Cell Signaling by Tryptophan Catabolism

Tryptophan (Trp) metabolism follows three main branches: the kynurenine (KP), serotonin, and indole (IP) pathways. These pathways generate bioactive metabolites that regulate immune responses, redox balance, neurotransmission, metabolic homeostasis, inflammation, and circadian rhythms. A common theme across these pathways is the activation of the aryl hydrocarbon receptor (AhR). Several metabolites from KP, IP, and serotonin act as endogenous AhR ligands or interact indirectly with AhR, but the downstream consequences of this interaction depend on the cellular environment and inflammatory context. In addition, Trp metabolites also impact other signaling pathways, including GPR35, NMDA receptors, serotonergic receptors, and NAD⁺ biosynthesis. Notably, our group recently discovered that the upregulation of the KP results in the formation of the novel redox-active mediator kynurenine-carboxyketoalkene. This finding expands the signaling repertoire of Trp metabolism to include the modulation of cysteine-dependent pathways, with important implications for the maintenance of cellular homeostasis and immune control. Overall, flux through the oxidative arm of the KP links inflammation to cellular energy metabolism, while microbial indole derivatives influence host-mucosal immunity and host-microbe communication. The serotonin pathway connects neuroendocrine signaling with the peripheral nervous system's regulation of metabolism. Shifts in Trp homeostasis caused by inflammation, alterations in microbial composition, or metabolic demand modify downstream signaling outputs under physiological and pathological conditions. In this regard, dysregulation of Trp metabolism is implicated in neurodegeneration, cancer, metabolic disease, cardiovascular dysfunction, and chronic inflammation. This review presents Trp catabolism as a distributed signaling network and offers new insights into its physiological functions.