Metabolism is the set of myriad chemical reactions through which cells transform energy, and metabolites are the small molecules broken down or built up through these reactions. So far, we know of almost two million metabolites in people. For certain diseases, like cardiovascular disease and diabetes, the levels of key metabolites in patients differ from those in healthy people; thus, metabolites can be effective disease biomarkers, helping to diagnose people and develop treatments.
Dr. Karl Morten is a principal investigator at the University of Oxford (UK) who focuses on how ME/CFS dysregulates metabolism. Because ME/CFS shares cardinal symptoms and comorbidities with fibromyalgia and Gulf War syndrome (like fatigue, post-exertional malaise, and POTS), his team hypothesized these diseases disrupt the same metabolic pathways. If the same metabolites are dysregulated, then drugs targeting these metabolites and metabolic pathways may help people with any of these diseases.
In this review, the team described how ME/CFS, fibromyalgia, and Gulf War syndrome dysregulate many of the same metabolites. Some dysregulated metabolites are important for breaking down or creating high-energy molecules or for reducing oxidative stress. For example, people with ME/CFS or Gulf War syndrome often have abnormal levels of purine metabolites, and people with ME/CFS or fibromyalgia often have abnormal levels of taurine. These metabolites are important for building high-energy molecules and antioxidants (like NADP, NADPH, and uric acid). Other dysregulated metabolites are important for breaking down or creating lipids.
People with ME/CFS or Gulf War syndrome can have abnormal levels of sphingomyelin-lipid metabolites, which are critical for muscles to function. And yet other dysregulated metabolites are important for brain signaling. People with ME/CFS or fibromyalgia can have abnormal levels of tryptophan metabolites, which can affect levels of melatonin (affecting sleep); serotonin (affecting appetite, mood, pain, and sleep); and 5-hydroxytryptophan (affecting fatigue). The team also noted that many of the commonly affected metabolites are simultaneously important for multiple things, like producing high-energy molecules, producing brain signals, and processing lipids.
To confirm how ME/CFS, fibromyalgia, and Gulf War syndrome affect metabolite levels, the team also reviewed how these diseases affect protein levels and whole-body images (e.g., magnetic resonance imaging and magnetic resonance spectroscopy imaging). Consistent with the metabolic results, these diseases affect levels of proteins important for processing high-energy molecules, lipids, and antioxidants. Also consistent with the metabolic results are imaging studies showing that ME/CFS and fibromyalgia increase lactate; and that ME/CFS and Gulf War syndrome change brain activities. (Exercise changes brain-activity images even more significantly for people with ME/CFS, consistent with the main ME/CFS symptom of post-exertional malaise.)
Overall, these results suggest antioxidants, melatonin, or high-energy supplements are effective for reducing symptoms common among ME/CFS, fibromyalgia, and Gulf War syndrome. Indeed, high-energy and antioxidant metabolites, like oxaloacetate and AXA1125, reduce symptoms in some people with ME/CFS or Long Covid. And melatonin supplements can help improve sleep.
The team did not review metabolite levels in people with Long Covid. However, several metabolites affected by the three reviewed diseases are affected by Long Covid too. And people with Long Covid experience fatigue, post-exertional malaise, and POTS as well. (In fact, symptoms of Long Covid, ME/CFS, and fibromyalgia overlap enough that many people with Long Covid meet criteria for ME/CFS or fibromyalgia). Thus, these treatments may also help reduce symptoms for people with Long Covid.
Dr. Morten and his team highlighted important future work to apply our understanding of abnormal metabolite levels in people with these diseases. For example, we must see whether metabolite levels change as symptoms change; a strong correlation between metabolite levels and symptom severity would give further reason to therapeutically target these metabolic pathways. Also, we must measure metabolites in specific organs most affected by these diseases, like the brain or the gut, not just rely on measuring metabolite levels in the blood plasma (as done in the reviewed studies). Focusing on metabolites in affected organs would increase our chance of finding reliable biomarkers and identifying relevant metabolic pathways.
Dr. Morten’s team summarized these results in their review article now published in the journal Frontiers in Neuroscience.
