The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Dehhaghi, Mona, Panahi, Hamed Kazemi Shariat, Kavyani, Bahar et al. · Aging and disease · 2022 · DOI
Quick Summary
This review examines how tryptophan, an amino acid we get from food, is processed differently in people with ME/CFS. The body normally converts tryptophan into important substances like serotonin (which affects mood) and NAD+, an energy molecule. The authors propose that this conversion process may become overactive in ME/CFS, depleting NAD+ and making fatigue worse. They suggest that NAD+ supplements might help reduce fatigue and improve quality of life.
Why It Matters
Understanding the biochemical mechanisms underlying ME/CFS is critical for developing targeted treatments. This review identifies a specific metabolic pathway that could explain multiple ME/CFS symptoms and proposes a testable therapeutic intervention. If NAD+ depletion is confirmed as a disease mechanism, supplementation strategies could offer patients a potential avenue to reduce fatigue and improve functioning.
Observed Findings
Impaired tryptophan metabolism is associated with ME/CFS and may play a significant role in disease pathobiology
The kynurenine pathway produces both neuroprotective metabolites (kynurenic acid) and neurotoxic metabolites (quinolinic acid), suggesting a potential imbalance in ME/CFS
Tryptophan availability and kynurenine pathway activation are regulated by gut microbiota composition
NAD+ depletion could contribute to the pervasive malaise and post-exertional malaise characteristic of ME/CFS
Altered tryptophan metabolism may affect brain regions responsible for behavioral and neurological functions
Inferred Conclusions
Hyperactivation of the kynurenine pathway may represent either a compensatory mechanism or a driving pathogenic mechanism in ME/CFS
NAD+ depletion secondary to altered tryptophan metabolism could explain multiple ME/CFS symptoms including fatigue and neurological impairment
Gut microbiota modulation of tryptophan metabolism provides a potential intervention target
NAD+ supplementation strategies warrant clinical investigation as potential therapeutic approaches for ME/CFS symptom management
Remaining Questions
Does kynurenine pathway hyperactivation in ME/CFS represent a primary cause or secondary consequence of disease pathology?
What This Study Does Not Prove
This review does not prove that KP hyperactivation causes ME/CFS or that NAD+ supplementation will be effective in patients—it proposes these as hypotheses for future investigation. Correlation between altered tryptophan metabolism and ME/CFS symptoms does not establish causation. The review cannot establish whether KP changes are primary disease drivers or secondary compensatory responses. Clinical efficacy of NAD+ supplements in ME/CFS remains untested and unproven.
Which specific NAD+ precursors (nicotinamide mononucleotide vs nicotinamide riboside) would be most effective, at what doses, and in which patient subgroups?
How do individual differences in gut microbiota composition influence tryptophan metabolism and ME/CFS severity, and can microbiota-targeted interventions improve outcomes?
Would clinical trials of NAD+ supplementation demonstrate efficacy, and would benefits be sustained or require continuous dosing?