Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle? (Kavyani, 2022)

[Consul]

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers. To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP). KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.


https://link.springer.com/article/10.1007/s00018-022-04380-5

 

[Consul]

From Glass et al 2023:

While kynurenate is the only tryptophan compound with correlations in both the time point and the ratio sides of the heatmap, the differences seen in plasma and urine correlations in the other eight compounds, which appear at various locations in the tryptophan pathway, attest to a profound dysregulation of this pathway in the ME/CFS patients compared to the controls.

 

[Wishful]

Seems like a well-written article, covering known research and what works for a few PWME and what doesn't work for most (GET/CBT). I recommend this paper for patients trying to educate their doctors about ME.

Before I knew about ME, I assumed I had some sort of rare chronic neuroinflammation, and that the KP played a major role. I don't think it's quite that simple, since there are plenty of modulators of the KP, and none have proven to be reliable modulators of ME symptoms. Maybe it plays a role in downstream effects of the core problem. Maybe "profound dysregulation" is a bit overblown.

 

[Wishful]

Peroxynitrite scavengers make my ME symptoms worse. My theory for this is that ONOO- is the main factor controlling the lifespan of IDO, so less ONOO- means more TRP catalyzed into kynurenines, including QUIN, which might be responsible for the "feeling lousy" symptoms.