a deficient Epstein
2013 Response in Patients Barr Virus-specific B and T-cell memory response in CFS patients and
Carmen with Chronic Fatigue Syndrome http://tinyurl.com/okexay9 suggest an impaired ability to control early steps of EBV reactivation.
Scheibenbogen
Elfaitouri A, et. al. Epitopes of microbial and human heat Plos One Levels of antibodies to specific parts of HSP60 were relatively high,
2013 shock protein 60 and their recognition both in ME/CFS patients and in control samples. However, significant
in myalgic encephalomyelitis http://www.ncbi.nlm.nih.gov levels of antibodies to Chlamydia pneumoniae-derived HSP60 were
/pmc/articles/PMC3842916/ present in around a quarter (24.6%) of ME/CFS patients – a far higher
Lead investigator: proportion than in the patients with other illnesses (0.003%).
Jonas Blomberg http://tinyurl.com/kmmdyq2
Horning et. al. Distinct plasma immune signatures in Science Advances This is the first study to demonstrate altered plasma immune
2015 ME/CFS are present early in the http://advances.sciencemag. signatures early in the course of ME/CFS that are not present in
course of illness. org/content/1/1/e1400121 subjects with longer duration of illness. Analyses based on disease
duration revealed that early ME/CFS cases had a prominent activation
of both pro- and anti-inflammatory cytokines as well as dissociation of
Author comment: intercytokine regulatory networks. We found a stronger correlation of
http://cii.columbia.edu/blog. cytokine alterations with illness duration than with measures of illness
aspx?cid=yEsoKU severity, suggesting that the immunopathology of ME/CFS is not static.
Huth et. al. Characterization of Natural Killer Cell Clinical & Cellular The data suggests that a combination of impairments in CD56dimCD56+
2014 Phenotypes in Chronic Fatigue Immunology NK cells from CFS/ME patients may contribute to reduced cytotoxic
Sonya Marshall- Syndrome/Myalgic Encephalomyelitis activity of this phenotype.
Gradisnik http://tinyurl.com/kaelzrx
Curriu et. al. Screening NK-, B- and T-cell Journal of Translational Findings suggest that alterations in T-cell phenotype and proliferative
2014 phenotype and function in patients Medicine. response along with the specific signature of NK cell phenotype may be
suffering from Chronic Fatigue useful to identify CFS individuals. The striking down modulation of T
Julia Blanco Syndrome http://www.ncbi.nlm.nih.gov cell mediated immunity may help to understand inter-current viral
/pmc/articles/PMC3614537/ infections in CFS.
Page 1 of 21
Author(s) Title
Bradley et. al. Altered functional B cell subset
populations in patients with chronic
2013 fatigue syndrome compared to
healthy controls
Lead Investigator:
Amolak Bansal
Brenu et. al. The Role of Adaptive and Innate
Immune Cells in Chronic Fatigue
2014 Syndrome/ Myalgic Encephalomyelitis
Hardcastle et. al. Analysis of the Relationship between
Immune Dysfunction and Symptom
2014 Severity in Patients with Chronic
Fatigue Syndrome/Myalgic
Encephalomyelitis (CFS/ME)
Huth et. al. ERK1/2, MEK1/2 and p38 downstream
signalling molecules impaired in CD56
2016 dim CD16+ and CD56 bright CD16
dim/− natural killer cells in ME/cfs
Hornig et al. Cytokine network analysis of
cerebrospinal fluid in M.E./cfs
2015
Wong et al. A Comparison of Cytokine Profiles of
Chronic Fatigue Syndrome/Myalgic
2015 Encephalomyelitis and Multiple
Sclerosis Patients
Mensah et al CD24 Expression and B Cell
Maturation Shows a Novel link with
2018 Energy Metabolism: Potential
Implications for Patients with ME/cfs
Journal & Link
Clinical & Experimental
Immunology.
http://tinyurl.com/q3njllt
International Immunology.
http://tinyurl.com/kxblzpf
Journal of Clinical & Cellular
Immunology
http://tinyurl.com/la862or
Journal of Translational
Medicine.
http://bit.ly/1T4o15r
Nature:
Molecular Psychiatry
http://bit.ly/1T69ZwN
International Journal of
Clinical Medicine
http://bit.ly/27dYi0u
Frontiers in Immunology
http://bit.ly/2GTxJIL
Page 2 of 21
Description of findings
CFS patients had greater numbers of naive B cells as a percentage of
lymphocytes: 6·3 versus 3·9% in HC (P = 0·034), greater numbers of
naive B cells as a percentage of B cells: 65 versus 47% in controls (P =
0·003), greater numbers of transitional B cells: 1·8 versus 0·8% in
controls (P = 0·025) and reduced numbers of plasmablasts: 0·5 versus
0·9% in controls (P = 0·013). While the cause of these changes is
unclear, we speculate whether they may suggest a subtle tendency
to autoimmunity.
Alterations in B cells, Tregs, NK cells and neutrophils suggest significant
impairments in immune regulation in CFS/ME and these may have
similarities to a number of autoimmune disorders.
This study is the first to determine alterations in NK, iNKT, B, DC and γδ
T cell phenotypes in both moderate and severe CFS/ME patients.
Immunological alterations are present in innate and adaptive immune
cells and sometimes, immune deregulation appears worse in CFS/ME
patients with more severe symptoms.
This is the first study to report significant differences in MAPK
intracellular signalling molecules in CD56 dim CD16+ and CD56 bright
CD16dim/− Natural Killer cells from CFS/ME patients. In CFS/ME
patients, dysfunctional MAPK signalling may contribute to reduced
Natural Killer cell cytotoxic activity.
The results indicate a markedly disturbed immune signature in the
cerebrospinal fluid of M.E./cfs patients that is consistent with immune
activation in the central nervous system, and a shift toward an allergic
or T helper type-2 pattern associated with autoimmunity.
Simmaron Research explanation of findings: http://bit.ly/24OgpeH
ME/cfs and MS patients both displayed abnormal cytokine levels, with
dual expression of Th1 and Th2 cytokines.
If-γ, IL-10 and IL-5 were significantly higher in the serum of both ME/cfs
and MS patients compared to the healthy controls.
In vitro findings confirmed dysregulation of CD24-expressing B cells
from ME/CFS patients previously suggested by immunophenotype
studies of B cells from peripheral blood. CD24-negative B cells
underwent productive proliferation whereas CD24+ B cells were either
unresponsive or susceptible to cell death upon BCR-engagement alone.
Author(s) Title Journal & Link Description of findings
Loebel et al. Antibodies to ß adrenergic and Brain, Behavior, and There is evidence for elevated autoantibodies against β2 AdR and M
muscarinic cholinergic receptors in Immunity (Feb 2016) AChR in a subset of patients with CFS. Although the function of these
2016 patients with CFS antibodies in CFS at present is unclear, the association of β2 AdR and M
http://bit.ly/1OX5upm AChR antibodies with immune activation markers and their decline in
Lead Investigator: CFS patients responding to B-cell depletion may support a pathogenic
Carmen role and warrants their testing as potential biomarkers in clinical trials
Scheibenbogen of B-cell/antibody depleting therapy.
Cabanas et al Loss of Transient Receptor Potential Molecular Medicine TRPM3 activity is impaired in CFS/ME patients suggesting changes in
Melastatin 3 ion channel function in intracellular Ca2+ concentration, which may impact NK cellular
2018 natural killer cells from Chronic https://www.ncbi.nlm.nih.go functions. This investigation further helps to understand the
Lead Investigator: Fatigue Syndrome/Myalgic v/pmc/articles/PMC6092868 intracellular-mediated roles in NK cells and confirm the potential role
Sonya Marshall- Encephalomyelitis patients. of TRPM3 ion channels in the aetiology and pathomechanism of
Gradisnik CFS/ME.
Nguyen et al. Impaired calcium mobilization in NK Clinical and Experimental This study showed that TRPM3 activity and function in NK cells in
cells from ME/cfs patients is Immunology CFS/ME patients is impaired, resulting in changes in Ca2+ ion
2017 associated with transient receptor concentration in the cytosol and intracellular stores which may, in turn,
potential melastatin 3 ion channels. http://onlinelibrary.wiley.co change the NK cells' activation threshold. Cytotoxic NK cells from
Sonya Marshall – m/doi/10.1111/cei.12882/fu CFS/ME patients may attempt to compensate for impaired TRPM3
Gradisnik ll receptors by increasing intracellular Ca2+ for sufficient NK cell activity.
& Increasing Ca2+ concentrations to activate the ERK signalling pathway
Don Staines may help to improve NK cell cytotoxicity in CFS/ME. Improvement of
Ca2+-dependent NK activity may help to improve the immune system
in CFS/ME patients to facilitate a quicker response to eliminate
pathogens. Moreover, improvement of cell-to-cell interaction could
improve the development of antigen-specific memory cells. This
investigation may inform the pathomechanism of reduced NK cell
cytotoxicity in CFS/ME patients.
Chacko et al Dysregulation of Protein Kinase Gene Libertas Academica: This study found that in severe CFS/ME patients, dysfunction in protein
Expression in NK Cells from Chronic Gene Regulation & Systems kinase genes may contribute to impairments in NK cell intracellular
2016 Fatigue Syndrome/Myalgic Biology signaling and effector function. Similar changes in protein kinase genes
Encephalomyelitis Patients. may be present in other cells, potentially contributing to the
http://bit.ly/2qNGqZO pathomechanism of this illness.

