Metabolic trap

Metabolic Trap is a medical hypothesis that attempts to explain ME/CFS as a vicious cycle that is potentiated by common genetic mutations, triggered by a stressor, and is difficult to escape without intervention.

Background
When the Open Medicine Foundation's Severely Ill Big Data study found some unexpected anomalies in ME/CFS patients, Dr Robert Phair investigated these further, and consulted with Ron Davis and others, and developed the "metabolic trap hypothesis".

Theory
The hypothesis is based on the idea that one or more important metabolic pathways may exhibit bistability. Thus, the pathway has two stable equilibrium states. One state is healthy, whereas the other is pathological. The bistability is believed to arise from one or more genetic mutations that cause the activity of an enzyme to decrease when the concentration of its substrate increases beyond a certain threshold.

Under ordinary circumstances, the concentration of the substrate would remain below the threshold, keeping a person in the healthy state. But once environmental conditions cause the substrate to increase beyond the threshold, a person would enter the pathological state and remain in it even if the environment returned to normal.

The relevant genetic mutations are believed to be common in the general population. Thus, presence of one or more mutations is a risk factor, but alone is not sufficient to cause ME/CFS.

Evidence
While Phair has stated that several candidate traps have been identified, presentations so far have focused on one particular candidate: the Kynurenine pathway.

Kynurenine pathway
[[File:IDO-MetabolicTrap-MECFS.png|thumb|right|An IDO metabolic trap in the kynurenine pathway may be the cause of ME/CFS.

Colored rectangles represent molecules in either extracellular space or serotonergic neuron cytosol. Arrows represent processes including transport and biochemical reactions. LAT1 = large neutral amino acid transporter (SLC7A5:SLC3A2), IDO = indoleamine-2,3-dioxygenase, AFMID = arylforamidase, TPH = tryptophan hydroxylase, AADC = aromatic amino acid decarboxylase. ''Citation: [https://www.mdpi.com/2075-4418/9/3/82 Phair, Davis and Kashi (2019). Diagnostics (9)3. doi 10.3390/diagnostics9030082]'']] Evidence supporting a trap in this pathway includes:
 * Prevalence of genetic mutations in the IDO2 gene, which codes for an enzyme that is responsible for metabolism of L-Tryptophan into N-formylkynurenine. Mutations of this gene are found in about 40% of the general population, but were found in all 20 of the 20 severly ill patients.  These severely ill patients averaged 1.7 mutated copies of the gene.
 * Consistency of cell-level test results with the trap kynurenine pathway trap model predicts. Specifically cells from several ME/CFS patients showed increased tryptophan, reduced kynurenine, and increased tryptophan/kynurenine ratio; whereas cells from healthy controls were normal.
 * Computer simulation results showing the trap would be very difficult to escape, but would be sudden when it does occur. This is consistent with the real world observation that recovery from ME/CFS is rare, but sometimes happens very suddenly.

Common and rare genetic mutations
The results from the ME/CFS Severely Ill, Big Data Study identified the variants R248W, Y359STOP, I140V, S252T and N257K as having potentially damaging mutations in IDO2 in patients with ME/CFS. At least two of these five mutations were found in 85% of the severely ill ME patients.

Treatment
Dr. Ron Davis has stated that if the IDO metabolic trap hypothesis is true, then he believes that ME/CFS would be curable. Moreover, the cure would not require development of a new drug (which is both costly and time-consuming). However, development of a treatment has not yet begun as the hypothesis has not yet been confirmed.

Importantly, Davis has expressed concern that patients may try to self-experiment with the kynurenine pathway because of the availability of substances like tryptophan on the open market. He cautioned that this is a dangerous pathway to experiment with, with particular risk of causing permanent autoimmunity which is not curable with present technology.

Notable studies and publications

 * 2019, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS (Full text)

Learn more

 * The IDO metabolic trap hypothesis for ME/CFS - Christopher Armstrong
 * Robert Phair, PhD | Metabolic Traps: A new way to think about ME/CFS (video) - View Transcript
 * Dr Phair Stanford Symposium 2018 metabolic trap
 * HealthRising: The Metabolic Trap Shines During the Symposium on the Molecular Basis of ME/CFS at Stanford