Long-term Recovery and Microbiota-Gut-Brain Axis Disruption After Traumatic Brain Injury

NCT06927063 | Not Yet Recruiting

• 1 other identifier: 21/1801/2022
• Study Type: observational
• Target: 160
• Locations: 0 countries
• Sites: N/A

Brief Summary

The OVERCOME-TBI project aims to collect multimodal data approximately 1-4 and 11-14 years after an earlier well-documented traumatic brain injury (TBI) and examine factors that influence disease progression in order to gain new scientific insights into the long-term pathophysiology of TBI and identify new therapeutic targets. TBIs are among the most serious health problems worldwide and represents a significant burden for the injured, their families and society. It is estimated that more than 50 million people in the world suffer a TBI every year and half of all people will suffer a TBI in their lifetime. TBI diagnostics has lagged significantly behind that of many other diseases. The current methods for assessing severity and predicting outcomes are based only on initial stage variables, and there are no objective tools for monitoring disease progression. The current acute severity indices have shown only a modest association with outcome, particularly in patients with mTBI. However, even in patients with moderate-severe TBI, clinical predictors and imaging together explain only 35% of the variance in outcomes. In the OVERCOME-TBI project, patients with a history of TBI sustained 1-4 and 11-14 years earlier will undergo extensive neurological, biochemical, microbiological, gastroenterological and imaging examinations. The patients have previously participated in the prospective studies of our research group, so that data on acute injuries, blood-based biomarkers and advanced imaging results are already available. The results are expected to yield objective diagnostic and treatment methods for the diagnosis of progressive brain disease after brain injury and for the identification of microbiome-gut-brain axis dysfunction associated with disease progression.

Conditions

Traumatic Brain Injury

Keywords

traumatic; brain; injury; traumatic brain injury; TBI; neuroinflammation; gut; microbiota; microbiota-gut-brain axis; DTI; diffusion tensor; biomarker; blood based biomarker

Outcome Measures

Primary Outcomes (5)

• Biochemical neuroinflammation burden (lipids and metabolites)

  Neuroinflammation burden as measured by levels of blood-based lipid biomarkers choline phospholipids (lysophosphatidylcholines, ether phosphatidylcholines, and sphingomyelins), branched-chain amino acids and medium-chain fatty acids

  1-14 years after traumatic brain injury

• Biochemical neuroinflammation burden (cytokines)

  Neuroinflammation burden as measured by levels of blood-based cytokines IL-6, IL-15, and MCP-1

  1-14 years after traumatic brain injury

• Functional outcome

  Functional outcome measured with Glasgow Outcome Scale Extended (GOSE, 1=dead - 8=complete recovery)

  1-14 years after traumatic brain injury

• Changes in microbiota

  DNA from fecal microbiome assessed by deep shot gun metagenomics approach, referenced to a population of healthy control subjects

  1-14 years after traumatic brain injury

• Inflammation burden on head positron emission tomography

  Neuroinflammation measured using the \[11C\]PK11195 radioligand

  1-14 years after traumatic brain injury

Secondary Outcomes (2)

• Changes in brain white and grey matter microstructure

  1-14 years after traumatic brain injury

• Accelerated brain ageing

  1-14 years after traumatic brain injury

Study Arms (2)

Patients with history of sustained traumatic brain injury

Patients with history of sustained traumatic brain injury 1-4 and 11-14 years earlier

Diagnostic Test: blood-based protein biomarker assessments; Diagnostic Test: blood-based metabolomic/lipidomic biomarker assessments; Diagnostic Test: Diffusion-weighted magnetic resonance imaging (brain); Diagnostic Test: Structural magnetic resonance imaging (brain); Diagnostic Test: PET imaging (brain); Procedure: Standard colonoscopy with pinch biopsies; Diagnostic Test: Fecal microbiome assessments

Control patients with history of orthopedic injury without traumatic brain injury

Patients with history of sustained orthopedic injury without traumatic brain injury 1-4 and 11-14 years earlier

Diagnostic Test: blood-based protein biomarker assessments; Diagnostic Test: blood-based metabolomic/lipidomic biomarker assessments; Diagnostic Test: Diffusion-weighted magnetic resonance imaging (brain); Diagnostic Test: Structural magnetic resonance imaging (brain); Diagnostic Test: PET imaging (brain); Procedure: Standard colonoscopy with pinch biopsies; Diagnostic Test: Fecal microbiome assessments

Interventions

blood-based protein biomarker assessments DIAGNOSTIC_TEST

Assessment of multiple blood-based biomarkers of different cellular origin and inflammatory mediators

