Tryptophan Metabolism in Neurodevelopment and Its Implications For Neurodevelopmental Disorders

The role of tryptophan metabolism has been recognized in a wide range of physiological and pathological processes but is still only partially understood. Growing evidence highlights the importance of maintaining tryptophan homeostasis throughout life, with its disruption now linked to various neuropsychiatric conditions spanning from early life to aging. While it is increasingly evident that alterations in tryptophan metabolism have significant implications for both neurodevelopmental and neurodegenerative disorders, research has predominantly focused on the latter, leaving neurodevelopmental aspects comparatively underexplored. This review provides a comprehensive overview of both preclinical and clinical studies, highlighting the intricate relationship between tryptophan metabolism and neurodevelopment. Particular focus is given to the kynurenine pathway and gut microbiota-derived indole production, two interconnected metabolic branches with profound effects on brain maturation, plasticity, and immune regulation. Finally, we examine the pathophysiological consequences of tryptophan dysregulation in neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and Rett syndrome. We also discuss potential therapeutic strategies targeting tryptophan metabolism in these conditions.