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

Traumatic injury followed by critical illness provokes pathophysiologic changes in the bone marrow and the gut that contribute to persistent anemia and changes in the microbiome which significantly impact long-term recovery. This project will define the interactions between the stress, chronic inflammation, bone marrow dysfunction, and an altered microbiome which will provide a strong foundation for future clinical interventions to help improve outcomes following severe trauma.

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. Our laboratory has conducted human 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 study 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.

Eligibility Criteria:
Severe Trauma Cohort

Inclusion Criteria:

1. All adults (age ≥18).
2. Blunt trauma with an injury severity score \> 15 and a long bone or pelvic fracture requiring open reduction internal fixation or intramedullary fixation
3. Blunt trauma patients with shock, defined by either a systolic BP (SBP) \<90 mm Hg or base deficit (BD) ≥5 meq or lactate ≥ 2 mmol/L or active red blood cell or whole blood transfusion within 6h or arrival

Exclusion Criteria:

1. Patients not expected to survive greater than 48 hours
2. Prisoners
3. Pregnancy
4. Previous bone marrow transplantation
5. Patients receiving chronic corticosteroids or immunosuppression therapies
6. Patients with End Stage Renal Disease
7. Patients with any pre-existing hematological disease
8. Surgery for repair of injury is greater than seven days after admission to the hospital for trauma
9. Burn injury greater than 20% TBSA

Elective Hip Cohort

Inclusion Criteria

1. All adults (age ≥55).
2. Patient undergoing elective hip repair for non-infectious reasons.
3. Ability to obtain Informed Consent prior to operation.

Exclusion Criteria

1. Patients not expected to survive greater than 48 hours
2. Prisoners
3. Pregnancy
4. Previous bone marrow transplantation
5. Patients receiving chronic corticosteroids or immunosuppression therapies
6. Patients with End Stage Renal Disease
7. Patients with any pre-existing hematological disease