Gut–Spinal Cord Axis in Spinal Cord Injury: Bidirectional Inflammatory Mechanisms and Microbiota-Targeted Therapeutic Strategies

Jinwang Dong,1,2 Tao Xie,1 Cunhu Shi,1 Gaoqi Feng,3 Hengheng Zhang,1 Zhengwei Xu,1 Liang Dong1 1Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Medicine, Yan’an University, Yan’an, Shaanxi, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Sengong Hospital of Shaanxi Province, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Liang Dong, Email [email protected]: Spinal cord injury (SCI) is a complex neurological disorder characterized not only by localized neuroinflammation but also by systemic immune dysregulation and multiorgan dysfunction. Emerging evidence has identified the gut microbiota as a critical extrinsic regulator of neural homeostasis, giving rise to the concept of the “gut–spinal cord axis”. This review systematically examines the dynamic and bidirectional alterations in the gut microbial composition following SCI, with a particular emphasis on the role of microbiota-derived metabolites in the gut–spinal cord axis. These metabolites are recognized as key mediators that shape the spinal inflammatory milieu by modulating specific signaling pathways. In addition, the mechanistic basis of the gut–spinal cord axis is further dissected through neural, immune, and metabolic regulatory frameworks, highlighting how gut dysbiosis following SCI contributes to spinal inflammation via the modulation of vagal nerve signaling, immune cell polarization, and metabolic homeostasis. Moreover, the translational potential of microbiota-targeted interventions—such as probiotics and fecal microbiota transplantation (FMT)—is evaluated in terms of their ability to suppress inflammatory amplification and restore the disrupted bidirectional gut–spinal cord feedback loop. By integrating multiomics approaches and adopting a spatiotemporal perspective, this review underscores the importance of cross-system therapeutic strategies in SCI, aiming to provide a theoretical foundation and practical guidance for future precision interventions and translational research.Keywords: spinal cord injury, gut–spinal cord axis, gut microbiota, neuroinflammation, probiotics, fecal microbiota transplantation