Traumatic brain injury (TBI) is a common cause of disability and mortality, affecting millions of people every year. The neuroinflammation and immune response post-TBI initially have neuroprotective and reparative effects, but prolonged neuroinflammation leads to secondary injury and increases the risk of chronic neurodegenerative diseases. Persistent microglial activation plays a critical role in chronic neuroinflammation post-TBI. Given the bidirectional communication along the brain–gut axis, it is plausible to suppose that gut microbiota dysbiosis post-TBI influences microglial activation. In the present study, hippocampal microglial activation was observed at 7 days and 28 days post-TBI. However, in TBI mice with a depletion of gut microbiota, microglia were activated at 7 days post-TBI, but not at 28 days post-TBI, indicating that gut microbiota contributes to the long-term activation of microglia post-TBI. In addition, in conventional mice colonized by the gut microbiota of TBI mice using fecal microbiota transplant (FMT), microglial activation was observed at 28 days post-TBI, but not at 7 days post-TBI, supporting the role of gut microbiota dysbiosis in persistent microglial activation post-TBI. The RNA sequencing of the hippocampus identified a microglial activation gene, Lyz2, which kept upregulation post-TBI. This persistent upregulation was inhibited by oral antibiotics and partly induced by FMT. 16s rRNA gene sequencing showed that the composition and function of gut microbiota shifted over time post-TBI with progressive dysbiosis, and untargeted metabolomics profiling revealed that the tryptophan metabolic phenotype was differently reshaped at 7 days and 28 days post-TBI, which may play a role in the persistent upregulation of Lyz2 and the activation of microglia. This study implicates that gut microbiota and Lyz2 are potential targets for the development of novel strategies to address persistent microglial activation and chronic neuroinflammation post-TBI, and further investigations are warranted to elucidate the specific mechanism.
Traumatic brain injury refers to the damage caused to intracranial tissues by an external force acting on the head, leading to both immediate and prolonged harmful effects. Neuroinflammatory responses play a critical role in exacerbating the primary injury during the acute and chronic phases of TBI. Research has demonstrated that numerous neuroinflammatory responses are mediated through the “microbiota–gut–brain axis,” which signifies the functional connection between the gut microbiota and the brain. The aryl hydrocarbon receptor (AhR) plays a vital role in facilitating communication between the host and microbiota through recognizing specific ligands produced directly or indirectly by the microbiota. Tryptophan (trp), an indispensable amino acid in animals and humans, represents one of the key endogenous ligands for AhR. The metabolites of trp have significant effects on the functioning of the central nervous system (CNS) through activating AHR signalling, thereby establishing bidirectional communication between the gut microbiota and the brain. These interactions are mediated through immune, metabolic, and neural signalling mechanisms. In this review, we emphasize the co-metabolism of tryptophan in the gut microbiota and the signalling pathway mediated by AHR following TBI. Furthermore, we discuss the impact of these mechanisms on the underlying processes involved in traumatic brain injury, while also addressing potential future targets for intervention.
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