Long-term recovery and microbiota-gut-brain axis disruption after traumatic brain injury (OVERCOME-TBI): protocol for a prospective, observational clinical study.

INTRODUCTION: Traumatic brain injury (TBI) is a major cause of long-term disability worldwide, but the pathophysiological mechanisms underlying its chronic sequelae remain incompletely understood. In addition to persistent neuroinflammation, evidence suggests that dysregulation of the gut microbiota influences brain recovery. The OVERCOME-TBI study investigates the long-term functional, cognitive, imaging, biochemical and gastrointestinal outcomes after TBI of all severities, with the aim of identifying biomarkers and microbiome signatures associated with progressive neurodegeneration and poor recovery. METHODS AND ANALYSIS: This is a prospective, observational study with long-term follow-up of two previously established TBI cohorts-the Evidence-based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries (TBIcare; recruited 2011-2013) and the Pathophysiological Characterisation of Severe TBI (PACoS-TBI; recruited 2020-2023). The design combines prospectively collected acute and subacute data from the original cohorts with new cross-sectional assessments performed at chronic time points (2-5 and 12-15 years post-injury). Participants are re-contacted and re-consented for these chronic-phase assessments. Up to 160 patients with TBI and 30 orthopaedic injury controls will undergo multimodal examinations: neurological and neuropsychological testing, advanced MRI including multishell diffusion and resting-state functional MRI, positron emission tomography (PET) with the radioligand [11C]PK11195, blood-based proteomics, lipidomics, metabolomics, faecal and intestinal microbiome profiling and colonoscopy biopsies. Moreover, 10 patients with multiple sclerosis (as a positive control group) will undergo PET imaging and sampling for blood biomarkers. Primary outcomes include neuroinflammatory burden (biochemical and PET), longitudinal functional outcomes (Glasgow Outcome Scale Extended) and gut microbiota composition. Statistical modelling, including regression models and machine learning, will be applied to identify predictors of outcome and disease progression. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethical Committee of the Wellbeing Services County of Southwest Finland. Written informed consent will be obtained from all participants. The results will be disseminated through peer-reviewed publications, conference presentations and stakeholder engagement, with the aim of developing personalised diagnostics and novel therapeutic targets to alleviate the chronic consequences of TBI. TRIAL REGISTRATION NUMBER: NCT06927063.