Orchestrating tryptophan metabolites to protect neurodevelopment from prenatal stress

Project Summary: Prenatal stress is pervasive and negatively impacts both the mother and the developing fetus; exposed offspring bear an increased risk of developing psychiatric disorders including autism spectrum disorder (ASD), anxiety, and depression. There is a converging line of evidence from our lab, and others, that prenatal stress alters maternal commensal microbes in a manner that is essential in shaping neurodevelopment. Indeed, there is a critical window in utero where neurodevelopment is both vulnerable to stress-induced alterations in the intrauterine environment and able to benefit from intervention. However, how alterations in the maternal intestinal microbiome are transmitted to the developing brain, contributing to behavioral alterations, requires elucidation. We have exciting supporting and preliminary data suggesting that Tryptophan (Trp) metabolism and transport is dysregulated in our model of prenatal stress. This is critical because bacterial metabolism of tryptophan results in the production of key neuromodulatory metabolites. For example, higher levels of 3-hydroxykynurinene has been implicated in aberrant brain development and inflammation, and indole containing compounds, such as indole-3-acetic acid are beneficial. We have further identified that Parasutterella excrementihominis (Pe), a Trp metabolizer, is significantly reduced in repeated experiments using our mouse model of prenatal stress. We have exciting preliminary data demonstrating that replenishing Pe can restore key aspects of neurodevelopment in offspring disrupted by prenatal stress, including social behavior and fetal inflammation. Therefore, to further our understanding of the transduction of peripheral microbial signaling to the developing brain, we will pursue our novel finding of dysregulated tryptophan metabolism following prenatal stress by establishing the extent to which Pe treatment modulates fetal microglia and the behavioral effects of prenatal stress. Next, we will delineate the interplay between Pe and Trp by determining how Trp availability affects Pe ability to influence offspring neuroinflammation and social behavior. Finally, we will determine whether Trp metabolites are sufficient to both cause and prevent the deleterious sequelae of prenatal stress using intraamniotic injection (IAI). Thus, this R01 will test the highly novel, and integrative overarching hypothesis that treatment with Pe restores the abundance of Trp metabolites, preventing the neuroinflammatory and behavioral sequelae of prenatal stress and that the metabolites are sufficient to modulate neurodevelopment. This proposal will address the following questions: 1) Does replenishing Parasutterella excrementihominis prevent stress- induced increases in Trp, fetal neuroinflammation, and social behavior? 2) What is the interplay between Parasutterella excrementihominis anti-inflammatory effects and Trp abundance? 3) Are prenatal stress effects on neurodevelopment mediated through Trp metabolites?