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

blood-based metabolomic/lipidomic biomarker assessments DIAGNOSTIC_TEST

Assessment of multiple blood-based TBI-related metabolomic and lipidomic biomarkers

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

Diffusion-weighted magnetic resonance imaging (brain) DIAGNOSTIC_TEST

Diffusion-weighted magnetic resonance imaging

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

Structural magnetic resonance imaging (brain) DIAGNOSTIC_TEST

Structural magnetic resonance imaging

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

PET imaging (brain) DIAGNOSTIC_TEST

Positron emission tomography imaging

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

Standard colonoscopy with pinch biopsies PROCEDURE

Standard colonoscopy including pinch biopsies from the bowel wall at several levels (terminal ileum, ascending colon, transverse colon, descending colon, and rectosigmoideum) for histology, microbiome analysis and metabolomics

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

Fecal microbiome assessments DIAGNOSTIC_TEST

Fecal microbiome assessments (DNA)

Control patients with history of orthopedic injury without traumatic brain injury; Patients with history of sustained traumatic brain injury

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

All those who are alive and give their consent will be included from our previous prospective studies (TBIcare or PACoS-TBI)

You may qualify if:

• All those who are alive and give their consent will be included from our previous prospective studies (TBIcare or PACoS-TBI)

You may not qualify if:

• Those patients and controls with contraindication for head MRI (MRI-incompatible heart pacemaker, weight over 200 kg, mechanical heart valve prosthesis, first trimester of pregnancy, orbital area tattoo) will not undergo head MRI. Instead, they we will undergo the other assessments
• For controls, those who have suffered a TBI or any other brain disorder after the TBIcare or PACoS-TBI study will be excluded.
• Diagnosis of IBD or other diagnosis besides IBS causing severe GI symptoms, such as microscopic colitis or bile acid diarrhea
• Poorly controlled celiac disease
• Colorectal cancer diagnosed within five years
• Antibiotic or probiotic treatment, on-going or previous month.
• Unwilling or unable to undergo colonoscopy and/or standard bowel preparation.
• Significantly increased risk of heart or kidney failure or electrolyte imbalances due to bowel preparation (frailty, serious pre-existing heart or kidney insufficiency).
• Altered bowel anatomy after significant operation. Appendicectomy or cholecystectomy are considered minor operations.

Sponsors & Collaborators

• Turku University Hospital: lead
• Aalto University: collaborator
• University of Geneva, Switzerland: collaborator
• Göteborg University: collaborator
• University of Cambridge: collaborator
• Örebro University, Sweden: collaborator
• University of Turku: collaborator

Related Publications (21)

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  PMID: 35377407 RESULT

• Shahim P, Politis A, van der Merwe A, Moore B, Ekanayake V, Lippa SM, Chou YY, Pham DL, Butman JA, Diaz-Arrastia R, Zetterberg H, Blennow K, Gill JM, Brody DL, Chan L. Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI. Neurology. 2020 Aug 11;95(6):e623-e636. doi: 10.1212/WNL.0000000000009985. Epub 2020 Jul 8.

  PMID: 32641529 RESULT

• Sundman MH, Chen NK, Subbian V, Chou YH. The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. Brain Behav Immun. 2017 Nov;66:31-44. doi: 10.1016/j.bbi.2017.05.009. Epub 2017 May 17.

  PMID: 28526435 RESULT

• Patterson TT, Nicholson S, Wallace D, Hawryluk GWJ, Grandhi R. Complex Feed-Forward and Feedback Mechanisms Underlie the Relationship Between Traumatic Brain Injury and the Gut-Microbiota-Brain Axis. Shock. 2019 Sep;52(3):318-325. doi: 10.1097/SHK.0000000000001278.

  PMID: 30335675 RESULT

• undefined

  RESULT

• Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012 Oct;13(10):701-12. doi: 10.1038/nrn3346. Epub 2012 Sep 12.

  PMID: 22968153 RESULT

• Dinan TG, Cryan JF. The impact of gut microbiota on brain and behaviour: implications for psychiatry. Curr Opin Clin Nutr Metab Care. 2015 Nov;18(6):552-8. doi: 10.1097/MCO.0000000000000221.

  PMID: 26372511 RESULT

• Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J. Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift. Neuron. 2017 Sep 13;95(6):1246-1265. doi: 10.1016/j.neuron.2017.07.010.

  PMID: 28910616 RESULT

• Koerte IK, Lin AP, Muehlmann M, Merugumala S, Liao H, Starr T, Kaufmann D, Mayinger M, Steffinger D, Fisch B, Karch S, Heinen F, Ertl-Wagner B, Reiser M, Stern RA, Zafonte R, Shenton ME. Altered Neurochemistry in Former Professional Soccer Players without a History of Concussion. J Neurotrauma. 2015 Sep 1;32(17):1287-93. doi: 10.1089/neu.2014.3715. Epub 2015 May 14.

