PHair and Davis have developed the itaconate shunt to explain what causes long-term consequences of MECFS.
This is the second video in a series of 2 that explains why long-term health consequences occur in MECFS.
The Itaconate Shunt Hypothesis, proposed by Dr. Robert Phair in collaboration with Professor Ronald Davis at the Open Medicine Foundation, is a novel metabolic theory aimed at explaining the complex pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This hypothesis builds on earlier metabolomic findings and proposes that a dysregulation in the itaconate pathway—a key immune-metabolic route—may underlie many of the hallmark symptoms of ME/CFS, including post-exertional malaise, energy production deficits, and immune dysfunction. Itaconate is a metabolite produced by immune cells, particularly macrophages, in response to inflammation, and it plays a role in modulating both metabolism and immune responses. According to the hypothesis, in ME/CFS patients, a metabolic "shunt" diverts key intermediates from the tricarboxylic acid (TCA) cycle into the itaconate pathway, leading to a bottleneck in energy production. This diversion may be triggered or sustained by chronic immune activation or a failure to properly regulate inflammatory responses. The result is a buildup of metabolic intermediates and toxic byproducts like ammonia, which the body struggles to clear due to impaired nitrogen disposal mechanisms. This could explain why ME/CFS patients often rely on amino acids for energy—despite the inefficiency and toxicity of this route—because their cells are unable to effectively utilize glucose or fatty acids. The hypothesis also suggests that this metabolic trap could be self-sustaining, locking patients into a low-energy, high-inflammation state. Ongoing research, including modeling and experimental validation at the Open Medicine Foundation’s Melbourne Collaboration, is testing this hypothesis to determine whether targeting the itaconate pathway could offer therapeutic potential for ME/CFS
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