Identifying Key Metabolites in the Microbiome-Gut-Brain Axis During Infancy

Award: $64,881

The human gastrointestinal system contains a vastly complex system of microbes. We know that the composition and interactions of these microbial communities impact our neurodevelopment, cognition, and emotional behavior, but how is still largely unclear. Researchers will study the interactions between gut bacteria, bacterial gene expression, the presence of stress hormones, and a number of other chemical and behavioral factors, in infants. If a pattern exists, the data could help identify risk factors for psychiatric illness, and lead to preventive therapies and treatments.

Rebecca Knickmeyer Santelli, Ph.D.
and John Gilmore, M.D.

Need/Problem: The composition of the gut microbiome (the trillions of microbes inhabiting the intestinal tract) impacts neurodevelopment, cognition, and stress-related behaviors relevant to a wide range of psychiatric illnesses, but the mechanisms by which specific microbes or microbial communities alter brain structure and function remain largely unknown.

Grant Summary:  This grant will apply cutting-edge techniques in broad-spectrum metabolomics to identify molecules that mediate gut microbes’ effects on brain development and stress reactivity in human infants.

Goals & Projected Outcomes: Our primary goal is to generate novel hypotheses about the biochemical pathways mediating microbial effects on the human brain by correlating metabolic profiles with gut microbial profiles, microbial gene expression, neuroimaging outcomes, and stress-reactivity in human infants. Key metabolites identified by this project will serve as biomarkers for future studies evaluating the impact of probiotics, prebiotics, and public health interventions on gut colonization, brain development, and risk for mental illness. They may also represent novel therapeutics for complex psychiatric illnesses or serve as targets for future drug discovery.

Grant Details: We will achieve our objective through 3 specific aims: 1) Identify metabolites associated with patterns of microbial colonization and gene expression during infancy. 2) Determine how gut-derived metabolites impact brain development during infancy. 3) Determine how gut-derived metabolites impact stress-reactivity during infancy.

Grant Details: Participants will include 38 typically developing infants enrolled in an NIMH-funded study of gut microbiota and anxiety-related behaviors. As part of the parent study, children are evaluated at 2 weeks and 1 year of age. At each visit, we collect two fecal samples. One will be used to determine what kinds of bacteria inhabit the gut; the other will be used to determine which bacterial genes are actually being expressed. We also collect blood spots for analysis of immune signaling molecules and a limited set of metabolites (specifically tryptophan, kynurenine, kynurenic acid and quinolinic acid); several saliva samples for the assessment of hormonal responses to stress; and magnetic resonance imaging (MRI) scans of the brain. Scans include a high-resolution structural scan to assess global and regional brain tissue volumes (as well as cortical thickness and surface area), diffusion tensor imaging (DTI) scans to assess anatomical connectivity between different brain regions, and resting-state functional MRI scans to assess functional connectivity. At age 1, children also receive detailed neurobehavioral assessments with a particular focus on anxiety-related behaviors when exploring a new environment or meeting a new person. For this Foundation of Hope study, we will quantify an additional 188 metabolites involved in a diverse range of cellular processes as well as 25 different neurotransmitters using existing saliva samples.