Possible role of tryptophan metabolism along the microbiota-gut-brain axis on cognitive & behavioral aspects in Phenylketonuria

Cognitive and psychiatric disorders are well documented across the lifetime of patients with inborn errors of metabolism (IEMs). Gut microbiota impacts behavior and cognitive functions through the gut-brain axis (GBA). According to recent research, a broad spectrum of GBA disorders may be influenced by a perturbed Tryptophan (Trp) metabolism and are associated with alterations in composition or function of the gut microbiota. Furthermore, early-life diets may influence children's neurodevelopment and cognitive deficits in adulthood. In Phenylketonuria (PKU), since the main therapeutic intervention is based on a life-long restrictive diet, important alterations of gut microbiota have been observed. Studies on PKU highlight the impact of alterations of gut microbiota on the central nervous system (CNS), also investigating the involvement of metabolic pathways, such as Trp and kynurenine (KYN) metabolisms, involved in numerous neurodegenerative disorders. An alteration of Trp metabolism with an imbalance of the KYN pathway towards the production of neurotoxic metabolites implicated in numerous neurodegenerative and inflammatory diseases has been observed in PKU patients supplemented with Phe-free amino acid medical foods (AA-MF). The present review investigates the possible link between gut microbiota and the brain in IEMs, focusing on Trp metabolism in PKU. Considering the evidence collected, cognitive and behavioral well-being should always be monitored in routine IEMs clinical management. Further studies are required to evaluate the possible impact of Trp metabolism, through gut microbiota, on cognitive and behavioral functions in IEMs, to identify innovative dietetic strategies and improve quality of life and mental health of these patients.

Automated summary

Cognitive and psychiatric disorders are common in patients with inborn errors of metabolism (IEMs). Gut microbiota plays a role in behavior and cognition through the gut-brain axis. Recent research suggests that disrupted tryptophan metabolism, possibly caused by alterations in gut microbiota, may contribute to a broad spectrum of gut-brain axis disorders. Early-life diets also influence neurodevelopment and cognitive deficits in adulthood. Phenylketonuria (PKU) is an IEM that involves a restrictive diet, and significant changes in gut microbiota have been observed in PKU patients. The alteration of tryptophan metabolism, particularly the imbalance of the kynurenine pathway, has been associated with neurotoxic metabolites in PKU patients on amino acid medical foods supplementation.