SUMMARY The ability to distinguish harmful and beneficial microbes is critical for the survival of an organism. Increasing evidence indicates that gut distension caused by bacterial colonization activates a broad innate immune response. We propose that microbial colonization and bloating of the intestine may be perceived as a danger signal that activates an immune fight-and-flight response. This innate immune activation depends on inputs from the intestine that can aid in the recognition of a broad range of microbes and can modulate host responses using a neural-gut axis that controls immune homeostasis. This proposal describes experiments designed to elucidate the mechanisms by which the nervous system may sense overall changes in host physiology during pathogen infections and coordinate innate immune responses. Using the nematode Caenorhabditis elegans, we have demonstrated that specific genes and neurons in the nervous system of the animal control immune responses, indicating that cell non-autonomous signals from different neurons may act on non-neural tissues to regulate innate immune responses at the organismal level. We propose the use of a variety of molecular and genetic techniques to explore the general hypothesis that alterations in host physiology caused by bacterial infections trigger innate immune responses against bacterial infections that are controlled at that whole animal level by the nervous system.