Page 3 of 21
Author(s) Title Journal & Link Description of findings
Lunde et al. Serum BAFF and APRIL Levels, T- PLOS One This was a study of patients who had undergone B Cell depletion
Lymphocyte Subsets, and therapy using Rituximab. Although no functional assays were
2016 Immunoglobulins after B-Cell http://bit.ly/2pQLld8 performed, the lack of significant associations of T- and NK-cell subset
Depletion Using the Monoclonal Anti- numbers with B-cell depletion, as well as the lack of associations to
Oystein Fluge & CD20 Antibody Rituximab in ME/cfs clinical responses, suggest that B-cell regulatory effects on T-cell or NK-
Olav Mella cell subsets are not the main mechanisms for the observed
improvements in ME/CFS symptoms observed in the two previous
trials. The modest increase in serum BAFF levels at baseline may
indicate an activated B-lymphocyte system in a subgroup of ME/CFS
patients.
Carmen Immunoadsorption to remove ß2 PLOS One This pilot trial shows that ImmunoAdsorption can remove
Scheibenbogen adrenergic receptor antibodies in autoantibodies against ß2 adrenergic receptor and lead to clinical
Chronic Fatigue Syndrome CFS/ME. http://bit.ly/2IrDVFl improvement. B cell phenotyping provides evidence for an effect of IA
2018 on memory B cell development.
Mady Hornig et al Immune network analysis of Nature: Network analysis revealed an absence of inverse inter-cytokine
cerebrospinal fluid in myalgic Translational Psychiatry relationships in CSF from atypical patients, and more sparse positive
2017 encephalomyelitis/chronic fatigue intercorrelations, than classical subjects. Interleukin 1 receptor
syndrome with atypical and classical http://www.nature.com/tp/j antagonist appeared to be a negative regulator in classical ME/CFS,
presentations ournal/v7/n4/full/tp201744a with patterns suggestive of disturbances in interleukin 1 signaling and
Ian Lipkin .html autoimmunity-type patterns of immune activation. Immune signatures
in the central nervous system of ME/CFS patients with atypical features
may be distinct from those with more typical clinical presentations.
Mensah et al. Extended B cell phenotype in patients Clinical & Experimental The study identified possible changes in B cell phenotype in patients
with myalgic encephalomyelitis / Immunology with ME/CFS.
2015 chronic fatigue syndrome: a cross- These may reflect altered B cell function and, if confirmed in other
sectional study. http://onlinelibrary.wiley.co patient cohorts, could provide a platform for studies based on clinical
m/doi/10.1111/cei.12749/p course or responsiveness to rituximab therapy.
Jo Cambridge df Contrary to earlier findings, (see Bradley et al (2013) above) the
researchers found no difference in percentages of classical subsets
between ME/CFS patients and Healthy Controls.
Moneghetti et al. Value of Circulating Cytokine Profiling Nature – Scientific Reports Cytokine profiling following exercise may help differentiate patients
During Submaximal Exercise Testing in with ME/CFS from sedentary controls. The most discriminatory
2018 Myalgic Encephalomyelitis/ CFS https://go.nature.com/2IshV cytokines post exercise were found to be CD40L, platelet activator
u2 inhibitor, interleukin 1-β, interferon-α and CXCL1.

Page 4 of 21
 Muscular & Exercise studies.

Author(s) Title Journal & Link Description

Brown et. al. Abnormalities of AMPK Activation and
2015 Glucose Uptake in Cultured Skeletal
Lead Investigator: Muscle Cells from Individuals with
Julia Newton Chronic Fatigue Syndrome
Keller et. al. Inability of myalgic encephalomyelitis
/chronic fatigue syndrome patients to
2014 reproduce VO2 peak indicates
functional impairment
Jones et. al. Loss of capacity to recover from
acidosis on repeat exercise in chronic
2011 fatigue syndrome: a case–control
study
Arroll et. al. The delayed fatigue effect in myalgic
encephalomyelitis/chronic fatigue
2014 syndrome (ME/CFS)
Twisk & Geraghty Deviant Cellular and Physiological
Responses to Exercise in M.E./ cfs
2015
Rutherford at al Understanding Muscle Dysfunction in
Chronic Fatigue Syndrome
2016
Plos One Overall, the evidence from this important study points to an exercise-
http://tinyurl.com/poqbecu related primary abnormality in the muscle tissues of ME/CFS patients
which, because it was observed in cultured isolated muscle cells, (and
For a detailed explanation: therefore not subject to external influencing factors, such as emotional
http://bit.ly/1Gq2Nbf stress or clinical depression) may well have a genetic or epigenetic
basis.
Journal of Translational ME/CFS patients exhibited significant post-exertional declines in VO2,
Medicine work, minute ventilation and O2 pulse at both maximal and ventilatory
threshold intensities. Consequently, classification of functional
http://www.ncbi.nlm.nih.gov impairment based on VO2peak and VO2 at ventilatory threshold over-
/pmc/articles/PMC4004422/ estimated the functional ability of 50% of ME/CFS in this sample when
based on only one CPET.
European Journal of Clinical When exercising to comparable levels to normal controls, CFS patients
Investigation. exhibit profound abnormality in bioenergetic function and response to
it.
http://tinyurl.com/p2vomfn
Fatigue: Biomedicine, Health These findings are suggestive of post-exertional symptom
& Behaviour exacerbation following mental effort. This may have implications for
http://tinyurl.com/nhn5vnk working environments that present cognitive demands to individuals
with ME/CFS.
Jacobs Journal of Physiology This article reviews observations which support the position that post-
exertional “malaise” in ME/CFS may be linked to a number of
http://bit.ly/1kDXkq7 observable deviant physiological responses to exercise, including
muscle weakness and myalgia, a substantial fall of oxygen uptake after
exercise, an increase in metabolite-detecting (pain) receptors,
increased acidosis, abnormal immune responses, and orthostatic
intolerance.
Journal of Aging Research There is increasing evidence to suggest that muscular biochemical
abnormality may play a major role in CFS/ME associated fatigue. The
http://bit.ly/22UyR4C literature suggests patients exhibit profound intramuscular dysfunction
regarding acid generation and clearance, with a tendency towards an
over-utilisation of the lactate dehydrogenase pathway following
relatively low-level activity.

