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

ABSTRACT Trauma remains the leading cause of death among people younger than 46-years of age and is the leading cause of years of potential life lost among those younger than 65. With more lives saved, trauma morbidity has increased, which has consequently revealed a lack of understanding of the impact of trauma survivorship on the

patients’ quality of life and long-term recovery. Severe injury when followed by chronic critical illness leads to persistent anemia, and the use of blood transfusions is associated with a linear increase in infectious complications. These conditions are due to prolonged bone marrow dysfunction associated with an exaggerated

catecholamine response, chronic stress, and systemic inflammation. The Principal Investigator (PI) has demonstrated significant productivity over the last decade, especially in the last five years, in this research field. The PI’s laboratory has conducted human and rodent research to establish that there are unique bone marrow

transcriptomic differences related to inflammation, the innate immune response, and known inhibitors of erythropoiesis following trauma. The laboratory has also discovered that chronic stress after trauma contributes to persistent anemia with impaired iron and erythropoietin function along with the prolonged loss of hematopoietic

stem progenitor cells (HSPC) from the bone marrow. Chronic stress after trauma also induces an altered microbiome with decreased alpha and beta diversity and changes in microbial composition leading to a persistent ‘pathobiome’. All of these factors influence outcomes. We hypothesize that there is a unifying interaction between

stress, inflammation, and the microbiome and this has an overall role in the regulation of HSPC and erythroid progenitor cell fate and function following trauma and critical illness. Therefore, the overarching goal for this application is to build upon this foundation and expand our understanding of HSPC fate and function following

trauma, including examining interventions aimed at reducing stress/inflammation and restoring the microbiome, thus, improving long-term outcomes. Severely injured patients with chronic critical illness at risk of long-term morbidity as well as our novel preclinical rodent model of multicompartmental trauma and chronic stress will be

employed. We intend: (1) to directly link changes in HSPC and erythroid progenitor cell fate and function with changes in the microbiota by examining specific mechanisms, including how stress-induced changes following trauma create a pathobiome that maintains altered erythroid progenitor function. With these studies, we will (2)

explore the unique interplay of the microbiome, the stress response, and HSPCs and erythroid progenitor cell fate in different cohorts of trauma, evaluating both age and sex; and (3) consider possible interventions that restore the microbiome and/or reduce chronic stress/inflammation which reestablishes HSPC homeostasis to

improve bone marrow function and long-term outcomes. Focusing on longitudinal interactions between the dysregulated stress response, the pathobiome, and HSPC fate is a novel, under-explored area of research that could improve the long-term management of severe trauma.