Effects of Tryptophan Supplementation and Exercise on the Fate of Kynurenine Metabolites in Mice and Humans

Abstract

The kynurenine pathway of tryptophan (TRP) degradation (KP) generates metabolites with effects on metabolism, immunity, and mental health. Endurance exercise training can change KP metabolites by changing the levels of KP enzymes in skeletal muscle. This leads to a metabolite pattern that favors energy expenditure and an anti-inflammatory immune cell profile and reduces neurotoxic metabolites. Here, we aimed to understand if TRP supplementation in untrained vs. trained subjects affects KP metabolite levels and biological effects. Our data show that chronic TRP supplementation in mice increases all KP metabolites in circulation, and that exercise reduces the neurotoxic branch of the pathway. However, in addition to increasing wheel running, we did not observe other effects of TRP supplementation on training adaptations, energy metabolism or behavior in mice. A similar increase in KP metabolites was seen in trained vs. untrained human volunteers that took a TRP drink while performing a bout of aerobic exercise. With this acute TRP administration, TRP and KYN were higher in the trained vs. the untrained group. Considering the many biological effects of the KP, which can lead to beneficial or deleterious effects to health, our data encourage future studies of the crosstalk between TRP supplementation and physical exercise.

Tryptophan Metabolism is a Physiological Integrator Regulating Circadian Rhythms

“…This observation, in combination with our data, suggests that physical exercise could rescue circadian rhythmicity in individuals with obesity via the regulation of systemic kynurenine oscillations. In fact, the notion that Trp metabolites are mediating their physiological effects by integrating behavioral signals are further supported by findings that Trp supplementation is deleterious for health in sedentary mice while it is beneficial in exercising mice 59 In conclusion, our findings introduce Trp metabolism as a circadian modulator that moderates diurnal rhythms and sustains circadian rhythms. Trp metabolism has been suggested as an attractive drug target for different diseases such as cancers and neurodegeneration 60 and the work presented here may indicate Trp-mediated circadian biology as underlying physiology for such therapeutic interventions 7,61 .…”

Tryptophan metabolism is a physiological integrator regulating circadian rhythms

“…This observation, in combination with our data, suggests that physical exercise could rescue circadian rhythmicity in individuals with obesity via the regulation of systemic kynurenine oscillations. In fact, the notion that Trp metabolites are mediating their physiological effects by integrating behavioral signals are further supported by findings that Trp supplementation is deleterious for health in sedentary mice while it is beneficial in exercising mice [ 71 ]. Furthermore, we found that phenyllactate is temporally regulated in a tryptophan- and light-dependent manner which might contribute to the metabolic and behavioral phenotype observed in these mice [ 53 ].…”

Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia

“…In addition, potential side effects of excessive Trp intake should be evaluated in different clinical settings [ 266 ]. Deranged activation of the TKP is common in COVID-19, and Trp supplementation may potentially increase the systemic concentration of harmful Trp metabolites [ 267 ].…”