TBA (26S191)

Exploring Microbiota-Derived p-Cresol as a Possible Contributor to Gastrointestinal Symptoms in Autism Spectrum Disorder

Author(s)

Morgane E. Le Dréan1,2,*, Carla Viñola-Renart1,2,*, Niall Hyland1,2,#, Friederike Uhlig1,2,# 1 University College Cork 2 APC Microbiome Ireland * shared first authors # shared last authors

Department(s)/Institutions

University College Cork, APC Microbiome Ireland

Introduction

The gastrointestinal (GI) tract and its intrinsic enteric nervous system are continuously exposed to microbial-derived metabolites present in the gut lumen and circulation, which can modulate GI physiology. The bacterial metabolite p-Cresol has been reported to be elevated in individuals with autism spectrum disorder (ASD), a condition frequently associated with gastrointestinal symptoms. However, whether p-Cresol directly affects GI physiology and could contribute to ASD-associated gastrointestinal dysfunction remains unknown.

Aims/Background

This study aims to investigate the acute and chronic effects of p-Cresol on gut physiology in mice.

Method

The effects of p-Cresol were assessed ex vivo in isolated mouse small intestine using Ussing chambers and organ baths to evaluate enteric nerve activity, epithelial ion transport, and gut contractility. In vitro, calcium responses were measured in primary enteric neuron cultures following p-Cresol exposure. All experiments were approved by the University College Cork Animal Experimentation Ethics Committee (#25-004).

Results

In Ussing chamber experiments, p-Cresol (500µM) significantly reduced basal and neuronally mediated epithelial secretory responses, as indicated by decreased ion transport following veratridine (30µM; p=0.0004; n=18) and carbachol (100µM; p=0.0054; n=18) stimulation, without altering epithelial integrity. In organ bath experiments, p-Cresol significantly reduced intestinal tone (50–500µM; p=0.0065; n=10) and cholinergic-induced contractile response (100µM, p=0.0147; n=10). In primary enteric neuron cultures, prolonged exposure to p-Cresol (50µM, 4 days) significantly reduced cholinergic-induced calcium responses (100µM, p=0.023; n=11). This suggests that sustained exposure to p-Cresol may be associated with enteric neuronal remodelling.

Conclusions

Together, these findings implicate p-Cresol in GI regulation, with potential relevance to ASD-associated gastrointestinal symptoms.