Traumatic spinal cord injury and the gut microbiota: current insights and future challenges

Individuals with traumatic spinal cord injury (SCI) suffer from numerous peripheral complications in addition to the long-term paralysis that results from disrupted neural signaling pathways. Those living with SCI have consistently reported gastrointestinal dysfunction as a significant issue for overall quality of life, but most research has focused bowel management rather than how altered or impaired gut function impacts on the overall health and well-being of the affected individual. The gut-brain axis has now been quite extensively investigated in other neurological conditions but the gastrointestinal compartment, and more specifically the gut microbiota, have only recently garnered attention in the context of SCI because of their vast immunomodulatory capacity and putative links to infection susceptibility. Most studies to date investigating the gut microbiota following SCI have employed 16S rRNA genomic sequencing to identify bacterial taxa that may be pertinent to neurological outcome and common sequalae associated with SCI. This review provides a concise overview of the relevant data that has been generated to date, discussing current understanding of how the microbial content of the gut after SCI appears linked to both functional and immunological outcomes, whilst also emphasizing the highly complex nature of microbiome research and the need for careful evaluation of correlative findings. How the gut microbiota may be involved in the increased infection susceptibility that is often observed in this condition is also discussed, as are the challenges ahead to strategically probe the functional significance of changes in the gut microbiota following SCI in order to take advantage of these therapeutically

Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2

Traumatic spinal cord injury (SCI) triggers an acute-phase response that leads to systemic inflammation and rapid mobilization of bone marrow (BM) neutrophils into the blood. These mobilized neutrophils then accumulate in visceral organs and the injured spinal cord where they cause inflammatory tissue damage. The receptor for complement activation product 3a, C3aR1, has been implicated in negatively regulating the BM neutrophil response to tissue injury. However, the mechanism via which C3aR1 controls BM neutrophil mobilization, and also its influence over SCI outcomes, are unknown. Here, we show that the C3a/C3aR1 axis exerts neuroprotection in SCI by acting as a physiological antagonist against neutrophil chemotactic signals. We show that C3aR1 engages phosphatase and tensin homolog (PTEN), a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, to restrain C-X-C chemokine receptor type 2-driven BM neutrophil mobilization following trauma. These findings are of direct clinical significance as lower circulating neutrophil numbers at presentation were identified as a marker for improved recovery in human SCI. Our work thus identifies C3aR1 and its downstream intermediary, PTEN, as therapeutic targets to broadly inhibit neutrophil mobilization/recruitment following tissue injury and reduce inflammatory pathology