Increasing evidence suggests that the intestine plays an important role in sensing not only the presence of pathogens but also changes in the microbiota, which ultimately result in changes in the regulation of immune pathways and behaviors by communicating with neurons. However, the complexity of the nervous and immune systems of mammals makes it difficult to dissect the mechanisms by which the neural-gut axis communicates using bidirectional signals to control intestinal immunity. Studies in the nematode Caenorhabditis elegans show that bacterial colonization of the intestine results in the activation of the expression of innate immune genes in the gut and the activation of a neuroendocrine signal that controls pathogen avoidance. The germline also plays a key role in the neural-gut axis not only by transmitting the immunological memory to the next generation but also by communicating pathogenic cues that travel from the gut to the nervous system to control innate immunity. The long-term goal of this proposal is to elucidate the mechanism by which the neural-germline-gut axis communicates to sense pathogens and/or infection-induced physiological changes to control innate immunity at the whole animal level. Thus, we will explore the general hypothesis that the neural-germline-gut axis plays a critical role in the organismal response against bacterial pathogens by helping the nervous system integrate signals from infected sites and different tissues to coordinate the immune response. Specific genes and neurons will be studied to dissect the neural circuits that regulate immune activation in response to pathogen exposure and pathogen-induced alterations of the animal’s physiology. A genetics approach will also be used to identify neurotransmitters and endocrine signals potentially involved in the neural-immune communication that takes place between neurons and different tissues and infected sites.