PVN CRF/CRF-R1 signaling links stress to bowel dysfunction, anxiety-like behavior, and colonic barrier injury and is modulated by electroacupuncture in IBS-D-like mice

Abstract Background Diarrhea-predominant irritable bowel syndrome (IBS-D) is frequently accompanied by anxiety and intestinal barrier dysfunction, yet the central mechanisms linking stress-related neural signaling to peripheral colonic injury remain incompletely understood. Aims To investigate whether paraventricular hypothalamic nucleus (PVN) CRF/CRF-R1 signaling acts upstream of colonic barrier dysfunction and whether electroacupuncture (EA) alleviates IBS-D-like and anxiety-like phenotypes by modulating this pathway. Methods An IBS-D-like mouse model with anxiety-like behaviors was established by combining chronic restraint stress with intermittent chemical stimulation. Visceral sensitivity, bowel dysfunction, and anxiety-like behaviors were assessed. PVN CRF signaling was bidirectionally manipulated by stereotactic microinjection, and downstream changes in colonic CRF/CRF-R1 signaling, mast cell activation, inflammatory signaling, tight junction-related proteins, and permeability-associated markers were evaluated. Results Model mice exhibited visceral hypersensitivity, diarrhea-like symptoms, anxiety-like behaviors, and colonic barrier impairment. EA improved both gastrointestinal and affective abnormalities and reduced PVN CRF/CRF-R1 overactivation. Intra-PVN CRF administration reproduced key bowel and behavioral abnormalities in otherwise normal mice, whereas CRF-R1 blockade alleviated these changes in model mice. Central manipulation of PVN CRF signaling was accompanied by corresponding alterations in colonic CRF/CRF-R1 expression, mast cell degranulation, TNF-α/NF-κB/MLCK signaling, tight junction-related proteins, and permeability-associated changes. Conclusions These findings support a PVN-driven brain–gut–barrier mechanism in which CRF/CRF-R1 signaling contributes to bowel dysfunction, anxiety-like behavior, and colonic barrier injury in IBS-D-like mice. EA alleviated these abnormalities, at least in part, through modulation of this pathway.