Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide.

To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry.

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Source: Abujrais S, Vallianatou T, Bergquist J. Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry. ACS Chem Neurosci. 2024 Sep 20. doi: 10.1021/acschemneuro.4c00444. Epub ahead of print. PMID: 39302151. https://pubs.acs.org/doi/10.1021/acschemneuro.4c00444 (Full text)

Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls

Abstract:

Objectives

A comparison of the nutritional biomarkers between ME/CFS subjects and healthy controls (HC) was undertaken on secondary data collected from an IRB approved cross-sectional study in ME/CFS patients.

Methods

ME/CFS participants were recruited per the 2018 revised Canadian Clinical Case Definition for ME/CFS along with age matched HCs. Self-reported information on demographics and supplement use was collected, and body mass index calculated. HEI was calculated from Willet FFQ and multiple day 24-hour recall data, and severity of fatigue measured by Multidimensional Fatigue Inventory (MFI). Lymphocyte transformation assay by SpectraCell Lab (Houston, TX) was employed for intracellular micronutrient status. A series of two-tailed Mann-Whitney U tests (ɑ = 0.05) were performed for the non-parametric data expressed as mean ± standard error of the mean. All statistical analyses were conducted in IBM SPSS Statistics version 25 (Armonk, NY).

Results

Out of the 21 participants (11 ME/CFS and 10 HC), 82% of ME/CFS and 50% of HC were female. Higher fatigue scores were observed in ME/CFS (16.64 ± 1.36) than HC (10.78 ± 2.14). ME/CFS had better HEI scores (63.36 ± 13.44) than the HC (38.55 ± 12.29). However, despite better diet quality and supplementation, ME/CFS group showed lower intracellular Vitamin B3 and manganese (Mn) (86.3 ± 2.42 and 53.6 ± 2.81 respectively) but higher calcium (Ca) (57.5 ± 3.55) as compared to HC (97.2 ± 2.31, 64.5 ± 1.87 and 46.5 ± 0.96 respectively).

Conclusions

The results align with the current literature on indications of mitochondrial dysfunction in ME/CFS. Reduced intracellular vit B3 provides suboptimal production of the NAD(P)(H)-cofactor family, thus affecting mitochondrial function and consequently energy production. The aberration in energy metabolism is compounded by other factors, such as reduced Mn but higher Ca intracellular levels seen in this study indicating disruptions in oxidative stress pathways, resulting in debilitating fatigue experienced by individuals with ME/CFS.

Source: Priya Krishnakumar, Camila Jaramillo, Shawn Kurian, Wendy Levy, Cara Milman, Nadine Mikati, Fatma Huffman, Maria Abreu, Amanpreet Cheema, Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls, Current Developments in Nutrition, Volume 6, Issue Supplement_1, June 2022, Page 745, https://doi.org/10.1093/cdn/nzac062.014

A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Abstract:

Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM).

 

Source: Blankfield A. A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Int J Tryptophan Res. 2012;5:27-32. doi: 10.4137/IJTR.S10085. Epub 2012 Sep 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460668/ (Full article)

 

On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics

Abstract:

Close similarities in the courses of multiple sclerosis and schizophrenia laid the theoretical ground for attempting to find a common infectious aetiology for the two diseases. Chlamydia pneumoniae, which belongs to the rickettsial family of microorganisms has been linked to both diseases. It is postulated that since rickettsial microorganisms are ubiquitous in human populations they and the human species normally live in peaceful coexistence. In rare cases, for unknown reasons, varieties of them may become aggressive and pathogenic.

The kynurenic acid hypothesis of schizophrenia has attracted much attention. It also seems to have initiated a paradigmatic shift from the hitherto prevailing serological research approach to one which focuses on immunological factors.

An open clinical pilot study in which, during 2006, eight female and five male patients with psychotic symptoms were treated with a combination of antibiotics is presented, to which, in the beginning of 2007 two female patients suffering from severe and long standing chronic fatigue syndrome were added. On one year follow-up, six out of the eight female patients showed stable excellent treatment results, whereas two were rated as showing significant treatment results. Four of the five men who entered the study were suffering from chronic schizophrenia, whereas the fifth, was a case of severe acute catatonic schizophrenia.

