Impact of autistic-derived metabolites on the dynamics and connectivity of neuronal cultures

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition with complex and largely unknown causes. While genetic factors are widely studied, growing evidence suggests that environmental influences, including gut microbiome alterations, may play a significant role in ASD pathophysiology. Recent hypotheses propose that disruptions in gut microbiota composition could impact brain function and contribute to the development of ASD. This study investigates the effects of ASD-associated microbiota metabolites on the dynamics and connectivity of neuronal cultures, which provide an accessible model to explore brain-like processes at the cellular level, offering insights into how neuronal abnormalities may lead to dysfunction and disease. To examine this, three types of cultures are analyzed: cultures treated with fecal-derived metabolites from individuals with ASD or neurotypical individuals, and control cultures. All samples contain metabolites that differentially influence neuronal behavior. Experimental data is combined with an in silico model to help understanding the relationship between neuron-level connectivity and network-wide collective behavior. Results show that ASD cultures exhibit alterations in spontaneous activity and effective connectivity as compared to the neurotypical condition, although these alterations are not preserved along development, an aspect that hints at the activation of plasticity mechanisms that counterbalance possible damage By elucidating the effects of ASD-associated microbiota metabolites on neuronal function, this study helps advance our understanding of gut-brain interactions in ASD and their role in neurodevelopmental disorders