Indole-3-propionic acid inhibits astrocyte inflammation and promotes motor function recovery after spinal cord injury via the AhR/NF-κB/MAPK axis.

Spinal cord injury (SCI) triggers persistent neuroinflammation, primarily driven by aberrant astrocyte activation, which exacerbates secondary neurodegeneration. Indole-3-propionic acid (IPA), a tryptophan-derived metabolite produced by the gut microbiota, has recently emerged as a potent anti-inflammatory agent in neurological disorders. However, its therapeutic potential and underlying mechanisms in SCI remain unexplored. In this research, using a TNF-α-stimulated astrocyte model in vitro and a mouse SCI model in vivo, we demonstrated that IPA significantly attenuated the expression of pro-inflammatory mediators (IL-6, IL-1β, iNOS, COX-2, CCL2, CXCL2, CXCL10) in astrocytes, both in vitro and in vivo. Transcriptomic and mechanistic investigations reveal that IPA suppressed NF-κB/MAPK signaling pathways by activating the aryl hydrocarbon receptor (AhR). In SCI mice, IPA treatment reduced glial scar formation, enhanced neuronal survival, and improved long-term motor function, as evidenced by increased BMS scores, inclined plane test performance, and gait coordination. MRI and histopathological analyses further confirmed reduced lesion volume and preserved tissue integrity. Our findings demonstrate that gut microbiota-derived IPA acts through the AhR/NF-κB/MAPK axis to mitigate secondary spinal cord injury by exerting anti-inflammatory and neuroprotective effects. This work not only provides novel pharmacological insights into a metabolite-based approach for SCI treatment but also establishes IPA as a promising endogenous metabolite therapy with high translational potential.