Two of the male patients showed significant treatment results, whereas three of them were rated as having had a slight to moderate improvement. No less than three of the women had suffered their first episode of psychosis after giving birth to their first (and only) child. This finding, as these women all responded excellently to treatment with antibiotics, indicates that post partum psychosis could be regarded as an infectious complication of childbirth of, as to the causative agent, unknown aetiology. High priority ought therefore be given to initiate controlled clinical trials with antibiotic treatment of this serious condition. The otherwise promising results of the pilot study seem to warrant further and controlled clinical trials with treatment with antibiotics of patients with psychotic symptoms.

As the second patient with psychotic symptoms to enter the study, had a long standing history of chronic fatigue, where an initial treatment with the antidepressant fluoxetine had only worsened her condition, whereas ninety days of treatment with antibiotics, combined with vitamin B injections, effected a complete recovery, the author decided, when two patients with long standing and incapacitating chronic fatigue syndromes sought the clinic in February and March 2007, to include them in the study. The first of them, after sixty days of treatment with antibiotics showed excellent treatment results on follow-up one year later, whereas the second, who also took the combination of antibiotics for sixty days, was rated as having shown a significant improvement.

Comment in: Hypotheses concerning rickettsial microorganisms, autoimmune diseases and new treatment strategies. [Med Hypotheses. 2010]

 

Source: Frykholm BO. On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics. Med Hypotheses. 2009 Jun;72(6):736-9. doi: 10.1016/j.mehy.2008.11.045. Epub 2009 Mar 6. https://www.ncbi.nlm.nih.gov/pubmed/19269110

 

Nutritional strategies for treating chronic fatigue syndrome

Abstract:

Despite considerable worldwide efforts, no single etiology has been identified to explain the development of chronic fatigue syndrome (CFS). It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome.

A detailed review of the literature suggests a number of marginal nutritional deficiencies may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential fatty acids. Any of these nutrients could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets. It is likely that marginal deficiencies not only contribute to the clinical manifestations of the syndrome, but also are detrimental to the healing processes.

Therefore, when feasible, objective testing should identify them and their resolution should be assured by repeat testing following initiation of treatment. Moreover, because of the rarity of serious adverse reactions, the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacologic effects, it seems rational to consider supplementing CFS patients with the nutrients discussed above, along with a general high-potency vitamin/mineral supplement, at least for a trial period.

Comment in: Nutritional strategies for treating chronic fatigue syndrome. [Altern Med Rev. 2001]

 

Source: Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev. 2000 Apr;5(2):93-108. http://www.altmedrev.com/publications/5/2/93.pdf (Full article)

 

Vitamin B status in patients with chronic fatigue syndrome

Abstract:

Some patients with chronic fatigue syndrome say they benefit from taking vitamin supplements. We assessed functional status for the B vitamins pyridoxine, riboflavin and thiamine in 12 vitamin-untreated CFS patients and in 18 healthy controls matched for age and sex.

Vitamin-dependent activities–aspartate aminotransferase (AST) for pyridoxine, glutathione reductase (GTR) for riboflavin, transketolase (TK) for thiamine–were measured in erythrocyte haemolysates before and after in-vitro addition of the relevant vitamin. For all three enzymes basal activity (U/g Hb) was lower in CFS patients than in controls: AST 2.84 (SD 0.62) vs 4.61 (1.43), P < 0.001; GTR 6.13 (1.89) vs 7.42 (1.25), P < 0.04; TK 0.50 (0.13) vs 0.60 (0.07), P < 0.04. This was also true of activated values: AST 4.91 (0.54) vs 7.89 (2.11), P < 0.001; GTR 8.29 (1.60) vs 10.0 (1.80), P < 0.001; TK 0.56 (0.19) vs 0.66 (0.08), P < 0.07. The activation ratios, however, did not differ between the groups.

These data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.

 

Source: Heap LC, Peters TJ, Wessely S. Vitamin B status in patients with chronic fatigue syndrome. J R Soc Med. 1999 Apr;92(4):183-5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1297139/ (Full article)