Project Summary/Abstract The gut microbiota has a plethora of important functions that promote human health. The impact of maternal gut microbiota on neonatal health, however, remains largely unknown. Sepsis is an important cause of morbidity and mortality among newborn infants, particularly in preterm infants. Our preliminary studies have unraveled a previously unknown function of the gut microbiota to induce antigen-specific IgG antibodies under homeostatic conditions, which can rapidly mediate clearance of pathogens bearing conserved IgG antigens during systemic infection. Importantly, we found robust levels of commensal-specific IgG antibodies in both mouse and human breast milk. Therefore, our central hypothesis is that 1) maternal commensal IgG confers critical protection to the neonate against infection; 2) maternal immunization with IgG-inducing beneficial gut symbiotic bacteria, or IgG-inducing antigens, may be a novel approach to treat neonatal sepsis, which can be caused by dissemination of gut bacteria. This hypothesis will be tested through three specific aims: 1) determine the role of maternal gut microbiota-induced IgG in neonatal enteric infection, 2) identify and characterize gut symbiotic bacteria that induce homeostatic antigen-specific IgG antibodies, and 3) determine whether maternal immunization with IgG-inducing bacteria or antigens confers protection in the neonate. The objective of the current application is to harness gut microbiota-induced IgG to develop therapeutics for neonatal sepsis, and for the PI to learn new skills such as developing neonatal infection models and vaccine nanoparticles, which are important for her to develop an independent research program with a focus on the gut microbiota and neonatal health. The research is significant because these studies will unravel potentially novel and effective approaches to treat neonatal sepsis. The distinguished mentoring team will allow the PI to complete the proposed studies with new skills and transition to independence in a new field of study. In addition, the excellent research environment of the University of Michigan will provide exceptional support for the proposed studies and the PI's career development.