Children with Autism Spectrum Disorder and Chronic Gastrointestinal Symptoms Have Alterations in Intestinal Neurotransmitter Pathways

BACKGROUND AND AIMS: Emerging evidence supports a strong bidirectional relationship between the gastrointestinal system and the central nervous system, referred to as the gut-brain axis. This axis has been proposed to be of particular importance in the context of neurodevelopmental disorders including autism spectrum disorder (ASD). While neurotransmitter dysregulation and synaptic dysfunction have been well documented in the brains of individuals with ASD, less is known about how these molecular changes manifest in the gut METHODS: In this study, we analyzed RNA signatures in biopsies from the ileum and colon of children with chronic GI symptoms, either with (cases) or without (controls) an autism diagnosis. RESULTS: Genes associated with serotonin signaling (AANAT, HTR1D, HTR3A, SLC6A4), dopamine synthesis and receptor function (DDC,DRD5), and glutamatergic pathways (GAD2, GRIK3, GLUD1, GRIN2C, SLC1A3, SLC38A1, GABRP, GABRB3, GRM4) were significantly altered in children with ASD, suggesting a broad disruption in neurotransmitter homeostasis in the gut. Additionally,several neuroactive compounds, such as NPY, GIP, NTS, AREG, GKN1, GHRL, LEP, PDYN, and EDN2, were also impacted,further implicating altered neuroimmune interactions and developmental pathways in gut tissues. CONCLUSIONS: These findings highlight the potential role of the gut as a critical modulator of neurodevelopmental processes in ASD and suggest that gut-brain axis dysregulation may contribute to the ASD phenotype. This study provides new insights into the molecular mechanisms in the gastrointestinal tract in individuals with ASD and suggests novel therapeutic targets for restoring healthy gut-brain communication.