  PMID: 25843317 RESULT

• Coughlin JM, Wang Y, Munro CA, Ma S, Yue C, Chen S, Airan R, Kim PK, Adams AV, Garcia C, Higgs C, Sair HI, Sawa A, Smith G, Lyketsos CG, Caffo B, Kassiou M, Guilarte TR, Pomper MG. Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study. Neurobiol Dis. 2015 Feb;74:58-65. doi: 10.1016/j.nbd.2014.10.019. Epub 2014 Nov 7.

  PMID: 25447235 RESULT

• Wilson L, Stewart W, Dams-O'Connor K, Diaz-Arrastia R, Horton L, Menon DK, Polinder S. The chronic and evolving neurological consequences of traumatic brain injury. Lancet Neurol. 2017 Oct;16(10):813-825. doi: 10.1016/S1474-4422(17)30279-X. Epub 2017 Sep 12.

  PMID: 28920887 RESULT

• Tenovuo O, Diaz-Arrastia R, Goldstein LE, Sharp DJ, van der Naalt J, Zasler ND. Assessing the Severity of Traumatic Brain Injury-Time for a Change? J Clin Med. 2021 Jan 4;10(1):148. doi: 10.3390/jcm10010148.

  PMID: 33406786 RESULT

• Posti JP, Dickens AM, Oresic M, Hyotylainen T, Tenovuo O. Metabolomics Profiling As a Diagnostic Tool in Severe Traumatic Brain Injury. Front Neurol. 2017 Aug 18;8:398. doi: 10.3389/fneur.2017.00398. eCollection 2017.

  PMID: 28868043 RESULT

• Mikolic A, Groeniger JO, Zeldovich M, Wilson L, van Lennep JR, van Klaveren D, Polinder S; Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Participants and Investigators. Explaining Outcome Differences between Men and Women following Mild Traumatic Brain Injury. J Neurotrauma. 2021 Dec;38(23):3315-3331. doi: 10.1089/neu.2021.0116.

  PMID: 34617454 RESULT

• Schneider ALC, Huie JR, Boscardin WJ, Nelson L, Barber JK, Yaffe K, Diaz-Arrastia R, Ferguson AR, Kramer J, Jain S, Temkin N, Yuh E, Manley GT, Gardner RC; TRACK-TBI Investigators. Cognitive Outcome 1 Year After Mild Traumatic Brain Injury: Results From the TRACK-TBI Study. Neurology. 2022 Mar 22;98(12):e1248-e1261. doi: 10.1212/WNL.0000000000200041. Epub 2022 Feb 16.

  PMID: 35173018 RESULT

• Nelson LD, Temkin NR, Dikmen S, Barber J, Giacino JT, Yuh E, Levin HS, McCrea MA, Stein MB, Mukherjee P, Okonkwo DO, Robertson CS, Diaz-Arrastia R, Manley GT; and the TRACK-TBI Investigators; Adeoye O, Badjatia N, Boase K, Bodien Y, Bullock MR, Chesnut R, Corrigan JD, Crawford K, Duhaime AC, Ellenbogen R, Feeser VR, Ferguson A, Foreman B, Gardner R, Gaudette E, Gonzalez L, Gopinath S, Gullapalli R, Hemphill JC, Hotz G, Jain S, Korley F, Kramer J, Kreitzer N, Lindsell C, Machamer J, Madden C, Martin A, McAllister T, Merchant R, Noel F, Palacios E, Perl D, Puccio A, Rabinowitz M, Rosand J, Sander A, Satris G, Schnyer D, Seabury S, Sherer M, Taylor S, Toga A, Valadka A, Vassar MJ, Vespa P, Wang K, Yue JK, Zafonte R. Recovery After Mild Traumatic Brain Injury in Patients Presenting to US Level I Trauma Centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. JAMA Neurol. 2019 Sep 1;76(9):1049-1059. doi: 10.1001/jamaneurol.2019.1313.

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• Brazinova A, Rehorcikova V, Taylor MS, Buckova V, Majdan M, Psota M, Peeters W, Feigin V, Theadom A, Holkovic L, Synnot A. Epidemiology of Traumatic Brain Injury in Europe: A Living Systematic Review. J Neurotrauma. 2021 May 15;38(10):1411-1440. doi: 10.1089/neu.2015.4126. Epub 2018 Dec 19.