Page 5 of 21
 Mitochondrial Dysfunction Studies:
Author(s) Title
Morris & Maes Mitochondrial dysfunctions in Myalgic
Encephalomyelitis / chronic fatigue
2014 syndrome explained by activated
immuno-inflammatory, oxidative and
nitrosative stress pathways
Myhill et al. Chronic fatigue syndrome and
mitochondrial dysfunction
2009
Booth et al. Mitochondrial dysfunction and the
pathophysiology of
Myalgic Encephalomyelitis/Chronic
2012 Fatigue Syndrome (ME/CFS)
Frank Comhaire Treating patients suffering ME/CFS
with sodium dichloroacetate: An
2018 open-label, proof-of-principle pilot
trial.
Journal & Link
Metabolic Brain Disease
http://bit.ly/1TQDmVY
International Journal of
Clinical Experimental
Medicine.
http://www.ijcem.com/files/
IJCEM812001.pdf
International Journal of
Clinical Experimental
Medicine.
http://www.ijcem.com/files/
IJCEM1204005.pdf
http://bit.ly/1XlwjaW
Medical Hypotheses
http://www.medical-
hypotheses.com/article/S03
06-9877(18)30105-1/fulltext
Page 6 of 21
Description of findings
Evidence suggests that immuno-inflammatory and Oxidative & Nitrosative
pathways may play a role in the mitochondrial dysfunctions and consequently
the bio-energetic abnormalities seen in patients with ME/cfs. Defects in ATP
production and the electron transport complex, in turn, are associated with an
elevated production of superoxide and hydrogen peroxide in mitochondria
creating adaptive and synergistic damage. It is argued that mitochondrial
dysfunctions, e.g. lowered ATP production, may play a role in the onset of
ME/cfs symptoms, e.g. fatigue and post exertional malaise, and may explain in
part the central metabolic abnormalities observed in ME/cfs, e.g. glucose
hypo-metabolism and cerebral hypo-perfusion.
The power and usefulness of the “ATP profile” test in confirming and pin-
pointing biochemical dysfunctions in people with CFS is discussed.
Observations strongly implicate mitochondrial dysfunction as the immediate
cause of CFS symptoms. However, it isn’t yet clear whether the damage to
mitochondrial function is a primary effect, or a secondary effect to one or
more of a number of primary conditions, for example cellular hypoxia [30], or
oxidative stress including excessive peroxynitrite
Measurements of Cell-free DNA show that ME/CFS patients have abnormally
high levels of damaged and necrotic cells and that there is strong correlation
with the measured mitochondrial dysfunction. The ATP Profile is an objective
test of ME/CFS and clearly shows that this illness has a physical basis.
Individually and collectively the biomedical quantities select patients whose
symptoms are the direct result of mitochondrial dysfunction. These quantities
also reflect the severity of the illness and, together with one or more
additional tests such as Cell-free DNA they demonstrate that it is not just
neutrophils that are dysfunctional but also other biological systems.
These preliminary findings sustain the hypothetical role of mitochondrial
hypo-metabolism due to inhibition of the activity of the pyruvate
dehydrogenase in the pathogenesis of primary ME/CFS, and suggest a possible
benefit of nutriceutical treatment by sodium dichloroacetate.
 Metabolomics Studies: See Cort Johnson’s explanatory article (Nov 2016) here: http://bit.ly/2qCgeEJ
Author(s) Title Journal & Link Description of findings
Armstrong et al. Metabolic profiling reveals anomalous Metabolomics The analysis reveals an inhibited glycolysis pathway exists in ME/CFS
energy metabolism and oxidative patients along with an oxidative stress pathway and a reduced level of
2015 stress pathways in chronic fatigue http://bit.ly/2bfgh1w amino acids. The researchers highlight the possible role this plays in
syndrome patients ME/CFS patients and it supports the current literature that proposes a
chronic immune activation and oxidative stress phenotype exists in
ME/CFS patients.
Naviaux et al Metabolic features of chronic fatigue PNAS This very important study showed that CFS has a chemical signature
syndrome. that can be identified using targeted plasma metabolomics.
2016 http://www.pnas.org/conten Receiver operator characteristic (ROC) curve analysis showed a
t/113/37/E5472.full diagnostic accuracy that exceeded 90%. The pattern and directionality
of these changes showed that CFS is a conserved, hypometabolic
Reply to comments by Vogt response to environmental stress similar to dauer (35).
et al in PNAS: Only about 25% of the metabolite disturbances found in each person
were needed for the diagnosis of CFS. About 75% of the metabolite
http://www.pnas.org/conten abnormalities were unique to the individual and useful in guiding
t/113/46/E7142.full personalized treatment.
Fluge & Mella et al Metabolic profiling indicates impaired JCI Insight The investigators hypothesized that changes in serum amino
pyruvate dehydrogenase function acids may disclose specific defects in energy metabolism in ME/CFS.
2016 in myalgic encephalopathy/chronic http://insight.jci.org/articles Analysis in 200 ME/CFS patients and 102 healthy individuals showed a
fatigue syndrome /view/89376# specific reduction of amino acids that fuel oxidative metabolism via the
TCA cycle, mainly in female ME/CFS patients. The amino acid pattern
suggested functional impairment of pyruvate dehydrogenase (PDH),
supported by increased mRNA expression of the inhibitory PDH kinases
1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells
from both sexes. Myoblasts grown in presence of serum from patients
with severe ME/CFS showed metabolic adaptations, including
increased mitochondrial respiration and excessive lactate secretion.
Nagy-Szakal et al Insights into Myalgic Nature: Scientific Reports This study (of 562 metabolites), found alterations in metabolites
Encephalomyelitis /chronic fatigue associated with mitochondrial energy metabolism. This is consistent
2018 syndrome phenotypes through https://www.nature.com/art with earlier reports that suggest metabolites linked to lipid and energy
comprehensive metabolomics icles/s41598-018-28477-9 metabolism are affected in ME/CFS. They extend earlier work, by
Ian Lipkin & Mady demonstrating that ME/CFS subjects with IBS co-morbidity have a
Hornig distinct metabolomic profile compared to subjects without IBS and
controls.
Page 7 of 21
 Brain & Neurological studies.
Author(s) Title
Barnden et. al. Evidence in chronic fatigue syndrome
for severity-dependent up-regulation
2015 of prefrontal myelination that is
independent of anxiety and
depression
Puri et. al. Regional grey and white matter
volumetric changes in myalgic
2014 encephalomyelitis (chronic fatigue
syndrome): a voxel-based
morphometry 3-T MRI study.
Nakatomi et. al. Neuroinflammation in Patients with
Chronic Fatigue Syndrome / Myalgic
2014 Encephalomyelitis: An 11C-(R)-
PK11195 PET Study
Kimura et. al. Brain abnormalities in Myalgic
Encephalomyelitis /chronic fatigue
2018 syndrome: Evaluation by diffusional
kurtosis imaging and neurite
orientation dispersion and density
imaging.
Shan et al. Progressive brain changes in patients
with chronic fatigue syndrome: A
2016 longitudinal MRI study
Barnden et. al. Autonomic correlations with MRI are
abnormal in the brainstem vasomotor
2016 centre in Chronic Fatigue Syndrome
Journal & Link
NMR in Biomedicine
http://tinyurl.com/lvt2l33
British Journal of Radiology.
http://www.birpublications.
org/doi/full/10.1259/bjr/938
89091
Journal of Nuclear Medicine
http://tinyurl.com/p8druw7
Journal of Magnetic
Resonance Imaging
https://onlinelibrary.wiley.co
m/doi/abs/10.1002/jmri.262
47
Journal of Magnetic
Resonance Imaging
http://bit.ly/1TkVJQa
NeuroImage: Clinical
http://bit.ly/1OhZk5p
Page 8 of 21
Description of findings
The severity-dependent elevation of myelination in the internal
capsule and prefrontal White Matter reported here, together with
midbrain volume loss and midbrain neuroinflammation in CFS reported
elsewhere (4,5), suggest that these midbrain changes are associated
with impaired midbrain nerve conduction. Impaired brain–body and
brain–brain communication through the midbrain could explain many
of the autonomic and cognitive symptoms of CFS.
These data support the hypothesis that significant neuroanatomical
changes occur in CFS, and are consistent with the complaint of
impaired memory that is common in this illness; they also suggest that
subtle abnormalities in visual processing, and discrepancies between
intended actions and consequent movements, may occur in CFS.
http://tinyurl.com/mov8n2x
Neuroinflammation was shown to be present in widespread brain
areas in CFS/ME patients and was associated with the severity of
neuropsychologic symptoms. Evaluation of neuroinflammation in
CFS/ME patients may be essential for understanding the core
pathophysiology and for developing objective diagnostic criteria and
effective medical treatments.
The study observed Right Superior Longitudinal Fasciculus (SLF)
abnormalities which may be a diagnostic marker for ME/CFS
The results suggested that CFS is associated with left inferior fronto-
occipital fasciculus (IFOF) White Matter deficits which continue to
deteriorate at an abnormal rate.
Vasomotor centre, midbrain and hypothalamus correlations were
abnormal in CFS. MRI group comparisons between CFS and controls
detected no differences. Regulatory nuclei and peripheral
effectors/sensors appear to function correctly. Signalling between
brainstem/midbrain regulatory nuclei appears to be impaired.
Author(s) Title Journal & Link Description of findings
Nguyen et al. Reduced glycolytic reserve in isolated Asian Pacific Journal of These findings suggest resting Natural Killer (NK) cells from ME/CFS patients
2018 natural killer cells from Myalgic Allergy and Immunology have reduced ability to increase glycolytic flux to respond to high energetic
encephalomyelitis/chronic fatigue demands for ATP production.
Sonya Marshall G & syndrome patients: A preliminary https://www.ncbi.nlm.nih.go
Don Staines investigation. v/pubmed/29981562
Dane Cook et al. Neural Consequences of Post-Exertion Brain, Behaviour & Immunity The objective of this study was to determine the neural consequences
Malaise in Myalgic Encephalomyelitis / of acute exercise using functional brain imaging.
2017 Chronic Fatigue Syndrome http://bit.ly/2ls1kvW Changes in brain activity were found to be significantly related to
symptoms for patients (p < 0.05). Acute exercise exacerbated
Alan & Kathy Light symptoms, impaired cognitive performance and affected brain function
in ME/cfs patients. These converging results, linking symptom
exacerbation with brain function, provide objective evidence of the
detrimental neurophysiological effects of post-exertion malaise.
Nakatomi et al Neuroinflammation in the Brain of Brain Nerve This study provides the first demonstration of cerebral
Patients with Myalgic (In Japanese- translates neuroinflammation in patients with ME / CFS by positron emission
2018 Encephalomyelitis / Chronic fatigue automatically with Google Chrome) tomography (PET). Neuroinflammation is shown to be present in a
Syndrome. wide range of brain regions of patients and has been associated with
http://bit.ly/2GRZ0f2 the severity of neuropsychological symptoms.
Finkelmeyer et al Grey and white matter differences in NeuroImage: Clinical Elevated GM volume in CFS is seen in areas related to processing of
Chronic Fatigue Syndrome – A voxel- interoceptive signals and stress. Reduced WM volume in the patient
2017 based morphometry study http://bit.ly/2IpdAHW group partially supports earlier findings of WM abnormalities in regions
of the midbrain and brainstem.
Shan et al Brain function characteristics of NeuroImage: Clinical Highlights
chronic fatigue syndrome: A task fMRI CFS patients recruit larger BOLD activation areas for the Stroop task.
2018 study https://www.sciencedirect.c BOLD signal complexities in CFS are lower in ten activated regions.
om/science/article/pii/S2213 The BOLD signal complexity is correlated with the SF-36 health score
Leighton Barnden + 158218301347 across all subjects.
Sonya Marshall G & The BOLD signal complexity explains more than 40% of variance in the
Don Staines health score across all subjects.
Evidence of widespread metabolite Brain Imaging and Behavior Magnetic Resonance Spectroscopy (MRS) is suitable for measuring
abnormalities in Myalgic brain metabolites linked to inflammation, but has only been applied to
2018 encephalomyelitis/chronic fatigue https://link.springer.com/art discrete regions of interest in ME/CFS. MRS analysis of ME/CFSwas
Jarred Younger syndrome: assessment with whole- icle/10.1007%2Fs11682-018- accomplished by capturing multi-voxel information across the entire
brain magnetic resonance 0029-4 brain.
spectroscopy. The findings may indicate that ME/CFS involves neuroinflammation.

