Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4100-4111.doi: 10.4103/NRR.NRR-D-25-01016

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A new paradigm of bidirectional regulation of the gut– spinal cord axis

Songzhi Ni1, #, Kai Chen1, #, Haojue Wang1, #, Shenyuan Chen2, #, Yuanyu Qiu3, Tianjiao Wang4, 5, Fengfeng Mo6, 7, Shige Wang8, Bo Li9, *, Yushu Bai1, *, Jiulong Zhao4, *, Xiao Zhai1, *, Zhaoshen Li4   

  1. 1Department of Orthopedics, Shanghai Changhai Hospital, Shanghai, China; 
    2Zhenjiang Key Laboratory of High Technology Research on sEVs Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 
    3Department of Gynecology and Obstetrics, the Affiliated Jiangyin Hospital of Southeast University, Jiangyin, Jiangsu Province, China; 
    4Department of Gastroenterology, Shanghai Changhai Hospital, Shanghai, China; 
    5National Digestive Endoscopy Improvement System, Shanghai, China; 
    6Department of Naval Nutrition and Food Hygiene, Naval Medical University, Shanghai, China; 
    7Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai Changhai Hospital, Shanghai, China; 
    8School of Materials and Chemistry, University of Shanghai for Science and Technology, Shanghai, China; 
    9Department of Orthopedics, Shanghai Changzheng Hospital, Shanghai, China

  • Online:2026-09-15 Published:2026-05-19
  • Contact: Xiao Zhai, MD, drzhaixiao@126.com; Jiulong Zhao, MD, jlzhao9@163.com; Yushu Bai, MD, spinebaiys@163.com; Bo Li, MD, smmulibo@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81701199 (to XZ), 82503076 (to KC); Application Demonstration Project for Innovative Drugs and Medical Devices under Shanghai’s 2024 “Science and Technology Innovation Action Plan”, No. 24SF1902800 (to YB); the Excellent Young Talent Program of Shanghai Municipal Health Commission, No. 2022YQ003 (to XZ); Changhong Talent Program of Changhai Hospital (to XZ).

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Abstract: The bidirectional interactions of spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis with the gut operate through a distinct gut–spinal cord axis, rather than being fully explained by the conventional gut–brain axis. The spinal cord, with its unique anatomical and physiological features, serves as a central hub of communication. The gut and spinal cord communicate through various pathways, including the immune system and the autonomic and enteric nervous systems. This review summarizes existing clinical and basic research on the relationship between gut homeostasis and spinal cord diseases. First, we present findings from epidemiological studies showing that patients with spinal cord disorders often exhibit altered gut function, which may be influenced by antibiotic exposure and environmental factors. Second, we review the key physiological and anatomical structures of the gut-spinal cord axis, including the intestinal barrier, gut microbiota, and enteric nervous system, all of which are involved in maintaining gut health, as well as sensory neurons, motor neurons, and interneurons in spinal nerve regulation. Third, we describe the roles of the three axes (microbial, immune, and neural) in bidirectional regulation and their pathological mechanisms. Moreover, vicious cycles involving these axes can exacerbate spinal cord disorders. Fourth, we outline potential biomarkers in the gut–spinal cord axis, such as uridine, hypoxanthine, and 5-methoxytryptophan. Fifth, we propose several treatment strategies with potential clinical applications, including fecal microbiota transplantation and the use of probiotics and prebiotics. Finally, this review emphasizes the gut–spinal cord axis as a promising therapeutic target, highlighting the need for multi-omics integration, longitudinal cohort studies, and individualized interventions to resolve existing debates. Overall, the recognition of the gut–spinal cord axis provides a conceptual shift that extends beyond the gut–brain framework.

Key words: autonomic regulation, biomarkers, enteric nervous system, gut microbiota, host-microbe interaction, intestinal barrier, microbial metabolites, multi-omics approaches, neurodegeneration, neuroinflammation