UCLA

The gut microbiome interacts with host physiology to influence neurodevelopment during critical periods of life. Brain-gut interactions during these critical periods can occur through direct communication, such as via gut-derived metabolites or vagal activity, or by indirect or secondary body systems, such as immune or endocrine signaling. Regardless of mechanism, these brain-gut interactions shape neurological trajectories for later-life function. The compilation of work making up this dissertation aims to profile mechanisms of developmental brain-gut interactions in response to environmental perturbations, and explore avenues of microbiota-targeted methods for amelioration of subsequent neurological impairment. Chapters 2 and 3 and Appendix 1 investigate how the microbiome responds to, and moderates effects of, perinatal malnutrition on the developing brain. Here, we report that the maternal microbiome modifies effects of protein undernutrition on fetal neurodevelopment and offspring behavior, and that gut-modulated metabolites ameliorate select phenotypes. Chapter 4 investigates signatures of gestational fluoxetine use on transcriptomic disruptions in the developing fetal brain, and reports a mediating role of the maternal microbiome. Chapter 5 is a translational study investigating correlations between metabolomic changes, functional brain connectivity, and psychiatric symptoms in adults following exposure to early life adversity. We find that four gut-modulated metabolites and connectivity of brain networks including sensorimotor, salience, and central executive, are associated both with early life adversity and with current stress, anxiety, and depression symptoms. Together, this body of work supports the notion of sensitivity of not only the brain, but also the gut, and interactions between the two, to environmental perturbations. Results indicates a causal role of the microbiome during critical windows of prenatal or postnatal development in shaping neurodevelopment and influencing persistent trajectories of behavior, and demonstrate that these interactions occur in response to outside influences including diet, medications, and stress. Finally, this work highlights the gut microbiome as a target of potential intervention for critical period neurodevelopmental disruptions.