Abstract

The gut-brain axis links gut inflammation to psychiatric symptoms in inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. We demonstrate that neuropeptide substance P (SP) alleviated intestinal injury and behavioral disorders induced by dextran sodium sulfate in mice. SP mitigated hippocampal neuroinflammation and inhibited microglial activation and astrocyte loss. Furthermore, SP improved gut microbiome dysregulation, and its protective effects depended on the putative roles of microbiota. Notably, through modulating microbiota, SP dampened the NF-κB pathway in microglia, and increased GABAergic/Ca 2+ signaling within astrocytes. SP elevated the microbiota-derived metabolite inositol. Supplementing inositol mimicked SP’s benefits and activated GABAergic signaling, while the inositol inhibitor reversed SP’s neuroprotective impacts, highlighting inositol’s indispensable role. Collectively, SP exerts beneficial effects via microbiota’s putative roles and inositol, involving the suppression of microglial NF-κB pathway while enhancing astrocytic GABAergic/Ca²⁺ signaling. Our findings underscore SP’s potential as a therapeutic intervention for these disorders in IBD.