Multiple sclerosis (MS) is an autoimmune disorder that targets oligodendrocytes, leading to neuroinflammation, demyelination, and neurodegeneration. Chronic inflammation is known to activate the kynurenine pathway (KP), which can generate the neurotoxic metabolites quinolinic acid (QA) and 3-hydroxykynurenine. Many studies have focused on QA and kynurenic acid (KA), as the QA/KA ratio provides an indication of whether the microenvironment is predominantly neurotoxic or neuroprotective.
In a recent study, Prof. Zimmer and colleagues used targeted metabolomics to investigate alterations in the KP metabolite profile in patients with MS. Individuals with MS showed a lower kynurenine/tryptophan (K/T) ratio, suggesting activation of the KP. The serum QA/KA ratio and 3-hydroxyanthranilic acid (3-HAA) levels were increased in MS patients compared to healthy controls. However, the overall concentrations of QA, KA, tryptophan, and kynurenine were lower.
When metabolite levels were grouped, two profiles emerged: a neurotoxic profile (positively correlated with neopterin and the K/T ratio) and a neuroprotective profile (correlated with KA). Patients with greater disease severity showed increases in neurotoxic profile metabolites and decreases in neuroprotective metabolites.
Additionally, higher body mass index (BMI) was correlated with increased kynurenine-to-tryptophan ratios and higher serum KP metabolite levels, including kynurenine, QA, 3-HAA, and KA. Previous studies have shown that physical exercise reduces inflammatory markers and modulates KP metabolites, potentially improving MS symptoms (MVS Rangel 2025 and R Hoseini 2025).
Taken together, these findings suggest that therapeutic targeting of the kynurenine pathway may improve clinical outcomes in MS.