Page 9 of 21
 Cardio-vascular studies.
Author(s) Title
Kunihisa Miwa Down-regulation of renin–aldosterone
and antidiuretic hormone systems in
2016 patients with ME/cfs
Reduced cardiac volumes in chronic
Julia Newton et al. fatigue syndrome associate with
plasma volume but not length of
2016 disease: a cohort study
Witham et. al. Association between vitamin D status
2014 and markers of vascular health in
Lead Investigator: patients with chronic fatigue
Faisal Khan syndrome/myalgic encephalomyelitis.
Baumont et. al. Reduced Cardiac Vagal Modulation
Impacts on Cognitive Performance in
2012 Chronic Fatigue Syndrome
Newton D et. al. Large and small artery endothelial
dysfunction in chronic fatigue
2011 syndrome.
Hollingsworth et al. Impaired cardiac function in chronic
fatigue syndrome measured using
2012 magnetic resonance cardiac tagging.
Journal & Link
Journal of Cardiology
http://bit.ly/2b6Bj0p
Open Heart
http://openheart.bmj.com/c
ontent/3/1/e000381.full
http://bit.ly/29ISg0I
Intl. Journal of Cardiology
http://tinyurl.com/le44d7f
Plos One
http://tinyurl.com/mf97jzk
International Journal of
Cardiology
http://tinyurl.com/pc5e2d7
Journal of Internal Medicine
http://bit.ly/1rGvYnf
Page 10 of 21
Description
Both the renin–aldosterone and ADH systems were down-regulated
despite the existence of reduction in cardiac preload and output in
patients with ME. The echocardiographic examination revealed that
the mean values for the left ventricular end-diastolic diameters, stroke
volume index, and cardiac index as well as the mean blood pressure
were all significantly smaller in the ME group than in the Controls.
This study confirms an association between reduced cardiac volumes
and blood volume in CFS. Lack of relationship between length of
disease, cardiac and plasma volumes suggests findings are not
secondary to deconditioning. The relationship between plasma volume
and severity of fatigue symptoms suggests a potential therapeutic
target in CFS.
There were significant correlations between 25(OH)D levels and
markers of inflammation, oxidative stress, endothelial function and
arterial stiffness.
http://tinyurl.com/qxgwa6x
A role for heart rate variability (HRV) in cognitive flexibility has been
demonstrated in healthy individuals, but this relationship has not as yet
been examined in CFS. These findings reveal for the first time an
association between reduced cardiac vagal tone and cognitive
impairment in CFS and confirm previous reports of diminished vagal
activity.
These findings provide direct evidence of endothelial dysfunction in
both the large and small vessels of patients with ME/CFS, which may
warrant a large prospective trial of cardiovascular outcomes in the
disease. This evidence collectively points to increased cardiovascular
risk in ME/CFS patients, which is borne out epidemiologically by
their high mortality due to heart disease
Patients with CFS have markedly reduced cardiac mass and blood pool
volumes, particularly end-diastolic volume: this results in significant
impairments in stroke volume and cardiac output compared to
controls. The CFS group appeared to have a delay in the release of
torsion.
Author(s) Title Journal & Link Description
Naschitz et al. Shortened QT interval: a distinctive Journal of Electrocardiology The average supine & tilted QTc intervals in CFS were significantly
feature of the dysautonomia of shorter than in healthy controls. Relatively short QTc intervals are
2006 chronic fatigue syndrome. http://bit.ly/1NqJWDy features of the CFS-related dysautonomia.
Tomas et al Elevated brain natriuretic peptide Open Heart This study confirms an association between reduced cardiac volumes
levels in chronic fatigue syndrome and BNP in CFS. Lack of relationship between length of disease
2017 associate with cardiac dysfunction: a http://openheart.bmj.com/c suggests that findings are not secondary to deconditioning. Further
case control study. ontent/4/2/e000697 studies are needed to explore the utility of BNP to act as a stratification
Julia Newton paradigm in CFS that directs targeted treatments.
Saha et al. Red blood cell deformability is Clinical Hemorheology and Since red blood cells (RBCs) are well-known scavengers of oxidative
diminished in patients with Chronic Microcirculation stress, and are critical in microvascular perfusion and tissue
Dec 2018 Fatigue Syndrome. oxygenation, the authors hypothesized that Red Blood Cell (RBC)
https://content.iospress.com deformability is adversely affected in ME/CFS.
Lead author: /articles/clinical- They observed from various measures of deformability that the RBCs
Prof. Ron Davis hemorheology-and- isolated from ME/CFS patients were significantly stiffer than those
microcirculation/ch180469 from healthy controls. Our observations suggest that RBC transport
through microcapillaries may explain, at least in part, the ME/CFS
phenotype, and promises to be a novel first-pass diagnostic test.
Stevens et al Cardiopulmonary Exercise Test Frontiers in Pediatrics Basic concepts of CPET are summarized, and special considerations for
Methodology for Assessing Exertion performing CPET on ME/CFS patients are detailed to ensure a valid
2018 Intolerance in Myalgic https://www.frontiersin.org/ outcome. The 2-day CPET methodology is outlined, and the utility of
Encephalomyelitis / Chronic Fatigue articles/10.3389/fped.2018.0 the procedure is discussed for assessment of functional capacity and
Syndrome. 0242/full exertion intolerance in ME/CFS.