  PMID: 26537996 RESULT

• Stewart WF, Kim N, Ifrah CS, Lipton RB, Bachrach TA, Zimmerman ME, Kim M, Lipton ML. Symptoms from repeated intentional and unintentional head impact in soccer players. Neurology. 2017 Feb 28;88(9):901-908. doi: 10.1212/WNL.0000000000003657. Epub 2017 Feb 1.

  PMID: 28148633 RESULT

• Priemer DS, Iacono D, Rhodes CH, Olsen CH, Perl DP. Chronic Traumatic Encephalopathy in the Brains of Military Personnel. N Engl J Med. 2022 Jun 9;386(23):2169-2177. doi: 10.1056/NEJMoa2203199.

  PMID: 35675177 RESULT

• Maas AIR, Menon DK, Manley GT, Abrams M, Akerlund C, Andelic N, Aries M, Bashford T, Bell MJ, Bodien YG, Brett BL, Buki A, Chesnut RM, Citerio G, Clark D, Clasby B, Cooper DJ, Czeiter E, Czosnyka M, Dams-O'Connor K, De Keyser V, Diaz-Arrastia R, Ercole A, van Essen TA, Falvey E, Ferguson AR, Figaji A, Fitzgerald M, Foreman B, Gantner D, Gao G, Giacino J, Gravesteijn B, Guiza F, Gupta D, Gurnell M, Haagsma JA, Hammond FM, Hawryluk G, Hutchinson P, van der Jagt M, Jain S, Jain S, Jiang JY, Kent H, Kolias A, Kompanje EJO, Lecky F, Lingsma HF, Maegele M, Majdan M, Markowitz A, McCrea M, Meyfroidt G, Mikolic A, Mondello S, Mukherjee P, Nelson D, Nelson LD, Newcombe V, Okonkwo D, Oresic M, Peul W, Pisica D, Polinder S, Ponsford J, Puybasset L, Raj R, Robba C, Roe C, Rosand J, Schueler P, Sharp DJ, Smielewski P, Stein MB, von Steinbuchel N, Stewart W, Steyerberg EW, Stocchetti N, Temkin N, Tenovuo O, Theadom A, Thomas I, Espin AT, Turgeon AF, Unterberg A, Van Praag D, van Veen E, Verheyden J, Vyvere TV, Wang KKW, Wiegers EJA, Williams WH, Wilson L, Wisniewski SR, Younsi A, Yue JK, Yuh EL, Zeiler FA, Zeldovich M, Zemek R; InTBIR Participants and Investigators. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. 2022 Nov;21(11):1004-1060. doi: 10.1016/S1474-4422(22)00309-X. Epub 2022 Sep 29.

  PMID: 36183712 RESULT

• Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Bragge P, Brazinova A, Buki A, Chesnut RM, Citerio G, Coburn M, Cooper DJ, Crowder AT, Czeiter E, Czosnyka M, Diaz-Arrastia R, Dreier JP, Duhaime AC, Ercole A, van Essen TA, Feigin VL, Gao G, Giacino J, Gonzalez-Lara LE, Gruen RL, Gupta D, Hartings JA, Hill S, Jiang JY, Ketharanathan N, Kompanje EJO, Lanyon L, Laureys S, Lecky F, Levin H, Lingsma HF, Maegele M, Majdan M, Manley G, Marsteller J, Mascia L, McFadyen C, Mondello S, Newcombe V, Palotie A, Parizel PM, Peul W, Piercy J, Polinder S, Puybasset L, Rasmussen TE, Rossaint R, Smielewski P, Soderberg J, Stanworth SJ, Stein MB, von Steinbuchel N, Stewart W, Steyerberg EW, Stocchetti N, Synnot A, Te Ao B, Tenovuo O, Theadom A, Tibboel D, Videtta W, Wang KKW, Williams WH, Wilson L, Yaffe K; InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017 Dec;16(12):987-1048. doi: 10.1016/S1474-4422(17)30371-X. Epub 2017 Nov 6. No abstract available.

  PMID: 29122524 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

blood samples

MeSH Terms

Conditions

Brain Injuries, Traumatic; Wounds and Injuries; Neuroinflammatory Diseases

Interventions

Diffusion Magnetic Resonance Imaging; Positron-Emission Tomography

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Magnetic Resonance Imaging; Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Image Enhancement; Photography; Radionuclide Imaging; Diagnostic Techniques, Radioisotope

Study Officials

• Jussi P. Posti, MD, PhD

  Turku University Hospital and University of Turku

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jussi P Posti, MD, PhD

CONTACT

+35823130282; jussi.posti@utu.fi

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Target Duration: 14 Years
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2024
• First Posted: April 15, 2025
• Study Start: May 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: April 15, 2025

Record last verified: 2025-04