Insights into the pathogenesis of ME/CFS through metabolomic profiling of cerebrospinal fluid, 2018, Fiehn - Preliminary results

[dreampop]

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling illness characterized by six months or more of unexplained profound fatigue with post-exertional malaise, sleep abnormalities, cognitive dysfunction and autonomic disturbances. Focusing on the pathogenesis of central nervous system abnormalities in ME/CFS, we pursued metabolomics analysis of cerebrospinal fluid (CSF) in 32 ME/CFS cases, 40 subjects with multiple sclerosis (MS), another fatiguing illness, and 19 healthy subjects with no neurological disease (ND). MS/ND subjects were frequency matched for age and sex to ME/CFS subjects.

Three untargeted metabolomic assays for primary metabolites, biogenic amines and complex lipids were performed with gas chromatography time-of-flight (GC-TOF) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) yielding profiles for 525 known metabolites. Mannose was a cardinal biomarker in ME/CFS subjects with reduced levels in ME/CFS compared to both MS and ND subjects. Levels of acetylcarnitine were reduced in ME/CFS vs. MS subjects. The predictive power of metabolomic analysis for diagnosis of ME/CFS vs. ND was higher (cross-validated AUC 0.875; 95% CI: 0.726~0.949) than with cytokine analysis alone (cross-validated AUC 0.865; 95% CI: 0.673~0.952) and improved with integration of both metabolomics and cytokine analyses (cross-validated AUC 0.916; 95% CI: 0.791~0.969).

Our findings confirm the biological basis of ME/CFS, and may enable new methods for diagnosis and insight into cognitive and autonomic disturbances in this syndrome.

Link
I thought I'd post this preliminary finding here so it gets some exposure. Credit to @wigglethemouse for digging in and finding this study. I believe it's part of Columbia's ME/CFS CFE and hopefully will be published soon.

 

[wigglethemouse]

Columbia did do cytokine analysis of cerebrospinal fluid and reported results in 2015. I wonder if the metabolimics was performed on the same samples but not published so far? Simmaron funded the cytokine work.

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome, 2015, Lipkin et al
https://www.nature.com/articles/mp201529

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction.

We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay.

Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment.

Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1a or interleukin 1ß, suggesting a disturbance in interleukin 1 signaling.

Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases 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.

Here is a link to the Simmaron hosted write-up of the study by Cort
Title : Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome
http://simmaronresearch.com/2015/04...ramatic-differences-chronic-fatigue-syndrome/

 

[dreampop]

Columbia did do cytokine analysis of cerebrospinal fluid and reported results in 2015. I wonder if the metabolimics was performed on the same samples but not published so far? Simmaron funded the cytokine work.

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome, 2015, Lipkin et al
https://www.nature.com/articles/mp201529


Here is a link to the Simmaron hosted write-up of the study by Cort
Title : Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome
http://simmaronresearch.com/2015/04...ramatic-differences-chronic-fatigue-syndrome/

Your probably right since both have the identical numbers of subjects (32me/cfs, 40ms, 19 hc).

 

[mariovitali]

I am very excited with this research, Oliver Fiehn's lab uses cutting edge analytical techniques that may help ME research tremendously

The findings are really interesting, here are my two cents :


a) Upon looking the four available DNA files from Dante Labs i currently have, all of them (including myself) have pathogenic SNPs to MBL2, associated with Mannose-Binding Lectin deficiency. (2 with rs5030737, 2 with rs1800450). Whether this has anything to do with lower mannose levels in CSF i do not know.

Mannose-binding lectin and ME patients study :

https://www.sciencedirect.com/science/article/abs/pii/S0198885915004656

b) Upon closer inspection to Mannose, we read (Bold letters added by me):

Mannose is present in numerous glycoconjugates including N-linked glycosylation of proteins. C-Mannosylation is also abundant and can be found in collagen-like regions.

The digestion of many polysaccharides and glycoproteins yields mannose, which is phosphorylated by hexokinase to generate mannose-6-phosphate. Mannose-6-phosphate is converted to fructose-6-phosphate, by the enzyme phosphomannose isomerase, and then enters the glycolytic pathway or is converted to glucose-6-phosphate by the gluconeogenic pathway of hepatocytes.

We note, N-Linked Glycosylation, Glucose-6-phosphate and Hexokinase. All of these topics were discussed on a document sent to Professor Ron Davis in 2017, from which i provide some snapshots:




and




Could low mannose levels be a consequence of impaired N-Linked glycosylation ?