Persons with multiple sclerosis reveal distinct kynurenine pathway metabolite patterns: a multinational cross-sectional study

Neuroaxonal damage in multiple sclerosis (MS) results from an interplay of neurotoxic pathomechanisms combined with a reduced neuroprotective capacity of neurons and glia to resist neurotoxic damage. Kynurenine pathway (KP) imbalance resembles some of the molecular mechanisms central to the incompletely understood MS pathophysiology. To study the role of the KP in MS, we performed targeted metabolomics on serum samples from 353 persons with MS and 111 healthy individuals, and detected MS-specific differences in concentrations of most kynurenines. Using exploratory factor analysis, we then identified two distinct KP metabolite patterns: the inflammation-driven neurotoxic pattern „NeuroTox“ and the neuroprotective pattern „NeuroPro“. Our results show that greater „NeuroTox“ and lower „NeuroPro“ were associated with higher disease severity. The novelty of our data-driven approach that identified distinct KP metabolite patterns in MS advocates for future studies using comparable approaches to investigate whether KP imbalance follows similar disease-specific patterns in diseases other than MS.