Microbial and environmental modulation of novel GUT-brain pathways following early life stress

The National Center for Complementary and Integrative Health, part of the Department of Health and Human Services National Institutes of Health, awarded $413,972 to Oklahoma State University Center for Health Sciences on August 12, 2026, under the Research and Training in Complementary and Integrative Health program (CFDA 93.213).

The award funds investigation of how early life stress triggers imbalances in gut bacterial genera, particularly Roseburia, and influences brain responses through modifications in astrocyte-neuron plasticity. The research examines whether favorable interventions can reverse stress-induced behavioral dysregulation by engaging distinct gut commensals and brain pathways.

The project comprises two aims. Aim 1 uses animal models to determine how Roseburia inoculation modifies emotional and cognitive behaviors in stress-exposed versus standard-reared mice, employs viral tools to visualize neuronal and astrocytic mitochondrial function in vivo, and manipulates epithelial signaling to test causal links between intestinal stress responses, microbial composition, and brain plasticity. Aim 2 examines how favorable environmental factors such as enrichment and cross-fostering reshape the gut-brain axis following early life stress, profiling gut microbiome composition, intestinal barrier integrity, and metabolite production through metagenomic and metabolomic analyses, while parallel brain-wide proteogenomic and single-cell sequencing identify molecular pathways for stress resilience.

Performance occurs in Tulsa, Oklahoma. The project period extends through May 31, 2031.

Abstract

The interaction between the GUT microbiome and the brain profoundly affects the brain's physiology, influencing mood and behavior, yet the specific mechanisms linking GUT microbes to brain responses in early-life psychosocial stressors remain largely unexplored. This proposal aims to address this GAP by investigating how early life stress (ELS) triggers imbalances in specific GUT bacterial genera, particularly roseburia, through the BMP-JMJD3 axis and influences behavior through modifications in astrocyte-neuron plasticity, and whether favorable interventions can reverse stress-induced behavioral dysregulation by engaging GUT commensals and brain pathways distinct from those dysregulated by ELS. Aim 1 experiment 1 will determine how roseburia inoculation modifies emotional and cognitive behaviors in limited bedding nesting (LBN) stress versus standard- reared mice, while experiment 2 will employ esyn- and gfap-driven mitogfp viral tools to visualize neuronal and astrocytic mitochondrial function in vivo. Experiment 3 will use paneth cell-specific CRE mouse lines to manipulate SMAD1 and JMJD3 to test whether epithelial BMP signaling controls microbial and neural adaptations to ELS, defining causal links between intestinal stress responses, microbial composition, and brain plasticity. In aim 2, we will examine how favorable environmental factors, such as enrichment and cross- fostering, reshape the GUT-brain axis after ELS. We will profile GUT microbiome composition, intestinal barrier integrity, and metabolite production through metagenomic and metabolomic analyses, while parallel brain-wide proteogenomic and TRAP2 single-cell sequencing will identify unique molecular pathways for stress resilience. Behavioral assays will assess social reward, affective regulation, and cognitive flexibility under these interventions. We predict that enrichment and cross-fostering will restore or promote beneficial GUT commensals distinct from those altered by ELS, leading to region-specific enhancements in OFC and amygdalar plasticity and uncovering SEX-dependent pathways through which the microbiome regulates behavior underlying favorable interventions. Together, these studies integrate microbial, epithelial, and neural mechanisms into a unified framework of ELS vulnerability, identifying key microbial and molecular targets that can buffer against stress- induced brain dysfunction. By bridging the BMP-JMJD3 GUT epigenomic axis with astrocyte-neuron mitochondrial plasticity, this project explores an unrecognized GUT-brain signaling mechanism. The findings will clarify how microbial restoration or environmental modification can promote distinct and adaptive neurodevelopment after early adversity. This multidisciplinary effort, combining microbiology, neuroepigenetics, and computational biology, will yield foundational data for developing GUT-targeted or enrichment-based therapies for stress-related neuropsychiatric disorders and transform understanding of how early adversity programs long- term brain and behavioral trajectories.