Page 11 of 21
 Genetics & Single Nucleotide Polymorphism (genetic mutation) studies.
Author(s) Title Journal & Link Description
Shimosako N, Use of single-nucleotide Journal of Clinical Pathology
The headline result was that 21 SNP alleles had significantly different
Kerr JR polymorphisms (SNPs) to distinguish http://tinyurl.com/pqmrysd ‘frequency distributions’ in ME/CFS patients than in depression control
2014 gene expression subtypes of chronic or healthy control subjects – seven of these SNPs were within the
fatigue syndrome/myalgic http://www.ncbi.nlm.nih.gov BMP2K gene and two were within the IL6ST gene.
encephalomyelitis /pubmed/25240059 http://tinyurl.com/k3d88tt
Sonya Marshall- Natural killer cells and single The Application of Clinical Detected a number of Single Nucleotide Polymorphisms and genotypes
Gradisnik nucleotide polymorphisms of specific Genetics - Dove Press for Transient Receptor Potential ion channels and Acetylcholine
ion channels and receptor genes in Receptors from isolated Natural Killer cells in patients with ME/CFS,
2016 M.E/cfs suggesting these SNPs and genotypes may be involved in changes in NK
http://bit.ly/1NquqaO cell function and the development of ME/CFS pathology. These
anomalies suggest a role for dysregulation of Ca2+ in AChR and TRP ion
channel signaling in the pathomechanism of ME/CFS.
Billing-Ross et. al. Mitochondrial DNA variants correlate Journal of Translational Analysis of mitochondrial genomes in ME/CFS cases indicates that
with symptoms in M.E./cfs Medicine. individuals of a certain haplogroup or carrying specific SNPs are more
2016 http://bit.ly/1TzZd1l likely to exhibit certain neurological, inflammatory, and/or gastro -
intestinal symptoms. No increase in susceptibility to ME/CFS of
Layman’s explanation: individuals carrying particular mitochondrial genomes or SNPs was
http://bit.ly/1sdqe4O observed.
Unger et al. Telomere Length Analysis in Chronic FASEB Journal These results indicate that CFS should be included in the list of
Fatigue Syndrome conditions associated with telomere shortening. Consequently, people
2016 http://bit.ly/1rVNALx with this illness are likely to have a reduced life-expectancy.
M.E. Research U.K. explanation: http://bit.ly/24oZVpQ
Herrera et al Genome-epigenome interactions Epigenetics The authors found significant associations of DNA methylation states in
associated with Myalgic T-lymphocytes at several CpG loci and regions with ME/CFS phenotype.
2018 Encephalomyelitis/Chronic Fatigue http://bit.ly/2trYiwB These methylation anomalies are in close proximity to genes involved
Syndrome with immune function and cellular metabolism. Also, significant
correlations of genotypes with methylation modifications associated
with ME/CFS were discovered. The findings from this study highlight
the role of epigenetic and genetic interactions in complex diseases, and
suggest several genetic and epigenetic elements potentially involved in
the mechanisms of disease in ME/CFS.

