The Systemic Nature of Severe Traumatic Brain Injury (MANTRA)

The Systemic Nature of Severe Traumatic Brain Injury: Multi-Omic Analysis of Neural Trauma, Autoantibodies and the Gut-Brain Axis: The MANTRA Study

Severe Traumatic brain injury (sTBI) is a very serious problem, and right now, doctors don't have special treatments to help stop additional injury. Previous studies showed that when a young person gets this kind of brain injury, their body's defense system reacts quickly and strongly. This can cause problems with the brain's protective barrier breaking down and the body making antibodies that attack its own cells. We think that changes in how the brain and the gut (the part of your body that digests food) talk to each other might make these defense reactions stronger. This study wants to figure out exactly how brain injuries change the gut and how that affects the body's defenses. To do this, we will use new ways to study body chemicals and genes [RNA, cell free DNA (cfDNA) and blood chemistry] to help us learn why the body reacts this way and how it can lead to more brain injuries and problems in adults with serious brain injuries.

Study Overview

• Status: Not yet recruiting
• Conditions: Severe Traumatic Brain Injury

Detailed Description

Severe traumatic brain injury (sTBI) is a devastating condition with no targeted therapies. Our pilot data in adolescents demonstrate that brain injury initiates an acute, strong immune response, marked by blood-brain barrier disruption and autoantibody formation, suggesting a novel avenue for therapeutic direction. Alterations in the gut-brain axis serve as a potential nidus of increasing immunogenicity and thus antibody formation. The major goal of this project is to define the immune mechanisms responsible for the interaction between brain injury and alterations in gut permeability via the gut-brain axis. Specifically, we will apply a novel multi-platform metabolomics approach, coupled with RNA sequencing, enabling identification of the mechanism responsible for early immune activation, secondary and tertiary brain injury, and neurodegeneration in adults with sTBI.

Current acute-management strategies remain largely focused on stabilizing cerebral physiology rather than addressing the molecular drivers of injury progression. The initial kinetic impact and subsequent secondary injury, such as neuroinflammation, neurotoxicity, and compromise of the blood brain barrier (BBB), potentiate a vigorous autoimmune response. Our pilot studies in adolescents demonstrated the activation of this strong immune response, marked by BBB disruption and autoantibody formation. This results in short and long-term inflammatory sequalae, including exacerbation of the initial injury, progression to chronic neurodegenerative diseases, and heightened disability and death.

Metabolomics comprehensively profiles (identifies and quantify) the small-molecule metabolites produced by cells, tissues, and microorganisms enabling the elucidation of metabolic pathways and their roles in addressing specific biological question. Although several omics studies have profiled time-resolved changes in adult and experimental models, no comparable work has been performed using multi-omics strategies in sTBI which remains essential. This represents a critical gap in our understanding of the developmental context of injury evolution. Lipids are essential for cellular functioning due to their pivotal roles in membrane composition, signaling, and energy metabolism, especially in the brain. Lipidomics, a subfamily of metabolomics, identifies and quantifies lips across cell types, organs, or full organisms. The investigation of cellular lipid pathways and networks provides critical insight into the molecular mechanisms underlying TBI. Emerging lipidomic studies show that circulating and CNS-derived lipid signatures correlate with injury severity, BBB breakdown, and long-term neurodegenerative risk thus making lipidomics essential in the comprehensive evaluation of sTBI pathogenesis.

The gut-brain axis, a bidirectional communication network between the gastrointestinal tract and central nervous system, has been identified in the pathophysiology of various forms of neurodegenerative disorders and recently implicated with TBI. Following sTBI, rapid alterations occur in gut motility, epithelial barrier integrity, immune signaling, and microbial community structure, collectively leading to gut dysbiosis and increased intestinal permeability. This is likely due to diffuse mucosal barrier dysfunction. In the gut, maintenance of mucosal integrity requires careful coordination between the epithelial lining and associated junctions, with immunologic contribution in regulating these relationships to alter permeability and absorption. The BBB, in contrast, carries a much greater degree of regulation and is relatively impermeable under normal physiological conditions, however, it is increased with brain injury thus permitting the influx of molecules that would not be present under normal conditions. These peripheral disturbances exacerbate neuroinflammation, oxidative stress, and neurodegeneration via the altered BBB. However, the precise mechanism by which this occurs has yet to be determined and remains a main objective of this study.

