Trauma, the gut, and the brain: the gut microbiota-microglia axis in traumatic brain injury

Project Summary/Abstract Trauma is the leading cause of death and disability in young adults in the United States. Traumatic brain Injury (TBI) contributes to over one third of all these trauma related deaths. In fact, TBI related healthcare expenditures near 80 billion dollars annually. The impact of TBI is highlighted not only by its high mortality rate, but also the significant long-term cognitive and psychiatric complications suffered by its survivors. Chronic neuroinflammation resulting from the constitutive activation of microglia is complicit in this process and represents a complex interplay between microglia and the gut microbiome via the gut-brain axis. However, the mechanism(s) underlying gut microbiota-microglia interaction have yet to be elucidated. Published Data from our laboratory shows a significantly altered gut microbial community after TBI, with increased relative abundance of several microbial species strongly associated with neurologic disease processes. In the same vein, it is known that reduced abundance of anaerobic bacteria capable of fermenting dietary fiber into short chain fatty acids (SCFAs) exacerbate lesion size and neuroinflammation after neurologic injury. Preliminary Data from our laboratory has shown improved neurocognitive outcomes with dietary supplementation of the SCFAs acetate, butyrate, and propionate after TBI. Nonetheless, the mechanism(s) linking TBI-induced alterations in the gut microbial community to the development of subsequent neurocognitive decline have yet to be fully elucidated. W hypothesize improve e that targeted microbial and dietary intervention will attenuate microglial activation and neurocognitive outcomes after TBI. To test this hypothesis,we will determine whether restoring a pre-injury gut microbial composition via fecal microbiota transplant, targeted microbiota replacement, or dietary supplementation of SCFAs attenuates the activation of microglia in wild type, germ-free, and genetic targeted replacement mice. We will use bulk population cell sorting (FACSorting) of microglia followed by single cell RNA sequencing (scRNAseq). We will compare candidate genes to microbial activity via fecal 16S rRNA gene amplicon sequencing and fecal metabolite analysis. Harmonized with the transcriptomic and gut microbial community profiling, all Aims will utilize longitudinal PET/CT imaging of the 18-kDa translocator protein (TSPO) with a novel fluorine-based radiotracer developed by our group to track and compare the onset, progression, and degree of microglial activation before, during, and after gut microbial and dietary intervention after TBI. Collectively, the proposed studies will identify the key role of gut microbial community structure and metabolic activity in the onset and progression of constitutive microglial activation over the course of TBI, thus raising the potential for novel therapeutic and biomarker development in TBI patients.