Metabolomics in Central Sensitivity Syndromes : Miller, Saona, Hackshaw Apr 2020

Sly Saint · Apr 24, 2020

Abstract
Central sensitization syndromes are a collection of frequently painful disorders that contribute to decreased quality of life and increased risk of opiate abuse. Although these disorders cause significant morbidity, they frequently lack reliable diagnostic tests. As such, technologies that can identify key moieties in central sensitization disorders may contribute to the identification of novel therapeutic targets and more precise treatment options. The analysis of small molecules in biological samples through metabolomics has improved greatly and may be the technology needed to identify key moieties in difficult to diagnose diseases. In this review, we discuss the current state of metabolomics as it relates to central sensitization disorders. From initial literature review until Feb 2020, PubMed, Embase, and Scopus were searched for applicable studies. We included cohort studies, case series, and interventional studies of both adults and children affected by central sensitivity syndromes. The majority of metabolomic studies addressing a CSS found significantly altered metabolites that allowed for differentiation of CSS patients from healthy controls. Therefore, the published literature overwhelmingly supports the use of metabolomics in CSS. Further research into these altered metabolites and their respective metabolic pathways may provide more reliable and effective therapeutics for these syndromes
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https://www.mdpi.com/2218-1989/10/4/164/htm

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2. Current State of Metabolomics Research in CSS
2.1. Chronic Fatigue Syndrome (CFS)
CFS has been associated with errors in the immune system, central nervous system, autonomic nervous system, and energy metabolism, however, these findings are not consistent enough to provide satisfactory sensitivity and/or specificity for a diagnostic test for CFS. As such, the cause of CFS remains unknown [38]. The condition has long been recognized, and has been described by many different terms (e.g., Da Costa's syndrome, effort syndrome, soldier's heart, neurasthenia, myalgic encephalitis /encephalomyelitis, Iceland disease, Akureyri disease, Royal Free disease, immune dysfunction syndrome) [39,40], and most recently, systemic exertion intolerance disease [21].

Clinical characteristics include at least six months of moderate to severe intensity symptoms at least 50% of the time chiefly dominated by fatigue. Criteria include persistent fatigue, post-exertional malaise, sleep problems, cognitive impairment, and orthostatic related symptoms amongst others [41].
Recent metabolomics analysis of plasma from CFS subjects and healthy controls revealed significant variations of intermediate metabolites from the tricarboxylic acid and urea cycles [42]. These findings allowed CFS patients to be discriminated from healthy controls based on variances in the ornithine/citrulline and pyruvate/isocitrate ratios (P < 0.0001 and P = 0.0069).

Further plasma metabolic profiling of CFS subjects and healthy controls quantified 832 metabolites, which identified significantly different concentrations of 14 metabolites related to redox imbalances in CFS subjects [43]. More recently, 361 plasma metabolites were compared between CFS patients and matched controls [44]. 74 of these metabolites were originally found to be significantly altered (P < 0.05), but only 35 were significant after statistical correction. The 35 metabolites were associated with various biological pathways, including taurine metabolism, glyoxylate and dicarboxylate metabolism, purine and amino acid metabolism, and energy metabolism.

Another analysis of plasma metabolites assessed 612 metabolites from 63 various biochemical pathways in CFS patients and controls using hydrophilic interaction liquid chromatography, electrospray ionization (ESI), and tandem mass spectrometry (MS/MS) [45,46]. The majority of these metabolite concentrations were decreased in CFS patients compared to controls, but significant abnormalities were identified in 20 unique metabolic pathways. These include an increase in pyrroline-5-carboxylate and decreases in sphingolipids, phospholipids, purines, cholesterol, and microbiome amino acids, to name a few. This finding is consistent with CFS as a hypometabolic state, but the pathways linked to these abnormal metabolite concentrations vary. One pathway consistently affected in CFS subjects is mitochondrial metabolism.

Since abnormal mitochondrial function is associated with fatigue, a recent study sequenced mitochondrial DNA (mtDNA) of 93 CFS patients and evaluated the sequences for mutations [47]. No clinically proven mtDNA mutations were realized in the CFS patients, suggesting that mtDNA mutations are not a common element in the etiology of CFS.

However, a more recent comparison of mtDNA mutations in CFS subjects and controls identified a significant difference in the percentage of CFS patients lacking a deleterious variant of mtDNA compared to the control group [48]. These findings are interesting, but the importance of these findings on the etiology and pathogenesis of CFS necessitates further study.

A 2003 systematic review analyzed 58 articles that were both directly concerned with CFS and had sample sizes larger than 10. After sorting and reviewing the articles according to quality of methodology, no consistent pattern of immunological abnormalities was identified for CFS patients [49].
Urine samples from CFS children and controls were collected before and after exercise to identify possible variances in metabolic profiles between the groups [50]. Pre and post-exercise metabolites were assessed using liquid chromatography-mass spectrometry (LC-MS), Principal Component Analysis (PCA), and orthogonal projections to latent structures-discriminant analysis. Prior to exercise, the CFS group was found to have significantly decreased creatine, indole-acetaldehyde, phytosphingosine, and pyroglutamic acid compared to the control group. Eleven metabolites (nonanedioic acid, methyladenosine, acetylcarnitine, capric acid, corticosterone, creatine, levonorgestrel, pantothenic acid, pyroglutamic acid, xanthosine, and xanthurenic acid) were selected for analysis after exercise.

