Abstract: Traumatic brain injury is a prevalent disorder of the central nervous system. In addition to primary brain parenchymal damage, the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury; however, the underlying pathogenesis remains unclear, and effective intervention methods are lacking. Intestinal dysfunction is a significant consequence of traumatic brain injury. Being the most densely innervated peripheral tissue in the body, the gut possesses multiple pathways for the establishment of a bidirectional “brain–gut axis” with the central nervous system. The gut harbors a vast microbial community, and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal, hormonal, and immune pathways. A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications. We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury, with a specific focus on the complex biological processes of peripheral nerves, immunity, and microbes triggered by traumatic brain injury, encompassing autonomic dysfunction, neuroendocrine disturbances, peripheral immunosuppression, increased intestinal barrier permeability, compromised responses of sensory nerves to microorganisms, and potential effector nuclei in the central nervous system influenced by gut microbiota. Additionally, we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury. This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the “brain–gut–microbiota axis.”

Key words: traumatic brain injury, brain–gut–microbiome axis, gut microbiota, neuroimmune, immunosuppression, host defense, vagal afferents, bacterial infection, dorsal root ganglia, nociception neural circuitry