The role of microbial-derived p-Cresol in autism spectrum disorder: A systematic review of the gut-brain axis.

This research looked at a chemical called p-Cresol made by gut bacteria and its connection to autism. Researchers reviewed 17 studies and found that autistic individuals typically had higher levels of this chemical in their urine or stool. Higher p-Cresol was linked to tummy problems like constipation and diarrhea, changes in gut bacteria, and more severe autism behaviors. The studies suggest gut bacteria might affect the brain through various pathways, but more research is needed to understand if p-Cresol causes autism symptoms or is just associated with them.

This systematic review examined the relationship between p-Cresol, a microbial metabolite, and autism spectrum disorder (ASD) through the gut-brain axis framework. Analyzing 17 studies, researchers found that individuals with ASD consistently showed elevated urinary or fecal p-Cresol levels compared to controls. These elevated levels were associated with gastrointestinal symptoms (particularly constipation and diarrhea), specific microbiota changes including increased Clostridium difficile and Desulfovibrio, and behavioral manifestations correlating with ASD severity. The gut-brain axis represents bidirectional communication between gut microbiota and brain function through immune, metabolic, and neural pathways.

While findings suggest p-Cresol may contribute to ASD pathophysiology, study heterogeneity, small sample sizes, and analytical variability limit generalizability.

p-Cresol may serve as a potential biomarker for ASD and gut dysfunction. The consistent associations suggest targeting gut microbiota producing p-Cresol could be therapeutic. However, longitudinal and mechanistic studies are needed before clinical applications. Current findings support gut-brain axis involvement in autism pathophysiology.

Study heterogeneity in designs, small sample sizes, and variability in analytical techniques limit generalizability of results. The review cannot establish causality between p-Cresol and ASD symptoms, only associations.

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). 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). 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. 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.