The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).
RESEARCH INDEX
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio commentary by Dr Katrina Pears
ME/CFS Research Published 31 January – 6 February 2023
It’s been another booming week for research, with ten new ME/CFS studies and seventeen new Long Covid studies.
We have highlighted one of the ME/CFS studies in detail below:
Paper five (5) is on investigating a biomarker to distinguish between the overlapping conditions of ME/CFS and Fibromyalgia (FM). This research particularly looked at the expression of 11 circulating microRNA (miRNA), which are molecules that help make proteins.
This study recruited 41 ME/CFS patients (ME/CFS), 29 ME/CFS patients with a comorbid diagnosis of FM (ME/CFS+FM), and 32 matched healthy controls (HC) using the Canadian Consensus Criteria. The study also had a FM only cohort (38 patients) but plasma for this group was collected from the CARTaGENE database and they were self-diagnosed.
The 11 microRNA chosen in this study were ones which had been of note in previous ME/CFS research associated with PEM and symptom severity (Nepotchatykh et al., 2020).
This study had a number of findings:
- Different microRNA expression signatures between ME/CFS, FM and ME/CFS+ FM, this also correlates to symptom severity between ME/CFS and ME/CFS+ FM groups.
- ME/CFS patients had higher levels of the microRNAs measured than healthy controls, FM patients had lower levels than healthy controls, while patients with ME/CFS+ FM were in the middle.
- However, in the ME/CFS patient group only three of the microRNAs were significantly different to healthy controls (specifically:miR-127-3p, miR-140-5p and miR-374b-5p). It’s these three microRNAs the authors say could provide breakthrough biomarkers to identify between ME/CFS and FM.
- The study developed a prediction model which used all 11 circulating microRNA levels and accurately allowed the authors to discriminate between patients suffering from ME/CFS, FM and ME/CFS+ FM.
- The authors concluded that these results prove that ME/CFS and FM are two distinct illnesses.
It’s a shame that this study didn’t obtain their own data for the FM only cohort, and hopefully this didn’t account for the differences seen, especially seeing as results from this group can be questioned as their microRNA levels were close to zero. Using a cohort from another study has limitations with different protocols used, such as sample preparation and it would be ideal to have the same recruitment process for all to control all factors.
This study is also limited by having a larger female population, as ME/CFS+FM participants were all women but the ME/CFS and FM were matched in sex. This study also only provides one snapshot in time, and longitudinal studies in this area may tell us a great deal about the progression of illness.
Overall, the results in this study are remarkable, it is worth a look at Figure 2 in the study as this clearly displays the results. However, if results are due to the different recruitment process of the FM only group then the results would be invalid.
You may also be interested this week in:
- Paper six (6) adds to the growing evidence for the role of endothelium dysfunction in ME/CFS. The endothelium is a thin membrane that lines the inside of the heart and blood vessels. Endothelial cells release substances that control vascular relaxation and contraction as well as enzymes that control blood clotting, immune function and platelet (a colourless substance in the blood) adhesion. This study showed reduced ability for blood vessels to dilate and lower micro-vascular regulation. We have previously covered endothelial dysfunction in our research summaries, covering the studies by Bertinat et al., 2022 and Blauensteiner et al. 2021.
- Paper seven (7) is on gastrointestinal symptoms in ME/CFS, Dr Charles Shepherd has covered the key points from this study here.
- Papers nine (9) and ten (10) are also on the gut, these two studies show that changes in the microbiome may be a signature for ME/CFS. There is further coverage of these two papers including expert comments on our website.
ME/CFS Research References and Abstracts
Xu W, Cao Y, Wu L.
International Journal of Environmental Research and Public Health. 2023; 20(3):2437.
Abstract
New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified.
To investigate whether infection with COVID-19 actually causes ME/CFS, this paper obtained pooled data from the Genome Wide Association Study (GWAS) and analyzed the relationship between COVID susceptibility, hospitalization and severity of COVID and ME/CFS, respectively, using two-sample Mendelian randomization (TSMR).
TSMR analysis was performed by inverse variance weighting (IVW), weighted median method, MR-Egger regression and weighted mode and simple mode methods, respectively, and then the causal relationship between COVID-19 and ME/CFS was further evaluated by odds ratio (OR).
