The Role of Brain-Bone Marrow-Gut Interaction Following Major Trauma

Link the changes in HSPC and erythroid progenitor cell fate and function with sympathetic stress-induced changes establishing brain-bone marrow communication following trauma.

The impact of the severity and duration of catecholamine secretion on the cellular biology of HSPCs and erythroid progenitor cells requires further detailed evaluation. At each stage of proliferation and differentiation, there is a complex interaction of cytokines, transcription factors, post-translational modification of histones, and miRs. Single-cell RNA-seq technologies using a novel second generation multi-omics technology, CITE-seq, will be used for identification of isolated HSPCs and erythroid progenitor cells. Such single cell sequencing technology is ideal for cell populations with a great deal of heterogeneity and is well-suited for bone marrow analysis. Isolated cells can then be characterized by their transcriptomic and epigenetic changes. We will also evaluate EVM cargo (specific proteins/RNA/miR) from both plasma and bone marrow to determine links to chronic stress exposure.

Determine the connection between changes in the microbiome with sympathetic stress-induced changes establishing gut-brain communication following trauma.

Focusing on the effects of autonomic nervous system on gut function and immune responses, in the setting of sympathetic activation, a serial evaluation of the gut microbiota and their metabolic products (ex. SCFAs: butyrate, propionate, and acetate) will be performed in trauma patients. Correlation of microbial diversity and alterations of the taxonomic composition will be correlated with plasma markers of inflammation and clinical outcomes. Longitudinal study of the trauma pathobiome will elucidate clinical course patterns (recovery and CCI) with microbial composition. The unique biology of the microbiome in different sexes and age groups will require additional subgroup analysis.

Link changes in the microbiome with altered HSPC and erythroid progenitor cells fate establishing gut-bone marrow communication following trauma

We will examine how stress-induced changes following trauma create a pathobiome that modulates HPSC differentiation and maintains altered erythroid progenitor function. The microbiota play a role in both lineage differentiation and also control systemic iron homeostasis by inhibiting intestinal absorption and increasing cellular iron storage. Bone marrow macrophages have a key role in late-stage erythropoiesis by supplying local iron to erythroblasts for hemoglobin production. Isolation of bone marrow macrophages and erythroblasts involved in EBIs and determination of local iron content will define microbiome-induced changes in terminal erythropoiesis.