The Role of Microbiome-Associated Metabolites and Their Clinical Implications in Traumatic Brain Injury: A Scoping Review.

Traumatic brain injury (TBI) is a major public health challenge, with heterogeneous mechanisms and limited targeted therapies. Despite advances in neurocritical care, interventions to meaningfully alter long-term outcomes have been elusive, and treatment remains largely supportive. Parallel to this, increasing evidence from both preclinical models and human studies implicates the gut microbiome as a dynamic modulator of neurologic injury and recovery through the microbiome-gut-brain axis, a bidirectional network linking the central nervous system, gastrointestinal tract, and intestinal microbiota. TBI and neurointensive care including mechanical ventilation, sedation, dietary modification, and antibiotics contribute to the development of dysbiosis and altered production of microbial metabolites. These bioactive molecules, such as short-chain fatty acids, tryptophan metabolites, bile acids, and polyamines, play critical roles in regulating blood-barrier integrity, immune activation, neurotransmission, and energy metabolism. In TBI, emerging preclinical and clinical data suggest that altered levels of these metabolites may influence secondary injury cascades and shape recovery. In this review, we synthesize current TBI-specific preclinical and clinical data on microbiome alterations and microbiome-associated metabolite signaling following TBI, and we place these findings in the broader context of microbiome-gut-brain research. Understanding these pathways could inform future strategies to optimize treatment, including targeted microbiome modulation, dietary interventions, or metabolite supplementation. We identify key knowledge gaps and outline priorities for translational research needed to determine whether monitoring and therapeutic manipulation of the microbiome-gut-brain axis can enhance patients' recovery trajectory.