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.[1]:6[2]

Background[edit | edit source]

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".[1]

Theory[edit | edit source]

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[edit | edit source]

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

Load video
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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.[1]:6[2]

Background[edit | edit source]

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".[1]

Theory[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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 [3]
  • 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 [4], 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 [5]
  • 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[edit | edit source]

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.[2] At least two of these five mutations were found in 85% of the severely ill ME patients.[2]

Treatment[edit | edit source]

Dr. Ron Davis has stated that if the IDO metabolic trap hypothesis is true, then he believes that ME/CFS would be curable.[citation needed] Moreover, the cure would not require development of a new drug (which is both costly and time-consuming).[citation needed] 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.[6]

Notable studies and publications[edit | edit source]

  • 2019, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS[2] (Full text)

See also[edit | edit source]

Learn more[edit | edit source]

References[edit | edit source]

  1. ↑ 1.0 1.1 1.2 1.3 Phair, Robert (November 2018). "Metabolic Trap presentation (transcript)" (PDF). Open Medicine Foundation.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Phair, Robert D.; Davis, Ronald W.; Kashi, Alex A. (2019). "The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS". Diagnostics. 9 (3): 82. doi:10.3390/diagnostics9030082.
  3. ↑ Tate, Warren (May 25, 2022). "Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses". Frontiers in Neurology. Retrieved February 11, 2023.
  4. ↑ Johnson, Cort (October 19, 2018). "HealthRising: The Metabolic Trap Shines During the Symposium on the Molecular Basis of ME/CFS at Stanford". Open Medicine Foundation. Retrieved June 3, 2019.
  5. ↑ Kavyani, Bahar (July 11, 2022). "Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?". PubMed Central (PMC). Retrieved February 11, 2023.
  6. ↑ Davis, Ronald (November 7, 2018). "Ronald W. Davis, PhD | What's next?". YouTube. Open Medicine Foundation - OMF.


Common and rare genetic mutations[edit | edit source]

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.[1] At least two of these five mutations were found in 85% of the severely ill ME patients.[1]

Treatment[edit | edit source]

Dr. Ron Davis has stated that if the IDO metabolic trap hypothesis is true, then he believes that ME/CFS would be curable.[citation needed] Moreover, the cure would not require development of a new drug (which is both costly and time-consuming).[citation needed] 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.[2]

Notable studies and publications[edit | edit source]

  • 2019, The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS[1] (Full text)

See also[edit | edit source]

Learn more[edit | edit source]

References[edit | edit source]

  1. ↑ 1.0 1.1 1.2 Phair, Robert D.; Davis, Ronald W.; Kashi, Alex A. (2019). "The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS". Diagnostics. 9 (3): 82. doi:10.3390/diagnostics9030082.
  2. ↑ Davis, Ronald (November 7, 2018). "Ronald W. Davis, PhD | What's next?". YouTube. Open Medicine Foundation - OMF.
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