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

Recruiting

• Conditions: Trauma Injury; Trauma; Critical Illness; Microbiome; Chronic Anemia; Acute Blood Loss Anemia
• Interventions: Other: Data and tissue collection

• Registration Number: NCT06606119
• Lead Sponsor: University of Florida

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2024-09-18
• Study First Submitted QC: 2024-09-18
• Study First Posted: 2024-09-20
• Status Verified: 2025-01
• Study Start: 2025-01-24
• Last Update Submitted: 2025-01-24
• Last Update Posted: 2025-01-28
• Primary Completion: 2027-10-01
• Study Completion: 2028-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 275

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

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Major Trauma Injury	Data and tissue collection	Severe blunt trauma patients diagnosed with shock with a long bone or pelvic fracture requiring open reduction internal fixation or intramedullary fixation.
Elective Hip Replacement	Data and tissue collection	Patients undergoing elective hip replacement surgery

Primary Outcome Measures

Name	Time	Method
Link the changes in HSPC and erythroid progenitor cell fate and function with sympathetic stress-induced changes establishing brain-bone marrow communication following trauma.	3 years	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.	3 years	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	3 years	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.

Trial Locations

Locations (3)

UF Academic Research Building; 🇺🇸 Gainesville, Florida, United States

UF Health at Shands Hospital; 🇺🇸 Gainesville, Florida, United States

UF Laboratory of Inflammation Biology and Surgical Science and Shands Hospital at UF; 🇺🇸 Gainesville, Florida, United States