Page 12 of 21
Author(s) Title Journal & Link Description
De Vega et al. Integration of DNA methylation & Epigenonics The authors discovered four ME/CFS subtypes associated with DNA
health scores identifies subtypes in methylation modifications in 1939 CpG sites, three RAND-36 categories
2018 myalgic encephalomyelitis/chronic http://bit.ly/2trZr7b and 5 DePaul Symptom Questionnaire measures. Methylation patterns
fatigue syndrome of immune response genes and differences in physical functioning and
Patrick McGowan post-exertional malaise differentiated the subtypes. This provides
additional evidence of the potential relevance of metabolic and
immune differences in ME/CFS with respect to specific symptoms.
De Vega et al. Epigenetic modifications and BMC Medical Genomics The results from this study indicate the existence of DNA methylation
glucocorticoid sensitivity in Myalgic modifications in cellular metabolism in ME/CFS despite a
2017 Encephalomyelitis/ http://bit.ly/2mHvfjk heterogeneous patient population, implicating these processes in
Chronic Fatigue Syndrome (ME/CFS) immune and HPA axis dysfunction in ME/ CFS. Modifications to
Patrick McGowan epigenetic loci associated with differences in glucocorticoid sensitivity
may be important as biomarkers for future clinical testing. Overall,
these findings align with recent ME/CFS work that point towards
impairment in cellular energy production in this patient population.
Yang et al. The expression signature of very long Journal of Translation The study examined the expression signature of 10 very long lncRNAs
non-coding RNA in myalgic Medicine and revealed a ME/CFS-associated very long lncRNA expression
2016 encephalomyelitis/chronic fatigue signature, which might reflect the regulatory response in ME/CFS
syndrome. http://bit.ly/2ts4xAu patients to oxidative stress, chronic viral infection and hypoxemia.
Carmen
Scheibenbogen
Mangalathu et al Association of chronic fatigue Journal of Translational This study found a significant association of ME/CFS with premature
syndrome with premature telomere Medicine telomere attrition that is largely moderated by female subjects < 45
2018 attrition years old. The results indicate that ME/CFS could be included in the list
http://bit.ly/2Im600M of conditions associated with accelerated aging.
Elizabeth Unger
Nguyen et al Associations between clinical Brain, Behavior, and This study identified 29 immune-gene sets linked to plasma
symptoms, plasma norepinephrine Immunity. norepinephrine level that could delineate CFS subgroups. Plasma
February 2019 and deregulated immune gene norepinephrine stratification revealed that lower levels of
networks in subgroups of adolescent norepinephrine were associated with higher fatigue. The data suggests
with Chronic Fatigue Syndrome. http://bit.ly/2GM69wW potential involvement of neuro-immune dysregulation and genetic
stratification in CFS.

Page 13 of 21
 Gastro-intestinal / Gut Microbiome studies.
Author(s) Title
Chia et. al. Functional Dyspepsia and Chronic
2015 Gastritis Associated with
Enteroviruses
Chia J & Chia A Chronic fatigue syndrome is
associated with chronic enterovirus
2008 infection of the stomach
De Merleir et.al. Plasmacytoid Dendritic Cells in the
Duodenum of Individuals Diagnosed
2013 with Myalgic Encephalomyelitis Are
Uniquely Immunoreactive to
Antibodies to Human Endogenous
Retroviral Proteins
Fremont et. al. Detection of Herpesviruses and
Parvovirus B19 in Gastric and
2009 Intestinal Mucosa of Chronic Fatigue
Syndrome Patients
Ludovic Giloteaux Reduced diversity and altered
composition of the gut microbiome in
2016 individuals with myalgic
encephalomyelitis/chronic fatigue
Maureen Hanson syndrome.
Nagy-Szakal et al. Fecal metagenomic profiles in
subgroups of patients with myalgic
2017 encephalomyelitis/chronic fatigue
syndrome
Mady Hornig
Journal & Link
Open Journal of
gastroenterology.
http://tinyurl.com/op5q65j
Journal of Clinical Pathology
http://jcp.bmjjournals.com/c
ontent/61/1/43.abstract
In Vivo
http://iv.iiarjournals.org/con
tent/27/2/177.full
In Vivo
http://iv.iiarjournals.org/con
tent/23/2/209.full
Microbiome
http://bit.ly/29u8Jco
Microbiome
http://bit.ly/2owJVaj
Page 14 of 21
Description
In this research by Dr. Chia on enteroviral involvement in ME/CFS, he
shows that the upset stomach, nausea, bloating and other stomach
symptoms common in ME/CFS patients as well as in healthy patients
without H. Pylori infection are due to enteroviral infection.
Enterovirus VP1, RNA and non-cytopathic viruses were detected in the
stomach biopsy specimens of CFS patients with chronic abdominal
complaints. A significant subset of CFS patients may have a chronic,
disseminated, non-cytolytic form of enteroviral infection, which could
be diagnosed by stomach biopsy.
In eight out of 12 individuals with ME, immunoreactivity to HERV
proteins was observed in duodenal biopsies. In contrast, no
immunoreactivity was detected in any of the eight controls.
Although the significance of HERVs present in the pDCs of individuals
with ME has yet to be determined, these data raise the possibility of an
involvment of pDCs and HERVs in ME pathology.
A most important finding is the higher frequency of parvovirus B19
positive biopsies in the CFS population, compared to the controls (38-
40% in CFS duodenum and stomach biopsies, versus less than 14% in
the controls). This difference suggests that parvovirus B19 may be
involved in the development and maintenance of CFS, at least for a
subset of patients.
These results indicate dysbiosis of gut microbiota in this disease and
further suggest an increased incidence of microbial translocation, (from
the gut into blood), which may play a role in inflammatory symptoms in
ME/CFS. From a diagnostic standpoint, using data obtained from the
16S rRNA gene and inflammatory markers, ME/CFS patients were
classified with an accuracy of 82.93 %.
Independent of IBS, ME/CFS is associated with dysbiosis and distinct
bacterial metabolic disturbances that may influence disease severity.
However, these findings indicate that dysbiotic features that are
uniquely ME/CFS-associated may be masked by disturbances arising
from the high prevalence of IBS co-morbidity in ME/CFS.
Author(s) Title Journal & Link Description
Wallis et al Open-label pilot for treatment Journal of Translational Results support the notion that specific microorganisms interact with
targeting gut dysbiosis in ME/cfs: Medicine some ME/CFS symptoms and offer promise for the therapeutic
2018 neuropsychological symptoms and sex potential of targeting gut dysbiosis in this population.
comparisons http://bit.ly/2Ipoc9M
Lombardi et al Failure of gut-associated pDCs to The Journal of Immunology The researchers observed that, in contrast to controls, gut-associated
express membrane bound APRIL and pDCs in subjects with ME/CFS lack expression of the binding ligands
2016 BAFF prevents their ability to promote http://bit.ly/288YeQ1 “APRIL” and “BAFF”. These data support a model of gut pathology in
low-affinity IgA expression in ME/CFS ME/CFS whereby dysregulated pDCs fail to promote the production of
Kenny De Merleir low-affinity IgA through the process of T cell independent activation of
B cells, thereby leading to bacterial overgrowth, dysbiosis, bacterial
translocation and systemic immune activation.

