Metabolic trap

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description=The Metabolic Trap theory in ME/CFS by Robert Phair, Nov 2018, Open Medicine Foundation conference. Transcript

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.

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description=The Metabolic Trap theory in ME/CFS by Robert Phair, Nov 2018, Open Medicine Foundation conference. Transcript

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

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: Phair, Davis and Kashi (2019). Diagnostics (9)3. doi 10.3390/diagnostics9030082

There is, as yet, little evidence for a strong role of the kyneruinine pathway in ME/CFS. Current research suggests involvement in the condition, but no more-so than would be expected based on the fact that the kyneurnine pathway has a wide variety of roles in inflammation, the immune response, and metabolism. As a result the metabolic trap hypothesis, while a valuable theory, should not be expected to have a great deal of explanatory power in the etiology of CFS

• CFS/ME patients do appear to exhibit mild over-representation of loss of function mutations in IDO2 gene

• The levels of KP metabolites in patients, while pointing to KP dysregulation, are not consistently correlated in the ways expected assuming a strong role for the metabolic trap in ME/CFS. Some studies do report higher TRP/KYN ratios in patients with CFS , while others report a lower KA/QA ratios, and a recent study showing higher levels of 3HK. Perhaps most relevantly, the finding in one study that there's no relationship between KP levels, cytokines and fatty acids

• 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 in the IDO2 gene as being potentially damaging. 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)

See also

• Indoleamine-2,3-dioxygenase 1 (IDO1)
• Open Medicine Foundation
• Ron Davis
• Robert Phair
• ME/CFS Severely Ill, Big Data Study
• How to check DNA data for certain genes

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

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 in the IDO2 gene as being potentially damaging. 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)

See also

• Indoleamine-2,3-dioxygenase 1 (IDO1)
• Open Medicine Foundation
• Ron Davis
• Robert Phair
• ME/CFS Severely Ill, Big Data Study
• How to check DNA data for certain genes

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

metabolic trap hypothesis An hypothesis which proposes that the normal metabolic functioning of the cell has become "trapped" in an abnormal state, which may lead to body-wide symptoms.

metabolic trap hypothesis An hypothesis which proposes that the normal metabolic functioning of the cell has become "trapped" in an abnormal state, which may lead to body-wide symptoms.

enzyme a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction.

indoleamine (IDO) - any derivatives of an indole (e.g., serotonin, tryptophan) that contain an amine group

indole (IDO) - a signalling molecule produced by bacteria as a result of metabolising tryptophan, found in the intestines

indoleamine (IDO) - any derivatives of an indole (e.g., serotonin, tryptophan) that contain an amine group

etiology The cause of origin, especially of a disease.

metabolite A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.

cytokine any class of immunoregulatory proteins secreted by cells, especially immune cells. Cytokines are small proteins important in cell signaling that modulate the immune system. (Learn more: me-pedia.org)

etiology The cause of origin, especially of a disease.