Metabolic studies into ME

Myalgic Encephalomyelitis: Multiple papers into energy metabolism indicate a hypometabolic state, impairment in the TCA cycle, reveal that post exertional malaise (PEM) is associated with changes in glycolysis and acetylation, redox imbalance and inadequate ATP generation in ME-patients. Acquisition of samples in conditions that increase patient symptoms (e.g., PEM) could further widen the observed gap between the plasma metabolome of patients and controls.

13. Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI. medRxiv [Preprint]. 2022 Jan 11:2021.06.14.21258895. https://doi.org/10.1101/2021.06.14.21258895

Conclusion/Main finding: «Our findings indicate a series of interconnected metabolic alterations in people with ME/CFS that may contribute to the pathogenesis of ME/CFS: (i) reduced levels of plasmalogens, unsaturated phospholipid ethers, and carnitines suggest peroxisomal dysfunction; (ii) reductions in levels of PCs and their downstream products indicate dysregulation of CDP-choline pathway, and (iii) elevations in the levels of dicarboxylic acids, particularly the TCA cycle intermediates α-ketoglutarate and succinate, are consistent with an impairment in the TCA cycle that may contribute to physical and cognitive fatigue.».

Inclusion criteria: All ME/CFS cases met the 1994 CDC Fukuda and Canadian consensus criteria for ME/CFS.

12. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/ chronic fatigue syndrome Fredrik Hoel, August Hoel, Ina K.N. Pettersen, Ingrid G. Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Alexander Fosså, Katarina Lien, Ingrid Herder, Hanne L. Thürmer,Merete E. Gotaas, Christoph Schäfer, Rolf K. Berge, Kristian Sommerfelt, Hans-Peter Marti, Olav Dahl, Olav Mella, Øystein Fluge, and Karl J. Tronstad, JCI Insight. 2021;6(16):e149217.  https://doi.org/10.1172/jci.insight.149217

Conclusion/Main finding: «Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/ CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.».

Inclusion criteria: Canadian consensus criteria

11. Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Germain A, Barupal  DK, Levine  SM, Hanson  MR.  Metabolites. 2020;10(1):34. Metabolites 2020, 10(1), 34; https://doi.org/10.3390/metabo10010034

Conclusion/Main finding: «We are reporting on the largest number of metabolites in the ME/CFS field to date, about 1750 plasma compounds, encompassing 20 super-pathways and 113 sub-pathways. However, we have not unequivocally identified a plasma biomarker or set of biomarkers with abundances drastically different between controls and ME/CFS patients, despite the fact that our clinical data indicates our patient cohort had a substantial level of disability. The same conclusion can be drawn from examining various groups’ prior reports, including ours, where distinct populations were recruited, alternate instrumentation was used, or even serum was analyzed instead of plasma.

Nevertheless, the metabolites emphasized as a result of our analysis, most specifically acyl cholines and steroids, should be considered in light of the metabolic impact even modest changes can have along with the complexity of sources that drain metabolites into the circulatory system. Indeed, the changes observed might result from a disturbance occurring in another part of the body (e.g., brain, muscles), one whose impact may be diluted in plasma. Acquisition of samples in conditions that increase patient symptoms (e.g., PEM) could further widen the observed gap between the plasma metabolome of patients and controls. Because liquid biopsies such as plasma and serum remain the most accessible resource from human subjects, our results combined with more explorative metabolomics will help stimulate our efforts before we move toward different, yet more invasive sample collection techniques. Furthermore, set-enrichment statistics with a control for false discovery rates can be used to identify chemical groups instead of individual metabolites that can be associated with a disease or phenotype. Follow-up studies can develop new targeted analytical methods to measure those chemical groups in studies with power calculations from this discovery stage data.».

Inclusion criteria: CDC/Fukuda 1994

10. Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases. McGregor NR, Armstrong CW, Lewis DP, Gooley PR. Diagnostics. 2019; 9(3):70. https://doi.org/10.3390/diagnostics9030070

Conclusion/Main finding: «This study revealed that post-exertional malaise is associated with changes in glycolysis and acetylation in ME/CFS cases. These changes are consistent with a hypoacetylation state and are likely to significantly alter histone acetylation and the actions of acetylation and deacetylation in controlling cellular enzymatic events. Well-designed studies evaluating these important factors are warranted.».

