The Role of Microbial-Derived p-Cresol in Autism Spectrum Disorder: A Systematic Review of the Gut-Brain Axis

Background & Aims Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition increasingly associated with gut microbiota alterations. Among microbial metabolites, p-Cresol has emerged as a potential contributor to the pathophysiology of ASD. This systematic review aims to examine the evidence linking p-Cresol and its metabolites with ASD and explore their potential role within the gut–brain axis framework, a bidirectional communication system where gut microbiota influence brain function via immune, metabolic, and neural pathways (e.g., vagus nerve, microbial metabolites). Methods A comprehensive literature search was conducted in PubMed, Web of Science, Scopus, and Cochrane up to March 2025, following PRISMA 2020 guidelines. Studies were included if they quantified p-Cresol or its derivatives in biological samples from individuals with ASD. Data extraction and risk of bias assessment were performed independently by two reviewers. The protocol was prospectively registered in PROSPERO (CRD420251007080). Results Seventeen studies met the inclusion criteria. Most reported elevated urinary or fecal p-Cresol levels in individuals with ASD compared to controls, with consistent associations found between p-Cresol concentrations and (1); gastrointestinal symptoms, particularly constipation and diarrhea; (2) specific microbiota alterations including increased Clostridium difficile and Desulfovibrio abundance; and (3) behavioral manifestations and ASD severity. However, heterogeneity in study designs, small sample sizes, and variability in analytical techniques limit the generalizability of the results. Conclusion p-Cresol and its microbial precursors may contribute to ASD pathophysiology through gut–brain axis interactions. Although current evidence supports this association, further longitudinal and mechanistic studies are needed to confirm causality and evaluate p-Cresol as a biomarker or therapeutic target in ASD.