Microbial metabolite p-cresol associates with constipation in adults with high-functioning autism spectrum disorder and induces constipation-like symptoms in mice

Gastrointestinal (GI) symptoms are prevalent in Autism Spectrum Disorder (ASD), yet their biological correlates remain poorly understood. The gut microbial metabolite p-cresol is reported to be elevated in ASD, but its link to specific GI symptoms in adult high-functioning adults remains unexplored. We examined the relationship between serum levels of p-cresol and its conjugates (p-cresol sulfate, p-cresol glucuronide) with five common GI symptoms (diarrhea, constipation, abnormal stool aspect, bloating, abdominal pain) in 272 adults with high-functioning ASD. Clinical and dietary assessments were performed, and serum metabolites were measured using targeted metabolomics in 177 patients. Females with ASD had higher rates of GI symptoms and elevated p-cresol compared to males. Multivariable regression analysis showed that serum p-cresol, but not its conjugates, was selectively associated with constipation frequency, independent of sex, age, and diet. No associations were observed with the other GI symptoms. In mice, chronic p-cresol exposure induced constipation-like GI dysfunction, supporting a causal link. These findings identify p-cresol as a possible mediator of constipation in ASD. This work supports the development of tailored interventions for GI symptoms in adults with ASD. LAY SUMMARYPeople with autism spectrum disorder (ASD) often experience gastrointestinal (GI) symptoms, but the role of the gut microbiota remains unclear. Elevated levels of p-cresol, a gut microbiota-derived molecule, have been reported in ASD, though its link to specific GI symptoms, particularly in adults, remains unknown. We studied 272 adults with high-functioning ASD and we found that women with ASD reported more frequently GI symptoms and had higher levels of p-cresol than men. Higher p-cresol levels were associated with more frequent constipation, but not with other GI symptoms. In mice, p-cresol treatment induced signs of constipation, suggesting a causal role. Overall, our findings indicate that p-cresol may contribute to constipation in adults with ASD and support the need personalized medical approaches to digestive health in adults with ASD.