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

Abstract Gastrointestinal (GI) symptoms are prevalent in Autism Spectrum Disorder (ASD), yet their biological correlates remain poorly understood, notably in adults. The microbiota-derived metabolite p- cresol is reported to be elevated in the urine and stool of ASD patients, 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 (mean age: 30.9 ± 10.3 years; 33.1% females). Clinical and dietary assessments were performed and circulating serum levels of p- cresol and its conjugates were measured using targeted metabolomics in a subsample of 177 patients. Serum levels were specifically measured to capture systemic exposure, in contrast to fecal or urinary levels, which primarily reflect luminal microbiota production or renal excretory capacity of microbial metabolites and their conjugates. Females with ASD had higher rates of GI symptoms and elevated p- cresol levels 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 exposure to p -cresol (50 mg/kg/day for 4 weeks) via drinking water to mimic GI exposure to microbial metabolites produced in the intestinal lumen, induced constipation-like GI dysfunction, supporting a causal link. These findings identify p -cresol as a possible mediator of constipation. This work supports the development of tailored interventions for GI symptoms in adults with ASD.