Impacts of microbially derived metabolites on neural development and neural gene expression in the context of neurological disorder

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Rea, Victoria
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University of Guelph

Colonization of the human gut microbiota begins before birth and continues through adulthood where it collectively consists of trillions of microorganisms. Studies have shown that the gut microbiota is required for proper organ development as an absence of microorganisms causes significant developmental deficits to their host. Given that an absence of microbiota has a negative impact on other developmental systems and that rapid nervous system development coincides with bacterial colonization, it was hypothesized that microbial absence also negatively impacts neural development. This was made with the assumption that this is at least in part due to the products of bacterial metabolism as certain metabolites such as short chain fatty acids are known to act as neurotransmitters and modulate neural cell functioning. The overall objective of this thesis was to use zebrafish neurodevelopment as a proxy for evaluating the contribution of gut-derived microbe metabolites to early neural development and gene expression. To this end, we first evaluated the contributions of metabolites isolated from the adult zebrafish gut to embryonic germ-free zebrafish and found that zebrafish gut derived metabolites are sufficient to rescue the expression of neurodevelopment genes. We then assessed the impact of metabolites in the context of neurological disorder by investigating differences in neural gene expression and nervous system development of germ-free embryos treated with metabolites derived from neurotypical (NT) individuals or individuals with autism (ASD). Here we found differences in gene expression and alternative splicing between the NT and ASD group, as well as between two ASD subgroups, pointing to the use of this research for further investigation into different ASD subtypes. Finally, we explore how prebiotics and antibiotics can impact fecal samples derived from individuals with neurological disorder via two independent case studies. In the first we found that prebiotic treatment increased abundance of Firmicutes and downregulated several ASD risk genes in an ASD sample. In the second we found that antibiotic treatment correlated with downregulation of ASD risk genes in a patient with PANDAS.

Microbiome, Zebrafish, Autism, RNAseq, Metabolites, Neurodevelopment
Rea, V. & Van Raay, T. J. Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts. Frontiers in Molecular Neuroscience 13, 207 (2020). doi:10.3389/fnmol.2020.575575
Rea, V., Bell, I., Ball, T. and Van Raay, T. Gut-derived metabolites influence neurodevelopmental gene expression and Wnt signaling events in a germ-free zebrafish model. Microbiome 10, 132 (2022).