Exercise-induced modulation of kynurenine pathway metabolite patterns in multiple sclerosis: a targeted metabolomics analysis across four randomized controlled trials.

Kynurenine pathway imbalance is a characteristic feature of multiple sclerosis (MS). Serum kynurenines contribute to latent factors reflecting a neurotoxic (NeuroTox) or neuroprotective pattern (NeuroPro). Previous single-metabolite studies show a favorable modulation of the kynurenine pathway by acute exercise, characterized by increased neuroprotective kynurenic acid. This study aims to investigate the acute and chronic effects of different exercise modalities on NeuroTox and NeuroPro. In this pooled analysis of randomized controlled trials, we followed four subcohorts of our previous work, in which we identified NeuroTox and NeuroPro. Serum concentrations of kynurenines were quantified by liquid chromatography-tandem mass spectrometry. Pattern stability was assessed by repeating exploratory factor analysis (EFA). Acute effects of a single session of combined strength-focused exercise (CE; FunTraiMS study) and chronic effects of exercise interventions, including CE (10 weeks; FunTraiMS study) and endurance exercise (3 weeks; HIITMS study and 24 weeks; EMSES and EXBRAIN studies), were evaluated using linear mixed-effects models. The four subcohorts included 273 participants (67.0% female; mean (SD) age: 44.5 (10.6) years). Repeated EFA resulted in similar factor loadings of serum kynurenines across subcohorts. CE induced an acute increase in NeuroPro (0.421, 95% CI [0.216, 0.626], p < 0.001) in FunTraiMS. Twenty-four-week endurance exercise induced a chronic decrease in NeuroTox (-0.432, 95% CI [-0.786, -0.080], p = 0.019) in EXBRAIN. NeuroTox and NeuroPro are temporally stable constructs. NeuroPro shows acute responsiveness to strength-focused exercise. NeuroTox may be chronically diminished by endurance exercise. Determinants and the clinical relevance of changes in NeuroTox and NeuroPro warrant further investigation.