The CFS group demonstrated significantly increased methyladenosine and creatine (P < 0.05), while the other metabolites were significantly decreased (P < 0.05) compared to the control group. The MetPA database was then used to associate the metabolites to their respective metabolic pathways. Prior to exercise, the CFS group exhibited a disordered arginine-proline metabolism pathway. Furthermore, three disordered metabolic pathways (marker metabolites) were identified in the CFS group post-exercise, which were arginine-proline metabolism (creatine), biosynthesis of pantothenic acid and CoA (pantothenic acid), and steroid hormone biosynthesis (corticosterone).
Analysis of peripheral blood mononuclear cells (PBMCs) from 52 CFS patients and 35 healthy controls to assess for consistent cellular patterns of oxidative phosphorylation (OXPHOS) and glycolysis of CFS patients. The data revealed consistently decreased markers of OXPHOS in PBMCs taken from CFS patients compared with healthy controls [51,52]. These markers result from various pathways, such as ATP production and non-mitochondrial respiration. Of note, the markers that best differentiated CFS patients from controls are associated with maximal respiration. Maximal respiration was consistently impaired in CFS patients (P ≤ 0.003). This lower maximal respiration implies that PBMCs in CFS patients cannot respond to extracellular stressors as effectively as healthy PBMCs and, therefore, cannot meet cellular energy needs.

Recently, a reproducible, broad-spectrum metabolomics technique was developed that allows for the simultaneous analysis of over 600 plasma metabolites from many biochemical pathways via a single injection [53]. This technique shows promise as a diagnostic tool for CFS and other multifaceted diseases.
Ventricular cerebrospinal lactate levels were compared in patients with CFS patients, Fibromyalgia (FM) patients, patients with overlapping CFS/FM, and controls using proton nuclear magnetic resonance spectroscopy (1HNMR) [54]. Although the mean lactate levels did not significantly differ between diseased groups, all three groups had markedly higher lactate levels compared to the healthy volunteers. As such, lactate levels in cerebrospinal fluid (CSF) cannot be used to distinguish FM patients from CFS patients.

Contrarily, the increased lactate concentration in patients with central sensitivity syndromes requires further study to determine what role this metabolite has in the various disease states.
Analysis of fecal and plasma samples from 24 CFS/IBS patients, 26 CFS patients, 1 IBS patient, and 49 controls identified decreased levels of choline, carnitine, and phosphatidylcholine in CFS patients. Additionally, increased levels of phosphatidylethanolmines, triglycerides, and ceramides were identified in CFS patients with IBS comorbidity [55]. Combined analysis of fecal metagenomic and plasma metabolomic data provides a more reliable predictive model for CFS than either data sets alone.
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spinoza577 · Apr 24, 2020

Very interesting.

In the conclusion they make an assessment on this sort of result:

... None of the conditions has had a reproducible reliable differentiating metabolite identified for diagnostic purposes. It is important to recognize that studies finding differences between two states (disease versus healthy) do not have found biomarkers, but rather differentiating metabolites. When within the same study, validation work is done we can speak about candidate biomarkers and only when these are validated in an independent study can you call them a real biomarker [218].
...
Reviewing the analysis of the biofluids suggests that the perceived optimal fluid (such as those in closest proximity with the target organ) does not necessarily provide the most illuminating results. This suggests that with our current level of understanding of these disorders, all readily accessible specimens should be evaluated. In some cases, metabolomics has provided promising discoveries with technologies such as vibrational spectroscopy which has led to future potential for biomarker discover in FM and interstitial cystitis. These technologies may lead to future discovery of molecules involved in the pathophysiology of these conditions. In other cases, metabolomics has not made as much of an impact in the last decade. New emerging powerful techniques such as vibrational spectroscopy coupled with ultra HP MS may provide clues to several candidate markers rather than single markers that would give evidence for new therapeutic targets towards the better treatment of these often chronically overlapping conditions, ...
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rvallee · Apr 24, 2020

As much improvement it is to do some actual science over useless psychometric questionnaire mathemagics, I can't really see much value here as there is about exactly 0 chance that a "CSS" cohort of CFS patients would be valid. They are probably a mix of several different things lumped together based on superficial features that exist only in the researchers' minds.

It is encouraging to see that there are still people in the CSS/FND/WHATEVER field trying to do some actual work but this is just doing the same thing that others have been doing with better-validated cohorts. They seem to be finding some of the same things but even well-validated cohorts are unlikely to be truly homogeneous.

As cohorts go, CSS is probably about less nonspecific than a cohort of random autoimmune diseases. Maybe there are universal processes to those but CSS is pretty much as meaningless a label as MUS. Still better than yet another iteration of the same 3 experiments in a loop, though.

Mithriel · Apr 24, 2020

Central sensitization syndromes are a collection of frequently painful disorders that contribute to decreased quality of life and increased risk of opiate abuse.
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I found the thought behind this sentence truly terrifying.

Painful disorders can be treated with painkillers but if anyone uses those painkillers they are drug addicts not patients.

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