Maternal gut microbiota in fetal programming of neurodevelopment and related disorders

Project Summary Social interaction is fundamental to the most universal of human experiences, such as family life, business, and romance; however, social dysfunction is a debilitating hallmark of major neurodevelopmental disorders, including autism and schizophrenia. Despite significant advances, the mechanisms underlying social dysfunction and other core behavioral symptoms associated with neurodevelopmental disorders remain elusive and interventions limited. There is growing consensus in support of a ‘two hit’ hypothesis for neurodevelopmental disorders, in which a secondary environmental factor initiates abnormal developmental programming that contributes to behavioral dysfunction in genetically predisposed individuals. Among environmental factors, diet is a leading factor contributing to host disease susceptibility. Notably, diet is the chief determinant of host gut microbiome composition. Through modulation of host immune function, and even the brain and behavior, the gut microbiome is emerging as a major influence on host health and well-being. Disruption, or ‘dysbiosis,’ of the gut microbiome is, in turn, associated with several common inflammatory disorders, including inflammatory bowel disease and metabolic syndrome. Dysbiosis is also observed in neuropsychiatric patient populations, who have a high rate of gastrointestinal symptom comorbidity; yet, the relationship between dysbiosis of the gut microbiome and neurodevelopmental or other neuropsychiatric disorders is poorly understood. In this project, we will determine if maternal high-fat diet (MHFD)-induced dysbiosis of the gut microbiome during pregnancy contributes to descendant neurobehavioral dysfunction and the underlying mechanisms. Previously, we reported that MHFD induces dysbiosis of the male offspring gut microbiome as well as social dysfunction and underlying deficits in synaptic plasticity in the social reward circuit. Recently, we identified a sexually dimorphic effect of MHFD on offspring behavior–stronger social deficits are evident in males versus females–however, we observed dysbiosis of both the male and female MHFD offspring gut. We reasoned that if the maternal gut microbiome is causally related to offspring social dysfunction, then enduring dysbiosis of the female MHFD offspring gut microbiome in the F1 generation may be sufficient to impair neurodevelopment and behavior in F2 males. Indeed, we observed robust social dysfunction in male, but not female, F2 offspring. Here, we will test the hypothesis that HFD-induced dysbiosis of the maternal gut microbiome drives abnormal fetal programming in F1 offspring that underlies social dysfunction in both F1 and F2 males. In Aim 1, we will ask how HFD/MHFD affects remodeling of the P/F1 maternal gut microbiome during pregnancy. In Aim 2, we will determine the effects of HFD/MHFD on maternal immune function, fetal immune imprinting, and the embryonic brain. In Aim 3, we will determine if modulation of the maternal gut microbiome during pregnancy can rescue descendant social dysfunction. This study will yield key insight into the mechanisms by which MHFD modulates fetal development and the potential for therapeutic targeting of the maternal microbiome to prevent adverse neurobehavioral outcomes in descendant generations.