Insights into the molecular mechanisms of bacterial metabolites in the pathogenesis of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder usually diagnosed at early age and characterized by impairments in social behavior and communication, the presence of repetitive behavior, and deficits in learning and memory. Two of these bacterial metabolites, p-cresol sulfate (pCS) and 4-ethylphenyl sulfate (4EPS), are reported to be enhanced in feces, blood and urine of people diagnosed with ASD. Moreover, pCS and 4EPS exposure in mice induces ASD-like behavior, but the exact underlying mechanisms remain to be investigated. Many sheddases are members of the so-called ADAM family and potentially play a role in the pathogenesis of disease. In addition, the phosphatase PTEN is an important enzyme that regulates neural cell growth and survival in the brain. This thesis is focused on gaining insights into the possible molecular mechanisms of bacterial metabolites in the pathogenesis of ASD to identify potential new targets for intervention and therapy. Using an ASD mouse model and a neuroinflammation cell model, this thesis illustrates that pCS and 4EPS affect the level and function of the sheddases, ADAM10 & ADAM17, and the phosphatase, PTEN, that might be involved in the ASD-associated changes in neuroimmune responses and/or neuronal network function in the brain. In addition, this thesis further identifies that ADAM10 might be a treatment-target for ASD either through direct pharmacological inhibition or via nutritional interventions targeting bacteria that are involved in pCS and 4EPS production aimed to reduce ASD-associated detrimental symptoms.