Short-Chain Fatty Acid Profile Is Associated With Outcome in Moderate-Severe Traumatic Brain Injury

Introduction: Secondary brain injury, driven in part by inflammation, is a key target in the critical care of patients sustaining moderate-to-severe traumatic brain injury (TBI). Short-chain fatty acids (SCFAs) modulate the immune response and are associated with favorable outcome in preclinical TBI models. We hypothesized that higher SCFA levels in patients early after TBI would be associated with better functional outcomes.


Methods: Hyperacute plasma samples (median 1.5 [IQR 0.9–2.3] hours post-injury) were collected from participants in the PROTIPS study at Oregon Health & Science University, which enrolled patients ≥15 years presenting with a Glasgow Coma Scale of 3-12 after TBI. SCFAs were measured by gas chromatography–mass spectrometry; GFAP, Tau, and NfL were measured via sandwich immunoassay. Outcome was assessed using dichotomized GOS at discharge (n=123) and GOSE at 6 months (n=88).
Partial least squares discriminant analysis (PLS-DA) modeled outcomes using log-transformed acetate, propionate, and butyrate. Acetate and propionate were selected for further analysis based on VIP >1. PCA and K-means clustering (k=2, selected via silhouette method) defined SCFA-based subgroups. Group differences were assessed with Mann-Whitney U and Chi-square tests. Logistic regression and likelihood ratio tests evaluated whether SCFA cluster assignment improved prediction beyond the IMPACT lab model.


Results: PLS-DA identified acetate and propionate (VIP >1) as key discriminators. Cluster 1 (n=47) had higher SCFA levels and was significantly younger but otherwise similar in injury severity when assessed using clinical, radiographic or blood biomarkers, compared to Cluster 2 (n=76). Cluster 1 had more favorable outcomes at discharge (83% vs 55%, p=0.003) and 6 months (78% vs 45%, p=0.005). Adding SCFA cluster to the IMPACT model improved AUROC for favorable outcome at discharge (SCFA+IMPACT 0.83 vs IMPACT 0.80, p=0.008) and at 6 months (0.84 vs 0.83, p=0.03). Plasma IL-6 trended lower in Cluster 1 (mean±SEM 28±4.3 pg/mL vs 66±17.0 pg/mL, p=0.06).


Conclusions: In this prospective cohort, early elevated SCFA levels were associated with better functional outcomes despite similar injury severity, suggesting SCFA modulation may be a promising therapeutic strategy in TBI.