Sympathetic Overactivation Drives Colonic Eosinophil Infiltration Linked to Visceral Hypersensitivity in Irritable Bowel Syndrome

BACKGROUND & AIMS: Mucosal immune alteration is a characteristic clinical manifestation of irritable bowel syndrome (IBS), and its symptoms are often triggered by psychological stress. The present study aimed to investigate the impact of early life stress-associated dysfunction of the sympathetic nervous system (SNS) on mucosal immune changes in the gastrointestinal tract (GI) and its contribution to visceral hypersensitivity of IBS. METHODS: We utilized a traditional animal model of IBS with maternal separation (MS) and evaluated colorectal hypersensitivity, immune alteration, and SNS activity in adult rats with MS. We conducted a series of experiments to manipulate peripheral SNS activity pharmacologically and chemogenetically to explore the interaction between SNS activity and GI events. RESULTS: The MS-induced IBS model exhibited visceral hypersensitivity and eosinophilic infiltration in the colonic mucosa, along with SNS overactivation. Degeneration of the SNS using 6-OHDA neurotoxin decreased eosinophil infiltration and visceral hypersensitivity in the MS model. Notably, specific chemogenetic activation of the peripheral SNS induced eosinophil infiltration in the intestinal mucosa through the noradrenergic signaling-mediated release of eotaxin-1 from mesenchymal cells. CONCLUSIONS: This study highlights the critical role of SNS overactivation in eotaxin-1-driven eosinophil infiltration in the colon, leading to the development of visceral hypersensitivity in IBS. The results provide important insights into the mechanistic links among increased sympathetic activity, mucosal immune alteration, and visceral hypersensitivity in individuals with IBS, suggesting potential therapeutic approaches.