A new open access publication in the Journal of Translational Medicine describes the work by Giloteaux et al. to uncover ways to detect the disease ME/CFS. Ludovic Giloteaux and Jiayin Li, joint first authors, took a collaborative approach to improve our understanding of ME/CFS. Giloteaux isolated extracellular vesicles from the plasma of 98 Chronic Fatigue Initiative individuals (49 ME/CFS and 49 controls) to study their signaling molecules (i.e., cytokines). Then he worked with Jiayin Li and David Ruppert, statisticians at Cornell, and using data generated by Columbia University investigators, the group combined plasma cytokine, EV cytokine, plasma proteomic, and demographic datasets to explore new ways to approach ME/CFS.
One of the key findings from the publication is the 86% accuracy in differentiating between people with ME/CFS and health controls. Giloteaux et al. leveraged multiple datasets to achieve this goal. The paper also outlines interesting correlations between various biological molecules and clinical surveys that measure disease severity. For example, higher levels of pro-inflammatory molecules (e.g., CSF2 & TNFa) were correlated with greater physical and fatigue symptoms in people with ME/CFS.
The publication is open access so see the website for more information. Additionally, the EV cytokine data is available on mapMECFS.
Cardiopulmonary exercise testing (CPET) was an integral part of our NIH-funded collaborative research center (CRC). The Cornell CRC used the CPET as a way to interrogate the hallmark symptom of ME/CFS—post-exertional malaise (PEM). CPET-associated samples are being analyzed to uncover the molecular basis of PEM. This molecular work gave us the opportunity to explore other aspects of PEM such as recovery following exertion.
Dr. Geoffrey Moore, M.D., Cornell CRC Clinical Core Co-director, led an effort to describe CPET recovery in ME/CFS. This work is now available in the journal Medicina under the title Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The paper documents a significant difference in recovery between sedentary controls (~2 days) and people with ME/CFS (~13 days). Moore et al. studied 84 people with ME/CFS and 60 controls using a self-reported symptom severity questionnaire. Both female and male participants from three different test sites across the United States were included in the study. The publication is open access so check it out for more information.
As shown in the graphical abstract above and explained in the video abstract below, we found a large number of metabolites at increased concentrations in the urine of controls 24 hours after CPET compared to baseline. However, we did not find significant changes in levels of any metabolites in the urine of ME/CFS patients after CPET.
When we looked at which metabolites were changing differently in ME/CFS patients and controls after exercise, we found the most compounds in the amino acid and lipid metabolic superpathways.
Overall, our data suggests that the metabolisms of sedentary controls undergo major changes that allow them to recover from exertion, while ME/CFS patients fail to make similar adaptive responses. This dysfunctional metabolic excretion could be contributing to exercise intolerance in ME/CFS patients.
Check out the paper to see many more results, including individual compounds that are significantly different between patients and controls and altered correlations between urine and plasma metabolites.
As discussed in the paper, there is more evidence for abnormal immunometabolism in ME/CFS. Maya utilized her expertise in flow cytometry and Seahorse flux analysis to demonstrate this dysfunction. She isolated natural killer (NK), helper T (CD4), and cytotoxic T (CD8) cell populations from both healthy donors and people with ME/CFS. These immune cell populations were studied in their circulating state and after stimulation. The stimulation process aims to mimic an immune response. Maya’s findings showed that all three of the cell types have an increased use of fats to power their activities when compared to healthy donors. Her results show that ME/CFS immune cells have a greater reliance on fats for energy when they are stimulated. Overall, these findings support the presence of an altered metabolic state in certain immune cells in individuals with ME/CFS.
Maya outlines these findings in her graphical and video abstracts inserted below.
Back in January 2020, Germain et al published a metabolomics paper in Metabolites stating:
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)…
This 65 million people with ME/CFS figure has brought about some attention resulting in this letter to the Editor. Importantly, this letter brings several more supporting references beyond the initial Valdez et alpublication. The key takeaway from the letter is that the prevalence of ME/CFS is likely much greater than the oft-cited figure of “20 million worldwide.”
This manuscript takes a look at 4,790 circulating plasma proteins from 20 ME/CFS women compared to 20 healthy women, over an unprecedented range, for ME/CFS, of 9 orders of magnitude.
Pathway analysis uncovered disrupted cell-to-cell communication, specifically in the ephrin-Eph signaling pathway. This pathway is crucial for many aspects of our body’s homeostasis, including development, physiology, and disease regulation.
Additionally, the paper outlines promising results for the development of a diagnostic test using protein ratios.
First author, Arnaud Germain, PhD, outlines these findings in a video abstract below.
Center investigator Dr. Ludovic Giloteaux is lead author of a new publication out in the Journal of Translational Medicine. The paper describes cytokine profiling in extracellular vesicles (EVs) in ME/CFS. The study specifically looks at EVs from the plasma of 70 participants, 35 of which are diagnosed with ME/CFS and compared with 35 healthy controls. Both female and male participants were included in this work. Dr. Jesus Castro-Marrero visited our lab from Spain on a fellowship to contribute to the project.
One key finding of the study is the noted disturbances in cytokine networks.. Disturbances in these cytokine networks were seen in both plasma and EVs, and provides further evidence of immune dysregulation in ME/CFS. We are using information from this work to inform our further studies on EVs from blood collected before and after an exercise challenge. Stay tuned for future publications from our Center on this topic.
Hanson Lab alumna, Alexandra Mandarano ’19 Ph.D., received the Laboratory Product Sales (LPS) award for her December 2019 JCI publication. The LPS award is granted to a student of the graduate field Genomics, Genomics and Development who is first author on what is judged to be the “best” student paper published in a calendar year. The award includes Mandarano’s name engraved on a plaque in the Department of Molecular Biology and Genetics office. Congratulations, Dr. Mandarano!
This methodologically focused review covers aspects of ME/CFS pathophysiology that are consistent with chronic enterovirus infection outcomes and then closely examines the technology used in in past ME/CFS publications to determine how rigorously the enterovirus theory of disease etiology has been investigated.
This study, led by Adam O’Neal, analyzed plasma antibodies to 122 different pathogen antigens in a case-control comparison including 103 individuals. The cohort of 59 ME/CFS and 44 healthy controls included both female and male participants. The anti-pathogen antibody assays were performed by Augmenta Bioworks. Although this study did not find one particular pathogen associated with ME/CFS, sex-based differences were uncovered. Check out this publication (link above) for more information.