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.
Highlights
Diagnostic measurements for a given disease are most definitive, most specific, and most useful when the measurements are closely related to the molecular basis of the disease
If we turn to the specific case—the IDO metabolic trap developed here—we find that this new theoretical model rests on three ideas: (1) the potential importance of common damaging mutations, (2) a possibly detrimental aspect of the phenomenon in enzyme kinetics known as substrate inhibition, and (3) the bistable metabolic system that can result
The IDO metabolic trap hypothesis for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests that four cell types are at risk of being driven into the pathological steady-state C (Figure 3): (1) antigen-presenting cells, (2) serotonergic neurons in the midbrain raphe nuclei, (3) serotonin-producing enterochromaffin cells in the intestinal mucosa, and (4) melatonin-producing pinealocytes
Summary
Diagnostic measurements for a given disease are most definitive, most specific, and most useful when the measurements are closely related to the molecular basis of the disease. For a disease like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), whose mechanistic basis is unknown, a specific diagnostic is difficult to identify. Medicine resorts to complex pattern recognition in lists of symptoms [1,2], statistical principal component analysis [3,4,5,6], advanced physical measurements of yet unproven specificity [7], and even, when just a few thousand critical cells are dysfunctional and standard blood measurements are unremarkable, the unhelpful assertion that patient is “not ill”. We aim to advance the search for underlying mechanisms by proposing a new class of theoretical models for ME/CFS and demonstrating that one specific member of that class, the IDO metabolic trap, can reproduce important features of the disease and promises to be experimentally testable.
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