"The Western world is experiencing a growing medical crisis. Epidemiologic and clinical reports reveal a dramatic increase in immune and neurological disorders: inflammatory bowel disease, asthma, type 1 diabetes, multiple sclerosis and autism. Emboldened by the 'hygiene hypothesis' proposed two decades ago, scientists have speculated that lifestyle changes (vaccination, sanitation, antibiotics) have predisposed developed societies to these disorders by reducing bacterial infections. However, the hypothesis remains without explanation as human exposure to most bacteria does not result in disease. Mammals are colonized for life with 100 trillion indigenous bacteria, creating a diverse ecosystem whose contributions to human health remain poorly understood. In recent years, there has been a revolution in biology toward understanding how (and more importantly, why) mammals harbor multitudes of symbiotic bacteria. Our laboratory has demonstrated for the first time that intestinal bacteria direct universal development of the immune system, and control complex behaviors in animal models; thus fundamental aspects of mammalian health are inextricably dependent on microbial symbiosis. As humans have co-evolved with our microbial partners for eons, have strategies used against infectious agents reduced our exposure to health-promoting bacteria, ultimately leading to increased disease? We propose that the human genome does not encode all functions required for health, and we depend on crucial interactions with products of our microbiome (collective genomes of our gut bacterial species). Through genomics, microbiology, immunology, neurobiology and animal models, we wish to define the molecular processes employed by symbiotic bacteria that mediate protection from disease. Advances in recent years have now made it possible to mine this untapped reservoir for beneficial microbial molecules. Ultimately, understanding the mechanisms of interaction between the beneficial gut microbiota and the immune and nervous systems may lead to natural therapeutics for human diseases based on entirely novel biological principles."