Environmental Enrichment-induced cognitive recovery after a moderate pediatric traumatic brain injury is related to gut microbiome and neuroinflammation

Pediatric traumatic brain injuries (TBI) are a significant health concern, yet access to rehabilitation therapies for children remains limited. Environmental enrichment (EE) is a clinical rehabilitation model that promotes behavioral recovery and reduces neuroinflammation after TBI. While the gut microbiota has recently emerged as a potential therapeutic target for treating TBI sequelae in adults, its role in EE-induced recovery after pediatric TBI remains unclear. Therefore, our aim was to assess the effect of EE on gut microbiota and its correlation with cognition and inflammation in a preclinical model of pediatric TBI. Male rats underwent moderate controlled cortical impact or sham procedures at postnatal day 21 and were then randomly assigned to either EE or standard (STD) housing conditions. Cognition was evaluated using the Morris water maze (MWM). Microglial morphology and the caecum microbiome were characterized at post-injury day 21. TBI + STD rats exhibited cognitive deficits in the MWM and increased microglial activation in the ipsilateral cortex and hippocampus. These effects were not observed in TBI + EE rats. Although TBI did not affect microbiome alpha diversity. PERMANOVA analysis showed differences between TBI and EE groups compared to Sham + STD. Furthermore, regression models indicated that an ASV from an uncultured bacterium of the Family XIII UCG001 and Cuneatibacter caecimuris predicted behavioral outcomes, while Prevotellaceae NK3B31 predicted neuroinflammation. In conclusion, our findings suggest that EE mitigates TBI-induced alterations in gut microbiota and that there is a complex interplay between EE, microbiota, and neuroinflammation that predicts behavioral recovery.