Trial Report Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in [ME] Patients and Healthy Volunteers, 2024, Abujrais+

Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry
Sandy Abujrais; Theodosia Vallianatou; Jonas Bergquist

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.

We observed significant alterations in several metabolic pathways, including the vitamin B3, arginine-proline, and aspartate-asparagine pathways, in the untargeted analysis. The targeted analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine in ME/CFS patients compared to the control group.

These findings suggest potential alterations in immune system response and oxidative stress in ME/CFS patients.

Link | PDF (ACS Chemical Neuroscience) [Open Access]

 

https://www.omf.ngo/altered-metabolic-pathways-mecfs/


The ME/CFS Collaborative Center at Uppsala, directed by Dr. Jonas Bergquist, recently published an article evaluating alterations in metabolic pathways, especially tryptophan, and their potential role in the pathophysiology of ME/CFS. This study used both targeted and untargeted approaches to measuring the metabolic networks in the plasma of 38 ME/CFS patients and 24 healthy controls.

The tryptophan metabolic pathway’s roles in immune function, neurotransmission, and energy metabolism have led to its specific investigation as a potential contributor to the pathophysiology of ME/CFS. One of tryptophan’s metabolites, kynurenine, performs immunosuppressive actions, while another, serotonin, helps regulate the sleep-wake cycle. In addition, metabolites further down the metabolic pathway play a role in the synthesis of NAD+, which is necessary for energy metabolism. Given the immune system dysregulation, problems with sleep, and issues with energy metabolism seen in ME/CFS, alterations in the tryptophan metabolic pathway may provide a deeper understanding of the disease pathophysiology.

In this study, the team used both an untargeted and targeted approach to measuring metabolites to gain a more holistic picture of changes seen in ME/CFS patients compared to healthy controls. The untargeted analysis found significant alterations in the metabolic pathways of vitamin B3, arginine-proline, and aspartate-asparagine.

For targeted analysis, the study team focused on tryptophan and its metabolites, tyrosine, phenylalanine, B vitamins, and hypoxanthine. This analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine. Together, these analyses indicate that an altered immune system response and oxidative stress are important components of the pathophysiology of ME/CFS.

 

"Human plasma samples were collected from 38 patients with ME/CFS, consisting of 27 females and 11 males, with an average age of 43 years (±13). These patients were recruited between 2013 and 2018 from two clinics: Stora Sköndal in Stockholm (SK), where the cohort included 19 patients (15 females and 4 males) with an average age of 44 years (±15), and Gottfries Clinic in Gothenburg (GC), which included 19 patients (12 females and 7 males) with an average age of 43 years (±12)."

How long were the samples transported, stored and otherwise handled (conditions & duration of each)? Was this different between the two clinics? How were the controls handled and how does this look in relation to each of the ME/CFS cohorts? (particularly given that they greatly overlap one ME/CFS cohort and not the other) Metabolites are very labile, all of these things can affect the results if they vary between groups.

controls: "These donors are employees in the Department of Analytical Chemistry at Uppsala University." possibility of selection bias?

 

"In addition, metabolites further down the metabolic pathway play a role in the synthesis of NAD+, which is necessary for energy metabolism."

Just how much do TRP metabolites contribute to a body's energy? My guess is that it's insignificant. It can affect ME symptoms, if that tiny contribution is in the wrong or right place, but that doesn't mean that PWME's common complaint about lack of energy is due to reduced TRP metabolite production.

Early in my ME, B3 made my symptoms much worse, as did TRP transport into the brain (blocked or delayed and spread out by taking BCAAs). My hypothesis was that the extra niacin in the bloodstream and CSF reduced the conversion of brain-cell-produced QUIN to NAD+, resulting in more of that toxic TRP metabolite remaining in the cells.

Since ME seems to be neurological, studying plasma metabolites seems invalid, since 95% of serotonin in the brain, for example, is produced in the brain, not carried in via plasma. That makes the link between plasma serotonin and sleep problems rather weak.

I find the mention of arginine-proline interesting, since I was intolerant of proline for quite a few months.