Investigating the role of gut-derived extracellular vesicles in PTSD following TBI

Abstract Veterans and the general public with traumatic brain injury (TBI) have a high risk of developing posttraumatic stress disorder (PTSD) and other psychiatric disorders, such as anxiety and depression. The pathophysiological basis that contributes to comorbid PTSD and other psychiatric disorders following TBI is not

yet understood, and there are currently few effective treatments for comorbid TBI/PTSD. Serotonergic dysfunction and neuroinflammation are strongly associated with TBI and psychiatric disorders. Gut microbiota dysfunction induces inflammation and affects tryptophan metabolism, a precursor of serotonin, which is

involved in serotonin biosynthesis. Studies conducted on patients with PTSD and other psychiatric disorders, as well as mice exposed to experimental stress, have shown a high correlation between perturbation in gut microbiota and mental disorders. TBI also induces gut microbiota dysbiosis. However, the cause-effect

relationship and the underlying mechanisms by which gut microbiota disruption following TBI impacts comorbid PTSD and other psychiatric disorders are still largely unknown. Extracellular vesicles (EVs), small nanovesicles, play a crucial role in cellular communication and carry various molecules. Bacterial EVs in the gut contain

bacterial genetic and biomaterials that are associated with virulence and considered causative agents in many diseases, while EVs produced by select probiotics have great therapeutic potential. Our pilot data reveal that administration of TBI-gut-EVs to gnotobiotic mice affects the expression of genes related to host serotonin

metabolites and neuroinflammation. In contrast, treatment of TBI animals with EVs derived from select probiotics significantly increases host serotonin levels and alleviates psychiatric-like behavior. Based on our novel findings, we hypothesize that the changes in gut microbiota-derived TBI-gut-EVs are involved in the regulation of

serotonergic neurons, neuroinflammation, and PTSD-like behavioral impairments following TBI. The successful completion of this study will not only provide new insight into the pathogenesis of TBI, but also promote the development of novel microbial-based therapy for preventing and/or treating comorbid TBI/PTSD, and potentially

other psychiatric disorders.