Inclusion criteria: Canadian consensus criteria

9. Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology Arnaud Germain, David Ruppert, Susan M. Levine and Maureen R. Hanson Metabolites. 2018 Dec; 8(4): 90. Published online 2018 Dec 6. doi: 10.3390/metabo8040090

Conclusion/Main finding: «In this study, we report on untargeted metabolomics profile of a relatively small cohort. Despite statistical challenges, we provide yet more evidence for a redox imbalance in ME/CFS patients. The rationale behind our theory is bolstered by parallels with our previous study and available datasets from other teams. The patient cohorts that have been used in our studies and others differ in geographical location, diet, treatment regimes, yet there are remarkable similarities among the findings. Thus, metabolomics may be revealing a fundamental feature of the disruption that occurs in victims of ME/CFS.».

Inclusion criteria: CDC/Fukuda 1994

8. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Germain A, Ruppert  D, Levine  SM, Hanson  MR. Mol Biosyst. 2017;13(2):371–379. https://doi.org/10.1039/C6MB00600K

Conclusion/Main finding: «Metabolomics is playing an increasingly important role in medicine to explore, predict and diagnose diseases, using an approach meant to be unbiased and not dependent on assumptions about the condition studied. Our metabolomics analysis implicates an aspect of metabolism—lipid metabolism–not previously linked to ME/CFS, even though lipid replacement has been one of the many ways explored to reduce fatigue symptoms in fatiguing illnesses. This pilot study has provided considerable new information which begs for verification and extension with a large cohort and a larger set of metabolites.».

Inclusion criteria: SEID criteria

7. The association of fecal microbiota and fecal, blood serum and urine metabolites in myalgic encephalomyelitis/chronic fatigue syndrome. Armstrong CW, McGregor NR, Lewis DP, Butt HL, Gooley, PR. 2016, Metabolomics 13, 8 (2017). https://doi.org/10.1007/s11306-016-1145-z

Conclusion/Main finding: «The workflow presented produced new information on the relationship of fecal metabolites and microbes with host blood serum and urine metabolites in ME/CFS. It is important to note that although correlations do not produce cause-effect results, the relationship of these variables allows for a basis for specific studies to observe the path of cause and effect. As expected in the non-ME/CFS cohort fecal SCFA negatively correlated with most metabolites in the serum and urine and increased production of SCFA in the gut by microbes associates with increased gluconeogenesis and reduced lipogenesis (Fig. 4). In the ME/CFS cohort, Bacteroides spp. decreased and Clostridium increased while fecal butyrate, valerate and isovalerate significantly increased and lactate decreased. These results were consistent with increased microbial fermentation at the expense of amino acids in the gut of ME/ CFS patients. By-products of amino acid fermentation may enhance gut epithelium permeability (Canfora et al. 2015) and we propose that an increased influx of larger than normal concentrations of SCFA into the blood may have deleterious effects on ME/CFS patients. Correlational analysis on the ME/CFS cohort provided a positive correlation of fecal amino acids with previously reported blood and urine metabolite anomalies in ME/CFS (Armstrong et al. 2015). Further research into the role of the gut microbiome and metabolites in ME/CFS pathogenesis is necessary, larger cohorts and longitudinal studies using a similar workflow as presented here are encouraged to replicate and further elucidate these findings.».

Inclusion criteria: Canadian consensus criteria

6. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome, Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl and Karl J. Tronstad, 2016, JCI Insight. 2016;1(21):e89376. https://doi.org/10.1172/jci.insight.89376

Conclusion/Main finding: «Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male 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. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.».

Inclusion criteria: Canadian consensus criteria

5. Metabolic features of chronic fatigue syndrome. Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E. Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5472-80. https://doi.org/10.1073/pnas.1607571113 Epub 2016 Aug 29. Erratum in: Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3749.

Conclusion/Main finding: «CFS has a chemical signature that can be identified using targeted plasma metabolomics. Receiver operator characteristic (ROC) curve analysis showed a diagnostic accuracy that exceeded 90%. The pattern and directionality of these changes showed that CFS is a conserved, hypometabolic response to environmental stress similar to dauer (35). Only about 25% of the metabolite disturbances found in each person were needed for the diagnosis of CFS. About 75% of the metabolite abnormalities were unique to the individual and useful in guiding personalized treatment. The study of larger cohorts from diverse geographical areas, and comparison with related medical disorders like depression and posttraumatic stress disorder, will be needed to validate the universality and specificity of these findings. The finding of an objective chemical signature in CFS helps to remove diagnostic uncertainty, will help clinicians monitor individualized responses to treatment, and will facilitate multicenter clinical trials.».

Inclusion criteria: All CFS patients met the 2015 IOM, Canadian and Fukuda diagnostic criteria for CFS.

4. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Armstrong CW, McGregor NR, Lewis DP, Butt HL, Gooley PR. Metabolomics 11, 1626–1639 (2015). https://doi.org/10.1007/s11306-015-0816-5

Conclusion/Main finding: «Here we have presented a metabolomics analysis of the blood and urine of ME/CFS patients compared to non-ME/ CFS subjects. The analysis reveals an inhibited glycolysis pathway exists in ME/CFS patients along with an oxidative stress pathway and a reduced level of amino acids. We have highlighted the possible role this plays in ME/CFS patients and it supports the current literature that proposes a chronic immune activation and oxidative stress phenotype exists in ME/CFS patients. The cause of this dysregulation remains unknown but the reduced glycolysis infers a reduced use of pyruvate and acetyl CoA is entering the citric acid cycle. The use of amino acids may be through glutamate forming 2-oxoglutarate via AST, which transfers the amino group to oxaloacetate to form and accumulate aspartate. This inefficient energy production and lowering of amino acid levels may both be important in producing a fatigue phenotype in patients with ME/CFS. The observed increased creatinine production may provide a means of anaerobic ATP energy for muscles as well as nitrogen removal from deaminated amino acids. This study has also identified allantoin as an ROS marker in ME/CFS linking the degradation of ATP and other purines to the oxidative stress phenotype that has been linked to the disorder.».

Inclusion criteria: Canadian consensus criteria

3. Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. Snell CR, Stevens SR, Davenport TE, Van Ness JM. Published: 01 November 2013 Physical Therapy, Volume 93, Issue 11, 1 November 2013, Pages 1484–1492, https://doi.org/10.2522/ptj.20110368

Conclusion/Main finding: «In conclusion, a serial CPET protocol with the measurement of expired gases was efficacious in distinguishing between people with CFS and people who were sedentary but otherwise healthy. As in the only other identified studies in which a dual CPET paradigm with the measurement of expired gases was used, participants with CFS showed a decrease in performance on the second test that was not seen in control participants. This functional deficit may provide an objective indication of PEM. Despite considerable patient heterogeneity with respect to illness duration and type of onset, analysis of data from the second test was able to correctly classify 49 of 51 participants with CFS and 9 of 10 control participants. Noninvasive biomarkers for CFS do not currently exist. Physical therapists may consider the use of CPET performance measurements to differentiate between people with CFS and people who do not have a disability but are sedentary. Work efficiency (ie, oxygen consumption and work output) at the VT or anaerobic threshold appears to have diagnostic potential for CFS. Cardiopulmonary exercise testing is a test modality compatible with physical therapist practice patterns and provides a way for the profession to make strong contributions to the diagnosis, treatment, and research of CFS.».

Inclusion criteria: CDC/Fukuda 1994. In addition, all participants with CFS reported exacerbation of symptoms after physical activity as a specific aspect of their diagnoses.

2. NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Armstrong CW, McGregor NR, Sheedy JR, Buttfield I, Butt HL, Gooley PR. Clinica Chimica Acta Volume 413, Issues 19–20, 9 October 2012, Pages 1525-1531. https://doi.org/10.1016/j.cca.2012.06.022

Conclusion/Main finding: «This preliminary analysis of blood sera of CFS patients using 1 H NMR spectroscopy as a metabolic profiling tool has revealed significant decreases in glutamine and ornithine levels within the blood serum of CFS patients. Correlation analysis of glutamine and ornithine in the CFS sera showed correlations with glucogenic amino acids and metabolites that participate in the urea cycle. These findings indicate a disturbance to amino acid and nitrogen metabolism. Further metabolic analyses of serum and other biofluids of CFS patients are warranted to improve the knowledge of these metabolite changes and to draw more insight into the underlying biochemical pathways for possible etiologic and clinical significance».

Inclusion criteria: Canadian consensus criteria

1. Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia. Elizabeth M Maloney, Roumiana S Boneva, Jin-Mann S Lin, William C Reeves Metabolism 2010 Sep;59(9):1351-1537. Epub 2010 Jan 27 https://doi.org/10.1016/j.metabol.2009.12.019  

Conclusion/Main finding: « In conclusion, persons with CFS had a significantly elevated prevalence of metabolic syndrome compared with healthy individuals. Metabolic syndrome is a known risk factor for type 2 diabetes mellitus, cardiovascular disease, and Alzheimer disease. Metabolic syndrome should therefore be evaluated in persons with CFS. If detected, appropriate treatment of abnormal metabolic factors should be implemented.».

Inclusion criteria: CDC/Fukuda 1994

Written by Jørn Tore Haugen

Master of Science in Engineering

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