Multiple Sclerosis and the Kynurenine Balance: When Body Chemistry Pushes the Brain Toward Harm or Healing

Multiple sclerosis (MS) is usually described as an immune-mediated disease where the immune system attacks the brain and spinal cord. That’s true, but it’s only part of the story. In recent years, researchers have become increasingly interested in how the biochemical environment inside and outside the brain might either protect nerve cells—or quietly push them toward damage over time. One pathway that keeps popping up is the kynurenine pathway, the main route by which the amino acid tryptophan is broken down. The new multinational study by Kupjetz and colleagues looked at this pathway in the blood of 353 people with MS and 111 healthy controls from Denmark, Germany, and Switzerland. Using high-throughput mass spectrometry, they measured a broad panel of kynurenine pathway metabolites and then used a data-driven approach to see whether these molecules form meaningful patterns that relate to disability, MRI markers, fitness, and body composition.

The Kynurenine Pathway: A Metabolic Balancing Act
On Figure 1A (page 3), the authors sketch the kynurenine pathway as a branching map starting from tryptophan. Along one direction, the pathway produces neurotoxic molecules, especially quinolinic acid (QA) and 3-hydroxykynurenine (3-HK), which can promote oxidative stress and glutamate-driven excitotoxicity. Along another, it generates neuroprotective metabolites, particularly kynurenic acid (KA) and related compounds like xanthurenic acid (XA) and picolinic acid (Pic). The balance between these branches is often summarized by the QA/KA ratio, sometimes called a “neurotoxicity index.” Another important readout is the kynurenine-to-tryptophan ratio (KTR), which reflects how strongly the pathway is being driven—often by inflammatory signals such as interferon-γ. By measuring this whole network at once, rather than a single metabolite, the authors hoped to capture a more realistic picture of how the pathway behaves in people living with MS.

How the Study Was Done
All participants were adults without major diseases other than MS. People with MS had mild to moderate disability (Expanded Disability Status Scale, EDSS ≤ 6.5) and were clinically stable—no current relapses or corticosteroid treatment. Blood was drawn, processed, and frozen at −80°C, then analyzed centrally using LC-MS/MS to quantify tryptophan, kynurenine, KA, QA, XA, Pic, anthranilic acid (AA), 3-HK, 3-hydroxyanthranilic acid (3-HAA), quinaldic acid (Qld), and neopterin (Neopt), a marker of immune activation. The team also collected EDSS scores, MRI metrics (e.g., lesion volume, gray and white matter parenchymal fraction), walking capacity (6-Minute Walk Test), fatigue (MFIS), cognition (SDMT and SRT), body mass index, body fat percentage, cardiorespiratory fitness (VO₂peak), and serum neurofilament light chain (sNfL) in a subset. Their statistical workflow, moved from simple comparisons between MS and controls, to correlation maps, and finally to exploratory factor analysis to uncover metabolite “patterns” hidden in the data.

Two Distinct Metabolic Signatures: “NeuroTox” and “NeuroPro”
When the authors let the data “speak” via factor analysis, two clear patterns emerged in the MS group (Figure 2, page 7). The first pattern, which they named NeuroTox, loaded positively on Neopt and KTR (indicating inflammatory activation of the pathway) and on the more neurotoxic metabolites 3-HK, QA, AA, and the QA/KA ratio. In plain terms, people with high NeuroTox scores had a kynurenine profile skewed toward inflammation and potentially harmful downstream products. The second pattern, NeuroPro, loaded positively on KA, Qld, XA, and Pic, and negatively on the QA/KA ratio—suggesting a shift toward neuroprotection and antioxidant capacity. Interestingly, 3-HAA sat in between, loading on both factors, which matches its mixed biological profile in the literature (sometimes antioxidant, sometimes pro-oxidant, depending on context). These patterns were remarkably consistent across the different MS cohorts and only partially mirrored in healthy controls, where NeuroTox was less clearly linked to QA and QA/KA, hinting at a more benign balance in people without MS.

How These Patterns Relate to Disability and Brain Health
The next question was obvious: do these metabolic fingerprints matter clinically? In correlation analyses, higher NeuroTox and lower NeuroPro both tracked with greater disability, as measured by EDSS (see scatter plots in Figure 4A–B, page 9). People whose blood showed a more inflammation-driven, neurotoxic profile tended to have more advanced MS, whereas those with a more neuroprotective profile tended to have milder disease. These trends remained visible in proportional odds regression models, though some lost statistical significance after adjusting for age and other covariates—likely because age itself is strongly tied to both EDSS and kynurenine imbalance. Notably, NeuroTox and NeuroPro were not clearly associated with MRI lesion volume, gray or white matter parenchymal fraction, or sNfL in this relatively well-functioning cohort, which had a mean EDSS of 3.1. The authors suggest that more pronounced structural damage and neurodegeneration might be needed before these blood-based patterns line up tightly with imaging and axonal injury markers.

Lifestyle, Body Composition, and the Metabolite Patterns
One of the most “human” aspects of this study is how strongly the patterns linked to everyday factors like age, body fat, and fitness. As shown in Figure 5A (page 10), NeuroTox increased with age, BMI, and body fat percentage, regardless of whether body fat was measured via bioelectrical impedance (BIA) or DXA. This fits with the idea of “inflammaging”—low-grade, chronic inflammation that accumulates with age and is amplified by visceral adiposity—which can push the kynurenine pathway toward neurotoxic products. In contrast, Figure 5B (page 10) shows that NeuroPro was higher in people with lower body fat and better cardiorespiratory fitness (higher VO₂peak). In other words, the same lifestyle components already known to benefit MS—maintaining a healthy weight, staying physically active—also appear to tilt the kynurenine pathway toward a more protective, KA-rich profile. Mechanistically, the authors point to prior work showing that exercise can both lower systemic inflammation and shift the QA/KA ratio in favor of KA, potentially enhancing resilience of the CNS.

Why This Matters and What Comes Next
Taken together, this study reframes the kynurenine pathway in MS not as a single “bad molecule” problem, but as a dynamic balance of two opposing metabolic constellations—NeuroTox and NeuroPro—that are shaped by both disease processes and modifiable lifestyle factors. A more NeuroTox-skewed profile may mark people at higher risk of accumulating disability, especially as they age or carry more body fat, whereas a more NeuroPro-skewed profile might reflect stronger endogenous neuroprotection, potentially enhanced by regular exercise. At the same time, the work has important limitations: it is cross-sectional (so we can’t infer causality), relies on blood rather than CSF, and was done in a group with relatively mild to moderate disability. The authors call for future longitudinal studies that track these patterns across the full disability spectrum, integrate molecular markers of excitotoxicity and oxidative stress, and test whether targeted lifestyle or pharmacologic interventions can deliberately shift people from a NeuroTox-dominated to a NeuroPro-dominated state. For now, the message is both scientifically rich and practically hopeful: the metabolic environment surrounding MS is not fixed—and some of it may be open to change.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Kupjetz, M., Langeskov-Christensen, M., Riemenschneider, M., Inerle, S., Ligges, U., Gaemelke, T., ... & Zimmer, P. (2025). Persons with multiple sclerosis reveal distinct kynurenine pathway metabolite patterns: a multinational cross-sectional study. Neurology: Neuroimmunology & Neuroinflammation, 12(6), e200461.