Eventually, we found that COVID-19 severity, hospitalization and susceptibility were all not significantly correlated with ME/CFS (OR:1.000,1.000,1.000; 95% CI:0.999–1.000, 0.999–1.001, 0.998–1.002; p = 0.333, 0.862, 0.998, respectively). We found the results to be reliable after sensitivity analysis.
These results suggested that SARS-CoV-2 infection may not significantly contribute to the elevated risk of developing CFS, and therefore ME/CFS may not be a sequela of COVID-19, but may simply present with symptoms similar to those of CFS after COVID-19 infection, and thus should be judged and differentiated by physicians when diagnosing and treating the disease in clinical practice.
Seton, Katharine.
PhD Doctoral thesis, University of East Anglia.
Abstract
Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) pathogenesis is thought to be multisystemic, including the immune and gastrointestinal systems. A proportion of patients experience gastrointestinal disturbances with evidence suggesting a leaky gut. It was hypothesised that a leaky gut and microbial translocation causes a breach in immune tolerance, promoting inflammation and autoimmunity.
Aims: A) determine whether severe ME/CFS patients have increased systemic and mucosal immunoglobulin (Ig) reactivity to the intestinal microbiome, and B) determine which intestinal microbes serum IgG was directed against.
Methods: Serum and stool samples were collected from five pairs of severe ME/CFS patients and matched household controls. Enzyme linked immunosorbent assays were developed to quantify IgG in serum, bound and non-bound IgA in stool and serum IgG levels reactive with autologous and heterologous stool bacteria. Flow cytometry methods were developed to quantify both stool microbial load and the proportion of stool microbes reactive with mucosal IgA and serum IgG. A ‘bug FACS’ method was developed to identify and quantify serum IgG reactivity to stool bacteria and fungi.
Results: The main finding was that severe ME/CFS patients have significantly lower levels of serum IgG reactive to heterologous stool bacteria compared to their matched household controls. In addition, severe ME/CFS patients do not have higher levels of serum IgG reactive to heterologous stool bacteria than autologous stool bacteria. Severe ME/CFS patients also have a non-significant increase of IgG binding to Campylobacter jejuni and Pseudomonas viridiflava compared to their matched household controls. Analysis of mucosal IgA found ME/CFS patients with a long disease duration had higher microbe bound IgA concentrations compared to their matched household controls.
Conclusion: This thesis presents results from the first ME/CFS study to investigate serum IgG immune reactivity to stool microbes. Findings suggest ME/CFS patients have an impaired serum IgG immune response to the intestinal microbiome.
Springer A, Oleksa-Marewska K, Basińska-Zych A, Werner I, Białowąs S.
PLoS One. 2023 Jan 26;18(1):e0280080.
Abstract
Increasing and changing demands for academic teachers worldwide are leading to different consequences, some of which are negative, such as physical and mental health impairment. With the job demands-resources model and the transactional model of occupational stress adopted as a theoretical framework, a cross-sectional study among Polish academic teachers was conducted.
The aim of the study is to identify the role of vital personal resources understood as selected health-promoting behaviours, such as (1) stress-coping strategies, (2) sleep hygiene, and (3) using annual vacation leave, in the process of the regeneration.
In a cross-sectional survey, the following variables have been assessed: 1) work-related stress using the Psychosocial Risk Scale, 2) occupational burnout using the Oldenburg Burnout Inventory (OLBI), 3) chronic fatigue using the Polish adaptation of the Checklist Individual Strength (CIS), and selected health behaviours of academic teachers 4) stress-coping strategies with the help of the Polish version of Mini-COPE and 5) rest: the amount of sleep and vacation days devoted to rest using a short questionnaire designed by the authors.
The sample (N = 340) was comprised of academic teachers employed at Polish higher education institutions who have experienced changes in the work environment in recent years.
We conducted a multiple regression analysis to determine the relationships among stress, burnout, and chronic fatigue, looking at coping strategies and rest as a moderator.
The results indicate that there is a strong relationship between stress resulting from an excessively demanding work environment on the one hand and occupational burnout and chronic fatigue on the other.
At the same time, selected health behaviours of academic teachers only slightly moderate the analyzed relationship.
Avoidance strategies strengthen the relationship between stress and its negative consequences, while rest and-to a limited extent-the amount of sleep only slightly contribute to weakening the analyzed relationship.
