Exploring gut microbiota and spinal cord injury: pathogenesis, treatment strategies and prospects

Abstract

Spinal cord injury (SCI) is a disabling central nerve system (CNS) injury, often caused by factors such as traffic accidents, falls from heights, violent trauma, and sports injuries, commonly resulting in permanent loss of motor and sensory function below the level of injury. Increasing evidence suggests that gut microbiota influences the occurrence and development of CNS diseases through the brain-gut axis. Recent studies indicate that patients with SCI frequently exhibit gut microbiota dysbiosis. Changes in gut microbiota can lead to gut barrier disruption, triggering neurogenic inflammatory responses, thereby hindering recovery after SCI, while reshaping gut microbiota may benefit the recovery of intestinal function and neurofunction after SCI. In this review, we summarize emerging literature on the role of microbiota after SCI. We elucidate the intrinsic connection between gut microbiota and SCI, explore the role of gut microbiota in the pathogenesis of SCI, and investigate potential intervention strategies targeting gut microbiota, including probiotic therapy, fecal microbiota transplantation (FMT), and regulation of metabolites, aiming to provide theoretical basis and translational prospects for developing innovative microecological targeted therapeutic approaches.

Keywords: fecal microbiota transplantation; gut microbiota dysbiosis; probiotics; spinal cord injury; treatment strategies.

Figure 1

Bidirectional regulation of SCI and gut microbiota. SCI leads to neuroinflammation, including excessive release of NLRP3 inflammasome, TLRs, and inflammatory factors, as well as damage to the spinal cord barrier. In addition, SCI causes autonomic dysfunction, which leads to altered intestinal motility and intestinal immune dysfunction. These changes result in dysbiosis of the gut microbiota and damage to the gut barrier. An imbalance of gut microbiota can exacerbate intestinal inflammation. Leakage of gut microbial components and their metabolic product, LPS, may enter the CNS through peripheral blood circulation and damaged intestinal and blood-brain barriers. This translocation aggravates neuroinflammation and hinders functional recovery from SCI. (SCI, Spinal cord injury; CNS, Central nerve system; NLRP3, NLR family pyrin domain-containing-3; TLRs, Toll-like receptors; TRP, Tryptophan; SCFAs, Short-chain fatty acids; GALT, Gut-Associated lymphoid tissue; LPS, Lipopolysaccharide).

Figure 2

The mechanism of gut microbiota dysbiosis in the pathological processes of multiple systems and the formation of complications after SCI. SCI can lead to gut microbiota dysbiosis by damaging autonomic neural function and intestinal barrier integrity. Gut microbiota dysbiosis further triggers various pathological cascade reactions, including impaired intestinal barrier function, enhanced oxidative stress, abnormal immune response, and neurological dysfunction. The reduction of SCFAs and changes in bile acid metabolism cause an imbalance in intestinal homeostasis. This imbalance leads to constipation, inflammation, and metabolic abnormalities. Oxidative stress and the accumulation of ROS activate macrophages and the NLRP3 inflammasome, promoting neuroinflammation and inhibiting neural remodeling. Meanwhile, the decrease in serotonin levels and the excessive activation of microglia jointly contribute to the occurrence of depression and neuropathic pain. The translocation of gut microbiota and their metabolites into the bloodstream can induce systemic infections, which further exacerbate nerve injury and inflammatory responses. (SCI, Spinal cord injury; SCFAs, Short-chain fatty acids; ROS, Reactive oxygen species; RNS, Reactive nitrogen species; NLRP3, NLR family pyrin domain-containing 3; LPS, Lipopolysaccharide).

Figure 3

Neuroprotection by normal intestinal microbiota through metabolic pathways after SCI. It mainly promotes the recovery of neurological function after injury through the SCFAs pathway and the tryptophan metabolic pathway. (SCI, Spinal cord injury; HDACs, Histone deacetylases; SCFAs, Short-chain fatty acids; GLP-1, Glucagon-like peptide-1; AhR, Aryl hydrocarbon receptors; IDO1/2, Indoleamine 2, 3-dioxygenase 1 and 2; TNF-α, Tumor necrosis factor – α; IL-6, interleukin-6; IL-10, Interleukin-10; TGF-β, Transforming growth factor - β).

Figure 4

The impact of gut microbiota dysbiosis on nerve function through immune pathways after injury. Gut microbiota dysbiosis mainly influences SCI through cytokines, toll-like receptors, and the NLRP3 inflammasome. (SCI, Spinal cord injury; PAMPs, Pathogen-associated molecular patterns; DAMPs, Damage associated molecular patterns; TLR4, Toll-like receports-4; NF-κB, Nuclear factor-κB; TNF-α, Tumor necrosis factor – α; IL-18, Interleukin-18; IL-6, Interleukin-6; ROS, Reactive oxygen species; IL-1β, Interleukin-1β; TGF-β, Transforming growth factor-β; NLRP3, NLR family pyrin domain-containing-3; MAPK, Mitogen-activated protein kinase; MD2, Myeloid differentiation factor-2; MyD88, Myeloid differentiation primary response 88).