Does microbiome composition moderate GI and CNS function in a VPA-induced mouse model of autism?

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Project Summary GI issues occur in 30-80% of autistic individuals and may result in significant pain and distress. Thus, there is an urgent need to understand why GI symptoms occur in ASD and to develop more effective interventions. Recent research suggests the gut microbiome may contribute to GI issues in ASD. Autistic people differ from controls in the microbes they carry, patterns that may be linked to autism-related dietary preferences and the adverse effects of ASD linked genes and ASD linked environmental exposures on gut development and function. In addition, transfer of microbes from people with ASD induces ASD-like behaviors in germ-free mice suggesting these differences, regardless of their causes, contribute to behavioral issues. Further, recent open label trials of fecal matter transplant and of a drug that binds and sequesters aromatic metabolites in the gut have shown promising results in autistic people. While these findings are exciting, there is still much to be done in terms of mapping the biological mechanisms connecting gut microbiota to GI and CNS function in ASD. The main objec- tive of this study is to evaluate the effect of humanized gut microbiomes on GI and CNS function in a valproic acid (VPA)-induced mouse model of ASD. We will achieve this objective via 2 aims. In Aim 1, we will determine if gut microbiome composition moderates the impact of prenatal VPA exposure on GI function by creating three groups of animals with differing microbiomes: specific pathogen-free (SPF) mice, mice with a human gut micro- biome dominated by Bifidobacterium (BIF), and mice with a human gut microbiome dominated by Bacteroides (BAC). Half of the animals will be exposed to VPA (500 mg/kg) on day 13 of gestation and half will receive a sham treatment. We will assess colonic transit and intestinal permeability in live adult offspring, discern neuro- enteric organization using immunostaining and RT-PCR, conduct ex vivo colonic motility assays, measure intes- tinal inflammation, and use electrophysiological methods to record from enteric nerve and muscle cells in isolated preparations of intestine to study synaptic and circular muscle neurotransmission. In Aim 2, we will determine whether gut microbiome composition moderates the impact of prenatal VPA exposure on CNS structure and function. Using the same groups as in Aim 1, we will evaluate juvenile and adult behavior using well established paradigms directly relevant to ASD. To investigate underlying mechanisms, we will assess neuroinflammation, dendritic morphology, and myelination in hippocampus, amygdala, and prefrontal cortex (PFC). The proposed study is innovative in combining a well-established preclinical model for ASD – gestational VPA exposure – with transplant of human microbial communities collected during infancy, a key period in the etiology of ASD. The proposed study is significant as it will enhance our understanding of the gut microbiome’s role in GI and CNS functions relevant to ASD. The project will have a positive impact because it will provide information and a novel modelling approach that will facilitate the development of novel microbiome-related interventions to ad- dress core ASD symptoms and comorbidities including intellectual disability, anxiety and GI issues.