Most research into autism and autism spectrum disorders (ASD) has focused on genetic, behavioral, and neurological aspects of the illness. However, a role for the immune system in the onset or progression of autism has recently gained significant attention. Striking alterations in the immune status of the brains of autistic subjects have been found. Moreover, many autistic children have been diagnosed with food allergies and are on special diets. There are a number of reports of inflammatory reactions in the gastrointestinal (GI) tract in ASD: a significant subset of autistic children display chronic inflammation of the colon; many ASD children have loose stool; diagnostic analysis of patients reveal elevated levels of inflammatory factors; the bacterial microbiota (the collection of beneficial bacteria within the intestine of humans) is altered in ASD; antibacterial treatments provide behavioral improvements in ASD. Thus, the connection between gut bacteria, intestinal inflammation and autism is a very promising area of investigation. However, a hypothesis-driven investigation in this area has not been attempted thus far. Combining two laboratories with different but relevant areas of expertise, we propose to study the ability of beneficial gut bacteria to ameliorate ASD-like symptoms in a mouse model. We will test for improvements in behavioral, neuropathologic, and GI abnormalities by introducing a probiotic microbe that has already been shown to reduce intestinal inflammation. In recent years, the notion that beneficial bacteria can provide a remedy for digestive diseases is becoming accepted by the public (many grocery stores carry yogurt products supplemented with probiotics). The Mazmanian laboratory was the first to show how a human symbiotic microbe prevents harmful intestinal immune responses. Since GI inflammation can dramatically alter behavior in animal models and in human disorders, our goal is to extend this connection to ASD. Combined with the expertise of the Patterson laboratory, which has developed an animal model for autism based on epidemiological research, we wish to validate the use of specific beneficial bacteria as a therapy for ASD. Namely, can we measure improvements in the ASD-like behaviors and neuropathology by curing intestinal symptoms associated with the disease? We have recently demonstrated that symbiotic intestinal bacteria direct the development of the mammalian immune system and confer protection from GI inflammation. Bacteria in our intestines actively promote our health, and therefore losing these "good" bacteria may lead to disease. As the incidence of autism diagnosis has risen dramatically in recent years, many have speculated lifestyle changes to be the cause for this increase. Have societal advances (including sanitation, "Western" diets, hygiene, and anti-bacterial therapeutics) paradoxically affected human health adversely by reducing our exposure to health-promoting gut bacteria? We propose that by restoring the balance of beneficial microbes, we can correct the environmental factor(s) that may be contributing to the development of autism in so many children today. If successful, our approach could provide clinical benefits to a broad range of ASD patients, including children, adolescents, and adults. The use of beneficial bacteria that are found in most healthy humans should pose very little risk to patients. Furthermore, as these therapeutics are natural and harmless, the time frame to achieve patient-related outcomes will likely be shorter than for therapies using synthetic chemicals. Our hope is that by understanding the biological reasons why individuals develop autism, and if treatment with specific probiotic bacteria to ASD children can be beneficial, we can design novel and natural therapeutics to prevent and/or cure this devastating disease.