BackgroundThe gut-brain axis has increasingly been implicated in the pathophysiology of traumatic brain injury (TBI). However, few human studies have simultaneously examined gut functional metagenomics and peripheral cytokine profiles across mild to moderate-to-severe TBI, which limits our understanding of how gut health may influence recovery outcomes in TBI patients.MethodsThis cross-sectional case-control investigation involved the collection of fecal and matched serum samples within 7 days post-injury from 60 mild TBI patients (MT; GCS 13–15), 45 moderate-to-severe TBI patients (MST; GCS ≤ 12), and 113 healthy controls (HC). Shotgun metagenomic sequencing examined gut microbiota. Serum IL-1β, IL-6, IL-8, and TNF-α were measured using a 4-plex Luminex test. Spearman correlation was utilized to construct a hypothesis relating cytokine levels to microbial severity-stratified abundance patterns.ResultsTBI was associated with severity-dependent remodeling of the gut microbiota. Alpha diversity decreased from HC to MST (p < 10−6), and community structure varied significantly among all three groups (PERMANOVA, p = 0.001). Serum TNF-α increased in a severity-associated manner (MST vs. HC and MT, padj < 0.015). Among 332 differentially abundant species, butyrate-producing commensals fell abruptly at MT with no additional decline in MST, suggesting an apparent floor-like pattern rather than confirming a true biological floor effect. For example, Faecalibacterium prausnitzii dropped from 9.02% in HC to 4.29% in MT. In terms of function, metagenomic inference indicated that pathways for fermentative metabolism and short-chain fatty acid (SCFA) biosynthesis were largely suppressed, suggesting a predicted reduction in microbial SCFA production capacity. On the other hand, secondary bile acid synthesis was specifically increased in MST-dominant KOs (85%). Systemically, reduced commensals showed weak, directionally consistent correlations with pro-inflammatory cytokines (|ρ| = 0.16–0.25), although none of the species-cytokine associations survived FDR correction.ConclusionAcute TBI is associated with severity-specific gut dysbiosis, which is accompanied by systemic neuroinflammation. The early reduction of butyrate-producing taxa in mild TBI suggests that the early post-injury period may represent a potential window for future gut-targeted intervention studies.