Early toxic stress can lead to enduring long-term effects on neurodevelopment and behavioral outcomes in children. One mechanism that may mediate these associations is the gut microbiome. There is robust evidence that patterns of gut microbiota may influence neurodevelopment and anxiety-related behaviors in rodents, but there is sparse literature on this association in humans. Recent findings from our research team are the first to reveal that the gut microbiome significantly predicts fear behavior in 1-year-old children. Thus, the proposed study will examine the influence of psychosocial stress on the development of gut microbiota, mediated by chronic HPA axis activation, as well as the bidirectional relationship between the developing microbiome and behavioral inhibition across the first four years of life. We will measure alterations in brain development across this time as a mediator of the relationship between the microbiome and behavioral inhibition. During this sensitive period the microbiome and brain are rapidly developing and may be most susceptible to environmental input. Participants (n = 200) will be drawn from a prospective longitudinal cohort study funded by NICHD (Brain and Early Experience Study (BEE); R01 HD091148-01A1). Assessments will be conducted during lab visits at 36 and 54 months and home visits at 6 and 24 months of age. Psychosocial stress will be assessed via observational assessments of negative parenting behavior and household chaos at 6 and 24 months, and HPA axis activation will be measured via hair cortisol at these visits. At all ages, fecal samples will be collected to assess microbial diversity and maturity and behavioral inhibition will be assessed via maternal report and observational measurement. Neuroimaging using high resolution magnetic resonance imaging, diffusion tensor imaging, and resting state fMRI will provide measures of volumetric growth of the mPFC and hippocampus from 15 months to 54 months, and structural and functional connectivity between the amygdala and mPFC. Finally, at 54 mos a brief structured diagnostic interview for major pediatric psychiatric disorders will be conducted (Mini International Neuropsychiatric Interview). This study will be the first to investigate the influence of early psychosocial stress on the gut microbiome, neurodevelopment and anxiety related behavior. Our long-term goal is to determine how colonization of the gut microbiome impacts human brain development and later risk for psychopathology in order to prevent the onset of psychiatric illness or reduce its severity. Findings from this study, during a sensitive period of early childhood, will provide important information that could inform intervention and prevention efforts soon after birth.
Millions of children aged 3-17 year have diagnosed anxiety disorders and are at higher risk for poor performance in school, difficulties in social situations, and increased substance use. The proposed study aims to examine the influence of exposure to toxic stress across the first years of life on the gut microbiota, which has been found to alter neurodevelopment and subsequent behavioral inhibition, leading to anxiety symptoms in later childhood. Given limited public health resources, it is important to identify these specific targets for early intervention and thus the proposed research has strong potential for advancing the NIMH's mission of transforming the understanding and treatment of mental illnesses.
