The serum kynurenine pathway metabolic profile is associated with overweight and obesity in multiple sclerosis.

Background: Overweight and obesity increase multiple sclerosis (MS) susceptibility, disease severity, and disability progression. Kynurenine pathway (KP) dysregulation is present in overweight and obesity, and in MS. Since the effect of overweight and obesity on KP dysregulation in persons with MS (pwMS) remains to be established, this study primarily aims to explore the effect of overweight and obesity on the serum KP metabolic profile in pwMS.

Methods: This cross-sectional study represents a secondary analysis of a randomized clinical trial at Valens rehabilitation clinic, Switzerland. Registration was performed on 22 April 2020 at clinicaltrials.gov (NCT04356248, https://clinicaltrials.gov/ct2/show/NCT04356248). The first participant was enrolled on 13 July 2020. Based on body mass index (BMI), 106 MS inpatients (Expanded Disability Status Scale (EDSS) score ≤ 6.5) were dichotomised to a lean group (LG, BMI < 25 kg/m), and an overweight/obese group (OG, BMI ≥ 25 kg/m). Targeted metabolomics (LC-MS/MS) was performed to determine serum concentrations of tryptophan (TRP), KP downstream metabolites, and neopterin (Neopt). Correlations between BMI, kynurenine-to-TRP ratio (KTR), and serum concentrations of TRP, KP downstream metabolites, and Neopt were calculated. ANCOVA was used to determine differences in KTR, and serum concentrations of TRP, KP downstream metabolites and Neopt between OG and LG, and across MS phenotypes.

Results: Higher BMI correlated with higher KTR (r = 0.425, p <0.001) and serum concentrations of most KP downstream metabolites, but not with EDSS score. Higher KTR (r = 0.470, p < .001) and serum concentrations of most KP downstream metabolites correlated with a higher serum concentration of Neopt. The OG (n = 44, 59% female, 51.68 (9.98) years, EDSS: 4.71 (1.37)) revealed higher KTR (0.026 (0.007) vs. 0.022 (0.006), p=.001) and serum concentrations of most KP downstream metabolites than the LG (n = 62, 71% female, 48.37 (9.63) years, EDSS: 4.60 (1.29)). KP metabolic profiles did not differ between MS phenotypes.

Conclusion: Overweight and obesity are associated with a systemic elevation of KP metabolic flux and an accumulation of most KP downstream metabolites in pwMS. Further research is needed to clarify if KP involvement serves as a mechanism linking overweight and obesity with symptom expression, disease severity, and disability progression in pwMS.