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Autism spectrum disorder (ASD) can be a devastating disease with a wide spectrum of manifestations that involve several behavioral deficits and, often, gastrointestinal (GI) dysfunction. A non-genetic (yet heritable) component of human physiology is the microbiome – indigenous microorganisms that have been implicated in immunologic, metabolic, and neurologic diseases. Gut bacterial communities, fecal and serum metabolites differ between ASD patients and matched controls, as well as in animal models of ASD between symptomatic and control mice. Because the microbiome rapidly adapts to dietary, chemical and infectious exposure, and is thought to be shaped by the host and impact disease outcomes, it represents an environmental factor that may contribute to ASD. The central hypothesis to be tested is that the ASD microbiome adopts a pathologic state, and that transplant of microbiota from ASD patients into germ-free mice will transfer behavioral deficits. Exciting preliminary data has been generated that supports this concept. The project will determine whether the microbiome from ASD patients plays a causative role in promoting symptoms associated with ASD, and will test molecular mechanisms by which gut bacteria alter behavior. Developing personalized animal models for ASD will provide revolutionary tools and concepts to test the contribution of environmental etiologies to this currently enigmatic disorder, as well as advance novel approaches for treatment of ASD.