An Interplay Between Hypothalamic Microstructure, Systemic Metabolism and Gut Microbiome Composition in Male Rats at Hyperacute Timepoint Post <scp>TBI</scp>

Traumatic brain injury (TBI) is an insult to the brain that impacts neuronal and non-neuronal cells/tissues. The study aimed to understand TBI-induced early changes in the brain and systemic physiology. The male rats were subjected to mild and moderate TBI, where serum and urine metabolic fingerprints of mild TBI rats showed a hypermetabolic response with increased energy metabolites, amino acids, and gut metabolites in serum and increased TCA cycle intermediates in urine. In contrast, the moderate TBI rats showed decreased lactate, pyruvate, amino acids (glycine and leucine) and gut metabolites [trimethylamine N OXIDE (TMAO), choline and acetate] in serum. The urine showed increased pyruvate, creatinine, and allantoin levels. To understand the brain's role in altered metabolic physiology, hypothalamus structure was assessed using diffusion tensor imaging (DTI) and stress levels were observed using serum corticosterone. The injured rats exhibited changes in DTI metrics in the hypothalamus, suggesting a potential disruption in the regulation of the hypothalamus-pituitary-adrenal axis (HPA) axis. These alterations were accompanied by increased TNF-α levels after moderate TBI. The injury induced allostatic overload, accompanied by impaired hypothalamic structure, and metabolic physiology also showed gut microbiome dysbiosis. The gut microbiome showed an increased Firmicutes: Bacteroidetes ratio after injury, with variable gut composition after both injuries. Therefore, the present study provides insight into an interplay between the HPA axis, metabolism, and gut microbiome following TBI. Importantly, this crosstalk between the regulatory systems was different after mild and moderate injury, highlighting the need to assess injury phenotype based on the severity.