The Tryptophan–AhR Circuit in the Gut: Microbial Indoles, Kynurenines, Serotonin, and Therapeutic Opportunities in Inflammatory Bowel Disease__A Comprehensive Review
Keywords:
Tryptophan metabolism, Aryl hydrocarbon receptor, Indoles, Kynurenine pathway, Serotonin, Inflammatory bowel diseaseAbstract
Tryptophan (Trp) metabolism serves as a pivotal interface linking diet, microbiota, and host immunity in the gut. Through three interconnected pathways__the kynurenine, indole, and serotonin branches__Trp is converted into bioactive metabolites that act as endogenous ligands for the aryl hydrocarbon receptor (AhR). Activation of AhR orchestrates epithelial repair, mucosal tolerance, and cytokine programs such as IL-22 and IL-10, maintaining intestinal homeostasis. Dysregulation of this circuit, characterized by enhanced kynurenine flux, depletion of microbial indoles, and disturbed serotonergic balance, contributes to the pathogenesis of inflammatory bowel disease (IBD). Microbiota-derived metabolites like indole-3-aldehyde and indole-3-propionic acid enhance barrier integrity, while kynurenine derivatives regulate immune signaling and serotonin pathways exert context-dependent effects. Restoring AhR tone through dietary ligands, microbial modulation, or metabolic targeting has demonstrated therapeutic potential in preclinical colitis models. This review synthesizes current mechanistic insights into the Trp–AhR axis, emphasizes microbiota–immune interactions in IBD, and discusses translational opportunities for biomarker-guided and personalized therapeutic interventions.
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