Tryptophan metabolism circadian regulation: clinical and pharmacological implications

Circadian clocks are endogenous systems that synchronize physiology and behavior to the light-dark cycle, regulating sleep-wake timing, hormonal rhythms, metabolism and immunity. Among metabolic pathways tightly linked to circadian rhythm, tryptophan (Trp) metabolism occupies a central position because its catabolism through the kynurenine (Kyn) pathway, the serotonin (5-HT)-melatonin pathway and the microbiota-derived indole-AhR pathway, produce molecules endowed with significant neuro-modulatory and immunoregulatory activities and directly involved in circadian regulation. Emerging evidence supports a bidirectional relationship between the clock system and Trp metabolism. The molecular clock regulates expression and activity of key Trp enzymes, creating time-of-day variation in Trp flux, Kyn-Trp ratio, serotonin/melatonin synthesis and AhR ligands availability. Conversely, Trp-derived metabolites in turn modulate clock function and downstream physiology, such as diurnal variations in metabolism and immune response. Here we discuss recent studies highlighting how this interplay has important pathophysiological implications and disruption of Trp metabolism oscillatory pattern influences our susceptibility to developing diseases, such as infectious, metabolic and neuropsychiatric diseases. Moreover, we highlight the importance of considering daily fluctuation when using these molecules as biomarkers and interpreting them in a clinical setting. Among circadian-based interventions, such as chronotherapy, light therapy or time-restricted feeding, we propose pharmacological targeting of Trp pathways or pharmacological use of Trp derivatives as a novel approach of circadian medicine, able to improve clinical outcomes across various fields.