4. Impact of Misdiagnosis in Case-Control Studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Malato J, Graça L, Sepúlveda N.
Diagnostics. 2023; 13(3):531.
Abstract
Misdiagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can occur when different case definitions are used by clinicians (relative misdiagnosis) or when failing the genuine diagnosis of another disease (misdiagnosis in a strict sense). This problem translates to a recurrent difficulty in reproducing research findings.
To tackle this problem, we simulated data from case-control studies under misdiagnosis in a strict sense. We then estimated the power to detect a genuine association between a potential causal factor and ME/CFS. A minimum power of 80% was obtained for studies with more than 500 individuals per study group.
When the simulation study was extended to the situation where the potential causal factor could not be determined perfectly (e.g., seropositive/seronegative in serological association studies), the minimum power of 80% could only be achieved in studies with more than 1000 individuals per group.
In conclusion, current ME/CFS studies have suboptimal power under the assumption of misdiagnosis. This power can be improved by increasing the overall sample size using multi-centric studies, reporting the excluded illnesses and their exclusion criteria, or focusing on a homogeneous cohort of ME/CFS patients with a specific pathological mechanism where the chance of misdiagnosis is reduced.
Nepotchatykh E, Caraus I, Elremaly W, Leveau C, Elbakry M, Godbout C, Rostami-Afshari B, Petre D, Khatami N, Franco A, Moreau A.
Sci Rep. 2023 Feb 2;13(1):1896.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia (FM) are two chronic complex diseases with overlapping symptoms affecting multiple systems and organs over time. Due to the absence of validated biomarkers and similarity in symptoms, both disorders are misdiagnosed, and the comorbidity of the two is often unrecognized.
Our study aimed to investigate the expression profiles of 11 circulating miRNAs previously associated with ME/CFS pathogenesis in FM patients and individuals with a comorbid diagnosis of FM associated with ME/CFS (ME/CFS + FM), and matched sedentary healthy controls. Whether these 11 circulating miRNAs expression can differentiate between the two disorders was also examined.
Our results highlight differential circulating miRNAs expression signatures between ME/CFS, FM and ME/CFS + FM, which also correlate to symptom severity between ME/CFS and ME/CFS + FM groups.
We provided a prediction model, by using a machine-learning approach based on 11 circulating miRNAs levels, which can be used to discriminate between patients suffering from ME/CFS, FM and ME/CFS + FM.
These 11 miRNAs are proposed as potential biomarkers for discriminating ME/CFS from FM. The results of this study demonstrate that ME/CFS and FM are two distinct illnesses, and we highlight the comorbidity between the two conditions.
Proper diagnosis of patients suffering from ME/CFS, FM or ME/CFS + FM is crucial to elucidate the pathophysiology of both diseases, determine preventive measures, and establish more effective treatments.
6. Endothelial dysfunction in ME/CFS patients
Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø.
PLoS One. 2023 Feb 2;18(2):e0280942.
Abstract
Objective: A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS.
Study design: The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures.
Results: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline.
Conclusions: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.
Steinsvik EK, Hausken T, Fluge Ø, Mella O, Gilja OH.
Scand J Gastroenterol. 2023 Feb 2:1-8.
Abstract
Background: Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description.
Objective: In this study, we aimed to characterize gastric motility and gastric symptoms in response to a liquid meal.
Methods: We included 20 patients with ME/CFS with abdominal complaints who were recruited to a double-blind randomized placebo-controlled trial of Rituximab. The patients of this sub study were examined with an ultrasound drink test, and gastrointestinal symptoms were evaluated using the Rome III questionnaire and Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) questionnaire.
Results: We found that patients commonly reported fullness/bloating (75%), abdominal pain (45%) and nausea (35%). Ultrasound measurements revealed lower proximal measurements of the stomach after a meal (p < 0.01) and larger fasting antral area (p = 0.019) compared to healthy controls. The patients had a stronger symptomatic response to the liquid meal compared to healthy controls regarding epigastric pain, discomfort and nausea (p < 0.05). Ninety percent of the patients reported bowel movement frequencies within the normal range but scored high on bowel habit dissatisfaction and life disruption.
Conclusion: The patients presented with fullness/bloating, nausea and epigastric pain, showed signs of impaired gastric accommodation and visceral hypersensitivity, showing that the gastrointestinal symptoms of ME/CFS patients are similar to functional dyspepsia.Key summary Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description.
