Contribution of the Gut Microbiome to Spinal Cord Injury Pain and Neuroinfammation
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Date
Authors
Bannerman, Courtney A.
Keyword
Spinal cord injury , pain , gut microbiome , neuro-immune interactions
Abstract
Spinal cord injuries (SCI) affect more than 10,000 Canadians annually, with 60-80% of this population developing chronic pain as a result of this condition. Aside from opioids, which have multiple side effects, few effective treatment options exist. Recent work has shown that the collection of bacteria in the gut, called the gut microbiome, may play a role in pain processing. We sought to understand how changes in the gut microbiome after SCI could alter injury pathologies. Moderate contusion (50 kdyn) injury with or without sustained compression (60 seconds) of the spinal cord was carried out on female C57BL/6J mice, with sham-injured mice only receiving the laminectomy. Injured or sham mice were then treated with an antibiotic cocktail, defined microbial communities, or water for the first 7dpi. Mice who received compression SCI experienced more severe hypersensitivity, increased gut dysbiosis, central demyelination, and Ly6c+ macrophage infiltration into the spinal cord and DRG. Contusion mice treated with antibiotics also experienced more severe mechanical hypersensitivity and increased demyelination in the spinal cord. Meanwhile, compression SCI mice treated with defined microbial communities experienced less mechanical hypersensitivity. SCI with antibiotics or defined microbial communities treatment caused acute changes in immune cell activation and infiltration to the spinal cord and chronic changes to the immune cell composition of the intestinal tract. One of the key immune cells infiltrating the spinal cord that was altered was γδ T cells. TCRδ-/- mice demonstrated significantly less mechanical hypersensitivity acutely after injury and had significantly more macrophages at 3dpi and less CD86+ microglia at 7dpi. Using the photoconvertible KIKGR33 mouse line, we determined that as early as 4h post-injury, γδ T cells are migrating from the small intestine to the injury site. This migration no longer occurs when mice are treated with resiniferatoxin or 6-OHDA to deplete sensory or sympathetic neurons. These results provide an in-depth characterization of γδ T cells' role in the onset of hypersensitivity and the immune response in the central nervous system post-injury. Potential future pain therapeutics stemming from this work could include modulating the gut microbiome through the use of probiotics, or altering the migration of immune cells from the small intestine to the site of injury.