Human Microbiome Studies

Author(s) Title Journal & Link Description
Amy Proal & Myalgic Encephalomyelitis/Chronic See below:
Trevor Marshall Fatigue Syndrome in the Era of the Frontiers in Pediatrics
Human Microbiome: Persistent
2018 Pathogens Drive Chronic Symptoms by https://www.ncbi.nlm.nih.go
Interfering With Host Metabolism, v/pmc/articles/PMC6288442
Gene Expression, and Immunity.
Expanding research on the human microbiome now allows ME/CFS-associated pathogens to be studied as interacting members of human microbiome communities.
Humans harbor these vast ecosystems of bacteria, viruses and fungi in nearly all tissue and blood. Most well-studied inflammatory conditions are tied to dysbiosis or
imbalance of the human microbiome. While gut microbiome dysbiosis has been identified in ME/CFS, microbes and viruses outside the gut can also contribute to the
illness. Pathobionts, and their associated proteins/metabolites, often control human metabolism and gene expression in a manner that pushes the body toward a
state of illness. Intracellular pathogens, including many associated with ME/CFS, drive microbiome dysbiosis by directly interfering with human transcription,
translation, and DNA repair processes. Molecular mimicry between host and pathogen proteins/metabolites further complicates this interference. Other human
pathogens disable mitochondria or dysregulate host nervous system signaling. Antibodies and/or clonal T cells identified in patients with ME/CFS are likely activated in
response to these persistent microbiome pathogens.
Patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.
Wang et al Chronic fatigue syndrome patients PLOS One Functional analysis from inferred metagenomes showed that bacterial
have alterations in their oral genera altered in CFS patients were primarily associated with amino
2018 microbiome composition and function http://bit.ly/2GOqtOi acid and energy metabolism. These findings demonstrate that the oral
microbiome in CFS patients is different from healthy controls, and
these differences lead to shifts in functional pathways with
implications for CFS pathogenesis.
Page 15 of 21
 A potentially very important discovery concerning Epstein Barr Virus:

Harley et al Transcription factors operate across Nature: Genetics Explanatory article here:
disease loci, with EBNA2 implicated in http://simmaronresearch.com/2018/04/autoimmune-virus-
2018 autoimmunity. https://www.nature.com/art groundbreaking-ebv-finding-help-explain-mecfs/
icles/s41588-018-0102-3
EBNA-2 is EBV’s main viral transactivator; i.e. it’s a transcription factor
that turns on genes in an infected cell that help EBV to survive.
Essentially EBNA-2 allows EBV to hijack a cell’s genetics and put them
to its own use.
The study demonstrated that once EBV infects B-cells, it turns on genes
that have been identified as risk factors for a boatload of autoimmune
diseases.
It turns out that even though the virus is, so to speak, latent; i.e. it’s
not replicating – its transcription factor is still active – altering the
expression of our genes. The genes that it affects just happen to be the
same genes that increase the risk of developing lupus, multiple
sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis
(JIA), inflammatory bowel disease (IBD), celiac disease, and type 1
diabetes. Apparently decades of genetic assault from EBV’s
transcription factor can set the stage or at least contribute to many
autoimmune diseases.

Page 16 of 21
 Potential Diagnostic Biomarkers:
Author(s) Title
Xu et.al. A new approach to find biomarkers in
chronic fatigue syndrome/myalgic
2018 encephalomyelitis (CFS/ME) by single-
cell Raman micro-spectroscopy.
Sun et. al. Orosomucoid as a potential Biomarker
for the diagnosis of Chronic Fatigue
2016 Syndrome.
Singh et al Humoral Immunity Profiling of
Subjects with Myalgic
2016 Encephalomyelitis Using a Random
Vincent Lombardi Peptide Microarray Differentiates
& Kenny De Cases from Controls with High
Meirlieir Specificity and Sensitivity
Lidbury et al. Activin B is a novel biomarker for
chronic fatigue syndrome/myalgic
2017 encephalomyelitis (CFS/ME) diagnosis:
a cross sectional study.
Natelson et al Elevations of Ventricular Lactate
Levels Occur in Both Chronic Fatigue
2018 Syndrome and Fibromyalgia.
Dikoma Shungu
Germain et al. Prospective Biomarkers from Plasma
Metabolomics of Myalgic
Dec 2018 Encephalomyelitis/Chronic Fatigue
Syndrome Implicate Redox Imbalance
Lead author: in Disease Symptomatology
Maureen Hanson
Journal & Link
Analyst
https://rsc.li/2GO3HWL
CNS Neuroscience &
Therapeutics
http://bit.ly/1TzWXY0
Molecular Neurobiology
http://bit.ly/2pjAzLo
Journal of Translational
Medicine
http://bit.ly/2qNh4Lz
Fatigue : Biomedicine,
Health & Behavior
http://europepmc.org/abstr
act/MED/29308330
Metabolites
https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC6315598
Page 17 of 21
Description
The experimental results show that Raman bands associated with
phenylalanine in ρ0 cells and CFS patient PBMCs were significantly
higher than those of the wild-type model and healthy controls.
A machine learning classification model achieved an accuracy rate of
98% correctly assigning Raman spectra to either the CFS group or the
control group.
Compared with a healthy control group, Orosomucoid (ORM) levels
were dramatically elevated in blood serum in Fukuda-defined CFS
patients. See M.E. Research U.K. explanation: http://bit.ly/1KHfOC9
This study revealed a subset of 25 peptides that distinguished M.E.
cases and controls with high specificity and sensitivity. Additionally,
Basic Local Alignment Search Tool (BLAST) searches suggest
that these peptides primarily represent human self-antigens
and endogenous retroviral sequences (HERVS) and, to a minor
extent, viral and bacterial pathogens.
Elevated activin B levels together with normal activin A levels identified
patients with the diagnostic symptoms of CFS/ME, thus providing a
novel serum based test. The activins have multiple physiological roles
and capture the diverse array of symptoms experienced by CFS/ME
patients.
While patients with CFS, FM and comorbid CFS and FM can be
differentiated from healthy subjects based on measures of CFS lactate,
this neuroimaging outcome measure is not a viable biomarker for
differentiating CFS from FM or from patients in whom symptoms of the
two disorders overlap.
Analysis of 832 metabolites, covering 8 biological classes, generated
important insight into metabolic disruptions that occur in ME/CFS.
There were 14 metabolites found with differences in abundance,
suggesting broad redox imbalance in ME/CFS patients.
Enrichment analysis provided information concerning similarities
between metabolite disruptions in ME/CFS and those that occur in
other diseases, while its biomarker analysis unit yielded prospective
plasma biomarkers for ME/CFS.
 Definitions and Models of Illness causation.

