Focused Ultrasound Stimulation on the Spleen Ameliorates DSS-Induced Neuroinflammation Through the Notch Signaling Pathway.

Abstract

OBJECTIVE: Inflammatory bowel disease (IBD) is frequently accompanied by neuropsychiatric symptoms linked to intestinal inflammation and neuroimmune activation. While pharmacological approaches provide limited remission, non-invasive alternatives such as low-intensity pulsed ultrasound (LIPUS) have emerged as promising strategies. METHODS: This study investigated whether splenic LIPUS stimulation attenuates dextran sulfate sodium (DSS)-induced colitis and associated neuroinflammation, focusing on the Notch signaling pathway. Male C57BL/6J mice were administered 3% DSS for 7 d to induce colitis and treated with splenic LIPUS from day 4 to 7. Disease activity was assessed by body weight, colon length, spleen weight and histological analysis. Transcriptomic profiling and qPCR were performed on prefrontal cortex (PFC) tissue. RESULTS: LIPUS modestly improved histological architecture in the colon, with partial preservation of epithelial integrity, although systemic indices such as body weight and disease activity index were not significantly altered. Transcriptomic analysis identified 1053 differentially expressed genes in the PFC, with significant downregulation of the Notch signaling pathway, including Notch1, Jag2, Maml1 and Dtx4, which was validated by qPCR. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed suppression of pathways linked to neuron projection development, gliogenesis and apoptosis, alongside enhancement of oxidative phosphorylation and mitochondrial respiratory activity. CONCLUSION: This study demonstrates that splenic LIPUS induces molecular alterations in neuroimmune-related pathways in the PFC, notably involving canonical Notch signaling and mitochondrial-associated processes. These results establish a mechanistic foundation for future investigations into the functional consequences of spleen-brain axis modulation and the potential application of LIPUS as a non-invasive strategy in IBD.