To discern the cells responsible for these alterations, scRNA-seq will be paired with global metabolomics, with an emphasis on detecting unique gut metabolites such as bacterial products and food antigens, not typically found in serum. scRNA will be used to identify circulatory cell type and clonal activation, integrated with metabolomics to specifically define the mechanism underlying the cytotoxicity of the gut permeability to the brain. This will be the first study to fully build a model examining the precise mechanism down to the cellular and molecular level with far-reaching impact. Ultimately, this may potentially identify targets for monoclonal deactivation and attenuation of secondary and tertiary brain injury.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Ashley Franklyn; Phone Number: 6163914051; Email: Ashley.Franklyn@corewellhealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with sTBI as defined as a Glascow Coma Scale (GCS) of 8 or less

Description

Inclusion Criteria:

• All patients must be between the ages of 18 to 65 at time of enrollment
• Study group cohort will consist of at least 20 patients admitted with severe TBI, defined as a GSC less than or equal to 8 with evidence of intracranial pathology on imaging.
• Trauma control cohort will include at least 10 patients matched on demographics and injury patterns without traumatic brain injury.
• Healthy control cohort will be comprised of 10 patients without acute traumatic injury or illness, matched to the sTBI patients based on demographics and medical comorbidities.

Exclusion Criteria:

• Pregnant Patients
• Prisoners
• Patients less than 18 years of age or greater than 65 years of age
• Patients with a penetrating brain injury mechanism, known neurodegenerative or psychiatric disorders, prior known traumatic brain injury, intracranial neoplasm, patients receiving massing transfusion or blood products prior to arrival, terminal illness or not expected to survive, confirmed or suspected brain death, known autoimmune or immunological condition, receiving immunosuppressant or immunomodulatory therapies, having a cardiac event leading to the injury, or for whom consent is unable to be obtained.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Study Group; The first cohort (Study Group) will consist of at least 20 patients admitted to CH Butterworth Hospital with a severe TBI, defined as a GCS ≤ 8 with evidence of intracranial pathology on imaging.
Trauma Control; The second cohort (Trauma Control) will include at least 10 patients matched on demographics and injury patterns without traumatic brain injury (head AIS 0).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic immune and metabolic responses after sTBI	Characterize the circulating cellular transcriptome using Bulk RNA-seq and single-cell RNA sequencing ScRNA-seq, compared to trauma and healthy controls to identify circulating cell types, clonal activity, and antibody formation that contribute to injury progression.	Time of injury and 1-month
Identifying the mechanisms of immune activation driving secondary injury	Define barrier disruption by performing both the 1H NMR and LC-MS metabolomic analysis (global, targeted, and lipidomics), transcriptomics, and proteomics to measure gut and blood-brain barrier permeability and markers of inflammation and neurodegeneration. Pinpoint cell types, pathways, and antibody-mediated mechanisms contributing to progressive brain injury by integrating transcriptomic and metabolomic datasets.	1 year
Establishment of a biorepository for future biomarker discovery and data integration with the sTBI patient registry for long-term follow-up.	Bank stool and oral flora samples to study gut dysbiosis and investigate the link between gut microbiome and TBI and longitudinal downstream metabolic consequences leading neurodegeneration and psychiatric pathologies· Bank bronchoalveolar lavage (when available), and plasma for additional future ScRNA analyses at defined timepoints. Establish longitudinal outcomes by leveraging a newly developed sTBI registry to follow patients over time, linking early immune and barrier changes with long-term risk of neurodegeneration.	1 year

Collaborators and Investigators

• Sponsor: Corewell Health West
• Collaborators: Corewell Health East
• Investigators: Principal Investigator: Elizabeth A Steensma, MD, FACS, Corewell Health West

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: June 25, 2026
• First Submitted That Met QC Criteria: June 25, 2026
• First Posted (Actual): July 1, 2026

Study Record Updates

• Last Update Posted (Actual): July 1, 2026
• Last Update Submitted That Met QC Criteria: June 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic
• Other Study ID Numbers: 2026-1285

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No