Inflammatory bowel disease (IBD) is increasingly recognized as a systemic disorder involving gut-brain axis dysfunction and neuropsychiatric comorbidities, yet safe and mechanistically defined neuromodulatory strategies remain limited. This study aimed to investigate whether non-invasive spleen-targeted ultrasound regulates gut-brain communication through peripheral neuroimmune signaling in colitis. Male C57BL/6J mice with dextran sulfate sodium (DSS)-induced acute colitis were treated with focused ultrasound stimulation of the spleen (sFUS) at intensities of 0.5 or 1.0 W/cm2. Subdiaphragmatic vagotomy (SDV) or sham surgery was performed before DSS induction and subsequent sFUS treatment to examine the involvement of vagal signaling. Therapeutic outcomes were evaluated using histological, molecular, microbiome, transcriptomic, and behavioral analyses. sFUS attenuated intestinal and neuroinflammation by reducing the mRNA levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, together with modulation of splenic cholinergic signaling and attenuation of systemic inflammatory responses. Furthermore, sFUS restored intestinal barrier integrity by increasing the expression of the tight junction proteins ZO-1 and Occludin, with significant restoration of ZO-1 only at 0.5 W/cm2, ameliorating histopathological damage and re-establishing gut microbiota homeostasis. These protective effects were associated with improvements in anxiety-like behavior and cognitive performance. Importantly, the therapeutic benefits of sFUS were abolished by SDV, demonstrating their dependence on intact vagal signaling, and were accompanied by activation of the nucleus tractus solitarius-locus coeruleus circuit and adrenergic-cAMP-MAPK-CREB/BDNF signaling in the prefrontal cortex. Our findings establish the spleen as an accessible peripheral neuroimmune hub and identify sFUS as a promising non-invasive strategy for IBD-associated dysfunction of the gut-brain axis.
Gut-Brain Axis