The maternal microbiome in childhood growth and immunity during undernutrition

Globally, undernutrition contributes to 44% of childhood deaths under the age of five 1. Stunting, or reduced linear growth, is a major complication of undernutrition that is associated with increased risk of metabolic and infectious disease, reduced educational attainment and poor cognitive function later in life 3. Stunted mothers are more likely to experience complications during childbirth, and to give birth to stunted children 5. In turn, many children that are born stunted do not recover despite current therapeutic interventions 4. Therefore, stunting is often referred to as an intergenerational syndrome, and new approaches are desperately needed to improve childhood growth in vulnerable populations. The maternal immune system plays a major role in shaping offspring physical, cognitive and immune development. The gut microbiota likewise influences both local and systemic immunity, raising the possibility that the maternal microbiome could influence fetal and childhood development. We hypothesize that maternal gut microbial composition shapes the fetal immune environment to control offspring growth and immune development during undernutrition. We propose to use a mouse model of intergenerational undernutrition to identify specific immune and microbial targets for therapeutic intervention. Our preliminary data demonstrate that breeding mice colonized with microbiota from healthy or severely stunted donors produce offspring with divergent weight, bone, and immune developmental phenotypes that persist into maturity. We will use this model to isolate the role of the maternal gut microbiome from the neonatal microbiome, giving critical insight into the window of potential intervention. We will also identify specific subsets of microbes that are capable of influencing offspring growth and immune development and characterize microbial metabolic products associated with these changes. Finally, we will identify maternal immune cells and signaling pathways that respond to these microbial communities to control healthy growth and immune development in offspring. These experiments will identify specific microbial species as well as host immune pathways to target therapeutically and define the appropriate developmental stage in which to intervene. The Cowardin lab is located within the Child Health Research Center at the University of Virginia, and as a member of the Trans- University Miocrobiome Initiative, is uniquely suited to pursuing these studies. The lab has both the infrastructure and expertise required for successful completion of these goals. Ultimately, this proposal will lead to potential probiotic and immunotherapeutic treatments to disrupt the transmission of stunting from mother to child.