Leveraging microbiota-metabolites to reduce inflammation and promote functional recovery following spinal cord injury in female mice

Spinal cord injury induces extensive neurological impairment and drives systemic and tissue-level inflammatory responses that accelerate secondary systemic damage. Emerging evidence suggests that gut microbiota-derived metabolites can influence post-injury inflammation, presenting a potential therapeutic approach. This study examines whether the tryptophan-derived metabolites indole and indole-3-propionic acid modulate inflammatory responses and improve outcomes following spinal cord injury. Female C57BL/6J mice received a severe thoracic-8 contusion-compression injury and were administered indole or indole-3-proprionic acid daily via oral gavage for the duration of the observation period. In an acute cohort, 7 days post-injury, neither treatment altered plasma inflammatory profiles relative to injury controls. However, both metabolites significantly reduced CD68⁺ macrophage presence within the injured spinal cord. In a chronic cohort, 42 days post-injury, metabolite treatment mitigated injury-induced body composition changes, improved locomotor recovery and reduced inflammatory pathologies within the liver and spinal cord. These findings identify gut-derived metabolites as a promising therapeutic strategy targeting the gut-spinal cord axis to attenuate systemic injury mechanisms and support recovery.