Background: The 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. Methods: This 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. Results: TBI 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, p _adj < 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. Conclusion: Acute 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.

Brain diseases such as ischaemic stroke, Alzheimer’s disease (AD), and glioma were characterized by high mortality and disability rate, and oxidative stress remains a major obstacle in treatment. Plasma–nanomedicine synergistic treatment technology provides a very attractive treatment strategy based on complementarity. This technology integrates cold atmospheric plasma (CAP) with nanomedicine. CAP produces active substances that regulate oxidative stress, while nanomedicine is specially designed for targeted delivery, controlled release, and microenvironmentally responsive activation of therapeutic agents. This integration generates new therapeutic functions and significantly improves the overall therapeutic effect. Despite the broad prospects of this emerging technology, researchers in the fields of medicine, physics, or pharmacy have not yet paid much attention to it. To fill this research gap, this review describes the physicochemical properties and biological effects of CAP and summarizes the latest advances in plasma nanomedicine strategies in the field of brain disease intervention, and reviews the four major nanomedical categories—metal-based, inorganic non-metallic, polymer-based and hydrogel systems—and their clinical applications in the treatment of brain tumors, strokes and neurodegenerative diseases in conjunction with CAP. Finally, we highlight a number of key challenges—limited resources of special CAP equipment, incomplete understanding of the mechanism, obstacles to transformation application—and put forward the future research direction to promote the development of accurate, safe, and clinical transformation value plasma–nanomedicine therapy for brain diseases.