In this study, patients with ME/CFS had signs of impaired gastric accommodation after a liquid meal. Out of 20 patients, 15 patients reported fullness/bloating, 9 reported abdominal pain, and 7 reported nausea. The patients showed signs of visceral hypersensitivity on a drink test.
Our findings suggest that patients with ME/CFS share many similarities with patients with Functional Dyspepsia. The findings were not typical for Irritable Bowel Syndrome.
Bethan Jones, Corin Bourne & Peter Gladwell.
Fatigue: Biomedicine, Health & Behavior
Abstract
Aim: To identify activities which people with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) report are impacted by their condition, and evaluate the ability of measures of function used by National Health Service (NHS) ME/CFS Services to represent these experiences.
Method: 122 participants completed ME/CFS Service questionnaires reporting activities that they had reduced or stopped doing, as well as Patient Reported Outcome Measures (PROMs). These data were coded using the International Classification of Functioning, Disability and Health (ICF) using established linking rules. Matrices identified the agreement rate between the outcome measures and the participant-generated list. Activities which could not be coded against the ICF were grouped using content analysis.
Results: Responses from participants related to codes from nine subsections of the ICF. The PROMs used by the ME/CFS service had agreement rates between 58% and 62.5% with the participant-generated list. The content analysis identified a range of activities that were meaningful to participants that they could no longer do. These included holidays and day trips, accessing the community independently, and sustaining activity into the evening. These were not captured in either the ICF or the service’s outcome measures.
Conclusion: The list generated by participants referred to a wide range of activities, including some not captured by the ICF. Comparison against the outcome measures suggests that the measures used in many NHS ME/CFS services nationally capture patients’ experiences moderately well. However, there are activities that patients value that are not captured by these measures.
Cheng Guo, Xiaoyu Che, Thomas Briese, Amit Ranjan, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, and Brent L. Williams
Cell Host and Microbe volume 31, issue 2, P288-304.
Highlights
- ME/CFS patients have substantial gut microbiome dysbiosis.
- Bacterial abundances, functions, SCFAs and species interactions deviate in ME/CFS.
- Reduced F. prausnitzii and E. rectale in ME/CFS may contribute to butyrate deficiency.
- Low F. prausnitzii abundance correlates with more severe fatigue symptoms in ME/CFS.
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, and orthostatic intolerance.
Here, we report a multi-omic analysis of a geographically diverse cohort of 106 cases and 91 healthy controls that revealed differences in gut microbiome diversity, abundances, functional pathways, and interactions.
Faecalibacterium prausnitzii and Eubacterium rectale, which are both recognized as abundant, health-promoting butyrate producers in the human gut, were reduced in ME/CFS.
Functional metagenomics, qPCR, and metabolomics of fecal short-chain fatty acids confirmed a deficient microbial capacity for butyrate synthesis.
Microbiome-based machine learning classifier models were robust to geographic variation and generalizable in a validation cohort. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity.
These findings demonstrate the functional nature of gut dysbiosis and the underlying microbial network disturbance in ME/CFS, providing possible targets for disease classification and therapeutic trials.
Ruoyun Xiong, Courtney Gunter, Elizabeth Fleming, Suzanne D. Vernon, Lucinda Bateman, Derya Unutmaz, Julia Oh
Cell Host & Microbe 31, 273–287
Highlights
- Multi-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS.
- Reduced gut microbial diversity and increased plasma sphingomyelins in ME/CFS.
- Short-term patients had more severe gut microbial dysbiosis with decreased butyrate.
- Long-term patients had more significant metabolic and clinical aberrations
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disorder manifesting as severe fatigue and post-exertional malaise. The etiology of ME/CFS remains elusive.
Here, we present a deep metagenomic analysis of stool combined with plasma metabolomics and clinical phenotyping of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) compared with healthy controls (n = 79).
First, we describe microbial and metabolomic dysbiosis in ME/CFS patients. Short-term patients showed significant microbial dysbiosis, while long-term patients had largely resolved microbial dysbiosis but had metabolic and clinical aberrations.
Second, we identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts. These revealed potential functional mechanisms underlying disease onset and duration, including reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate.
In addition to the insights derived, our data represent an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
