The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.

Biomedical Insights That Inform the Diagnosis of ME/CFS

“…The metabolomic biochemistry theme is further explored by Kashi et al [10], who propose the indolamine-2,3-dioxygenase (IDO) metabolic trap hypothesis. The hypothesis explores the link of IDO biochemistry in the context of kynurenine pathways, and the amino acid transporter LAT1, through mathematical models of tryptophan metabolism.…”

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

“…Genetic predisposition: Research also suggests there may a genetic element in the pathogenesis of ME/CFS ( 213 – 216 ). Our hypothesis is compatible with a possible genetic predisposition for ME/CFS.…”

Extremely Severe ME/CFS—A Personal Account

“…Their condition is likely never to get better [ 23 ]; their only hope is a cure or treatments, but there’s no funding for scientists to do research to find treatments or a cure. The Open Medicine Foundation-funded research, spearheaded by Ronald Davis out of Stanford University, is the first extensive, collaborative research effort into ME/CFS [ 24 ], but it is pretty new. For the last 40 years (the illness has likely been around for much, much longer than that, but was even more covered up, prejudiced against and misunderstood, to the point that there was not even recognition of its existence), there has been nothing but small efforts at research, even if a few have been well-meaning and well-conceived.…”