Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression

Abstract

Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers.

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

“…Here, we showed that higher relative abundance of kynurenine in the serum is associated with higher relapse rate in pediatric patients with MS. Unlike the previous report,16 we did not find a correlation between other kynurenine pathway metabolites and the risk of developing MS or physical or cognitive disability scores in our cohorts. This discrepancy might be due to the difference in the age of participants (pediatric vs. adult) or statistical modeling (e.g.…”

“…Finally, higher kynurenine levels were associated with higher relapse rate. These results are generally in line with our understanding of the effects of different tryptophan metabolites on the risk and severity of MS 13, 14, 16. While metabolomics analyses have identified alterations in multiple metabolic processes in MS, these techniques have not been previously applied to pediatric MS and have not studied the tryptophan pathway as a whole 30.…”

“…Pro‐inflammatory cytokines stimulate indoleamine 2,3‐dioxygenase, the first enzyme in the kynurenine pathway. Kynurenine metabolites have pro‐inflammatory, as well as, neurotoxic and neuroprotective effects, and the kynurenine pathway metabolic signature may discriminate clinical disease subtypes 16. Here, we showed that higher relative abundance of kynurenine in the serum is associated with higher relapse rate in pediatric patients with MS.…”

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

“…Conversely, raising kynurenic acid levels in the CNS by inhibiting the enzyme kynurenine‐3‐monoxygenase (Forrest et al ) has overall neuro‐inhibitory and neuroprotective effects which are potentially of value in the treatment of neurodegenerative disorders, especially Huntington's disease (Stone ; Stoy et al ; Giorgini et al, , ; Guidetti et al ; Forrest et al ; Schwarcz et al ; Stone et al ,b; Lovelace et al ; Jacobs et al, ). Kynurenine metabolites, especially quinolinic acid and kynurenic acid may also be involved in the brain damage resulting from cerebral infarcts (strokes), and may be involved in dysfunctional conditions such as multiple sclerosis (Lovelace et al , ; Lim et al ).…”

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

“…The kynurenines produced by Trp catabolism may be neuroprotective (kynurenic acid, picolinic acid) or neurotoxic (3‐hydroxykynurenine, quinolinic acid), with dysfunction suggested in MS by greater activity in pathways leading to production of neurotoxic mediators 22. With measurement of greater IDO1 mRNA in cells from patients with CIS, the present study suggests greater flux through the kynurenine pathway early in the MS disease course.…”