Pre-injury hypercholesterolemia is associated with microbiota-associated neurobehavioral vulnerability following traumatic brain injury.

Traumatic brain injury (TBI) is increasingly recognized as a systemic disorder associated with long-term neuropsychiatric sequelae. However, substantial inter-individual variability suggests that pre-injury metabolic status may influence neurobehavioral vulnerability following TBI. We investigated whether pre-injury hypercholesterolemia is associated with altered microbiota-associated neurobehavioral interactions after TBI. Male Sprague-Dawley rats were fed a high-fat diet prior to moderate fluid percussion injury, followed by behavioral, biochemical, histological, and microbiota analyses on day 15 post-injury. Pre-injury hypercholesterolemia was associated with increased depression-like behavior, reduced peripheral serotonin levels, greater TTC-negative injury burden, and increased TUNEL positivity. These changes co-occurred with reduced microbial diversity, depletion of Prevotella spp., and enrichment of Akkermansia muciniphila. Predicted microbial functional annotations suggested alterations in amino acid and tryptophan-related pathways associated with behavioral and biochemical measures. Correlation analyses demonstrated inverse associations between peripheral serotonin levels and depression-like behavior, while Akkermansia muciniphila abundance was negatively correlated with peripheral serotonin levels. Network analyses further revealed coordinated associations among microbial taxa, peripheral serotonergic-related markers, and behavioral outcomes. Together, these findings support coordinated microbiota-associated neurobehavioral interactions following traumatic brain injury.