Circulating Short-Chain Fatty Acid Profile Predicts Functional Outcome After Moderate-to-Severe Traumatic Brain Injury.

Abstract

Short-chain fatty acids (SCFAs) are immunometabolites produced by the gut microbiome. In animal models, SCFAs affect traumatic brain injury (TBI) severity by modulating the immune response and serving as an energy source. The goal of this study was to assess whether SCFAs are associated with functional outcome in adult patients with moderate-to-severe TBI (msTBI). Prospective cohort study. Urban Trauma Center. Adults (age ≥ 15 yr) who had TBI with Glasgow Coma Scale 3-12, intracranial hemorrhage on head CT scan, and at least one reactive pupil. Blood samples had to be collected within 3 hours of trauma. None. Univariate and multivariate analyses demonstrated that plasma SCFAs were associated with better functional outcomes at discharge and 6 months, an association driven primarily by differences in plasma acetate and propionate. K-means clustering of acetate and propionate levels identified two patient clusters with distinct discharge and 6-month functional outcomes but similar clinical, biomarker, and radiographic injury severity. Cluster 1 (n = 47) had higher SCFA levels compared with cluster 2 (n = 76) and cluster 1 had more favorable outcomes at discharge (Glasgow Outcome Scale 4-5: 83% vs. 55%; p = 0.003) and 6 months (Extended Glasgow Outcome Scale 4-8: 78% vs. 45%; p = 0.005). Multivariable logistic regression adjusting for the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)lab model identified an independent association between the SCFA cluster and functional outcome at discharge (p = 0.001) and 6 months (p = 0.03). Adding the SCFA cluster to the IMPACTlab model improved the area under the receiver operating characteristic curve for the prediction model for a favorable outcome. Our study suggests that SCFA levels are associated with functional outcome after msTBI. Future studies will focus on identifying mechanisms through which SCFAs may improve msTBI outcomes and what drives interpatient variation in their levels, which could position SCFAs as prognostic biomarkers and therapeutic targets in TBI.