Author(s) Title Journal & Link Description of findings

Ellen Wright- Beyond Myalgic Encephalomyelitis / National Academy of Science ME/CFS is a multisystem and often long-lasting disorder, with
Clayton. Chronic Fatigue Syndrome: Redefining Institute of Medicine manifestations that can cause substantial morbidity and can severely
an Illness. impair patients’ health and well-being. Patients with ME/CFS are
2015 An IOM report on redefining an illness http://bit.ly/24oZVpQ typically unable to perform their normal activities, and as many as one-
fourth are homebound or bedridden, sometimes for extended periods.
This report describes efforts to develop diagnostic criteria for clinical
use and recommend new terminology for the disorder.
Edwards et. al. The biological challenge of M.E./cfs: Fatigue: Biomedicine, HealthSee comments below:
A solvable problem & Behaviour.
2016 http://bit.ly/1QDv5A5
Suggests that three major categories of causal model appear of most interest for future M.E./cfs research:
1. The brain is responding normally and symptoms are due to persistent signal input from peripheral tissues, such as cytokines or metabolites, based on persistent
immune dysregulation (as in autoimmunity, for example, or, conceivably, low-grade infection).
2. There is a persistent abnormality of ‘housekeeping’ processes in the brain, such as an increase in activation of microglia following an initial insult, which leads to
distorted processing of peripheral signals including autonomic pathway activation.
3. There is a persistent abnormality in neural signalling in sensory pathways. This may be quantitative (comparable to dopamine depletion in Parkinson’s disease) or
qualitative (comparable to post-concussion amnesia or post-traumatic stress disorder) due to CNS structural or regulatory changes following an initial insult.
Morris et. al. The Emerging Role of Autoimmunity in Molecular neurobiology See comments below.
2013 ME/cfs http://tinyurl.com/l6sycph
Low Natural Killer Cell function is a source of disrupted homeostasis and prolonged effector T cell survival. Low ATP production and mitochondrial dysfunction is a
source of autoimmunity by inhibiting apoptotic and stimulating necrotic cell death pathways and hence decreasing immunosuppression at the termination of the
immune response and increasing inflammation. Elevated levels of pro-inflammatory and other cytokine species conspire together to impair the normal homeostatic
mechanisms which govern T and B cell activation differentiation and survival. This leads to an imbalance of regulatory and effector lymphocytes. Elevated O&NS
damage lipids and proteins leading to the formation of neo-epitopes which become immunogenic leading to the disruption of many essential cellular processes.
Elevated levels of NF-κB not only contribute to prolonged lymphocyte survival but also increase the generation of autoreactive B cells. Elevated levels of pro-
inflammatory cytokines result in elevated levels of NO and leptin. Both entities lead to disruption of homeostatic mechanisms via interaction of mTOR. Elevated levels
of NO lead to blockade of the methionine cycle and hypomethylation of DNA. Finally, increased levels of pro-inflammatory cytokines and NF-κB conspire to disrupt
epithelial tight junctions in the intestine allowing the potential translocation of bacterial LPS into the general circulation.

Page 18 of 21
Author(s) Title Journal & Link Description
Morris et. al. Myalgic encephalomyelitis or chronic Metabolic Brain Disease See comments below.
2018 fatigue syndrome: how could the
illness develop? http://bit.ly/2GRWfdf
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward,
starting with a consideration of the post-infection role of damage-associated molecular patterns (DAMP) and the development of chronic inflammatory, oxidative and
nitrosative stress in genetically predisposed individuals.

There is strong evidence of this illness being associated with a wide range of biological abnormalities, most notably in the neuroendocrine, autonomic, neurological,
bioenergetic, redox and immunological domains. It has also been seen that epigenetic variation in immune response genes plays a major role in determining the
development of DAMPs post-infection, which is pertinent from the perspective of the aetiology of the illness as the production or presence of these molecules can
‘convert’ an acute pathogenic infection into a state of escalating chronic systemic inflammation, which in turn can give rise to many of the reported symptoms and
biological abnormalities. It has further been demonstrated in this paper how this relatively simple concept does indeed lead to a novel explanatory model which
explains the major biological observations.

Page 19 of 21
 Review Articles:

Author(s) Title Journal & Link Description

Navena A Role for the Intestinal Microbiota Journal of Clinical Medicine. This article provides a comprehensive review of the current evidence
Navaneetharaja and Virome in ME/CFS? supporting an infectious aetiology for ME/CFS leading the authors to
et al. http://www.mdpi.com/2077 propose the novel concept that the intestinal microbiota and in
-0383/5/6/55 particular members of the virome are a source of the “infectious”
2016 trigger of the disease. Such an approach has the potential to identify
disease biomarkers and influence therapeutics.
Newberry et al Does the microbiome and virome Clinical Science This article provides a comprehensive review of the current evidence
contribute to myalgic supporting microbiome alterations in ME/CFS patients. Additionally,
2018 encephalomyelitis /chronic fatigue http://www.clinsci.org/conte the pitfalls and challenges associated with microbiome studies are
Simon Carding syndrome? nt/132/5/523.long discussed.
Fane Mensah et al Chronic fatigue syndrome and the Clinical Neurophysiology In this review, the authors discuss the potential of different
2017 immune system: Where are we now? components of the immune system to be involved in the pathogenesis
Jo Cambridge http://bit.ly/2pPsMGd of ME/CFS.
Santa Rasa et al Chronic viral infections in myalgic https://www.ncbi.nlm.nih.go At least in a subset of patients, the mitochondrial dysfunction and
encephalomyelitis/chronic fatigue v/pmc/articles/PMC6167797 elements of autoimmunity that characterize ME/CFS may be linked to
2018 syndrome (ME/CFS) viral pathogenesis. Lack of extensive analysis of molecular mechanisms
Carmen linking viral pathogens to ME/CFS restricts our understanding of this
Scheibenbogen disease.
Campagnolo et al. Dietary and nutrition interventions for Journal of Human Nutrition This review identified insufficient evidence for the use of nutritional
the therapeutic treatment of chronic and Dietetics supplements and elimination or modified diets to relieve CFS/ME
2017 fatigue syndrome/myalgic symptoms. Studies were limited by the number of studies investigating
Sonya Marshall encephalomyelitis: a systematic http://onlinelibrary.wiley.co the interventions, small sample sizes, study duration, variety of
Gradisnik & review m/doi/10.1111/jhn.12435/fu instruments used, and studies not reporting dietary intake method.
Don Staines ll Further research is warranted in homogeneous CFS/ME populations.
Jonas Blomberg et Infection Elicited Autoimmunity and Frontiers in Immunology A hypothetical but logical path, from gastrointestinal tract dysbiosis, to
al Myalgic Encephalomyelitis/Chronic formation of pathogenic autoimmune B cells, to inhibition of energy
Fatigue Syndrome: An Explanatory http://bit.ly/2Ipw9vH production and deficient cognition, to flares of cytokine production,
2018 Model can be delineated. The natural history indicates that in many cases
infections can elicit or worsen this autoimmunity.
Jean Monro & A Molecular Neurobiological Approach Molecular Neurobiology This article briefly discusses the history and definition of this disorder,
Basant Puri to Understanding the Aetiology of considers a wide variety of molecular neurobiological factors and then
Chronic Fatigue Syndrome with http://bit.ly/2Iptkuy describes an evidence-based approach to the treatment of
2018 Treatment Implications CFS/ME/SEID.

Page 20 of 21
Author(s) Title Journal & Link Description of findings
Noda et al Glial Activation and Expression of the Frontiers in Psychiatry This mini-review summarizes evidence for a role for microglia and
Serotonin Transporter in Chronic astrocytes in the onset and the maintenance of immunologically
2018 Fatigue Syndrome. https://www.ncbi.nlm.nih.go induced CFS. In a model using virus mimicking synthetic double-
v/pmc/articles/PMC6250825 stranded RNA, infection causes sequential signaling such as increased
blood brain barrier (BBB) permeability, microglia/macrophage
activation through Toll-like receptor 3 (TLR3) signaling, secretion of IL-
1β, upregulation of the serotonin transporter (5-HTT) in astrocytes,
reducing extracellular serotonin (5-HT) levels and hence reduced
activation of 5-HT1A receptor subtype.

Page 21 of 21