Vagus nerve stimulation limits colonic inflammation through distinct neuroimmune circuitry shaped by inflammatory history

Bidirectional communication between the nervous and immune systems has been demonstrated to limit or enhance immune cell function across organ systems and conditions. Although these neuroimmune circuits can become activated as an anti-inflammatory reflex, vagus nerve stimulation (VNS) reduces inflammation in models of endotoxemia, rheumatoid arthritis, and intestinal inflammation. In the spleen during endotoxemia, VNS activates a "cholinergic anti-inflammatory pathway" (CAIP), whereby choline acetyltransferase (ChAT)-expressing T cells release acetylcholine to reduce macrophage activation. VNS can also drive CAIP-independent pathways to reduce inflammation in the spleen and intestinal tract, although the circuitry modulating colonic inflammation remains underexplored. Here, we demonstrate that left cervical VNS reduces acute LPS-induced inflammation, evidenced by reduced Tnfa expression in colon and spleen and decreased circulating TNF. In the colon, these protective effects required efferent but not afferent VNS and were independent of ChAT+ T cells, IL10, {beta}-adrenergic signaling, and colonic sympathetic innervation. Critically, the ability of VNS to modulate colonic inflammation depended on prior tissue-specific inflammation. Mice recovering from DSS colitis, despite near-complete histological recovery, were refractory to the protective effects of VNS in the colon. This lack of efficacy in the colon was not reflected in measures of inflammation in the spleen or serum, highlighting the need for target-organ-specific monitoring. This loss of efficacy after colonic inflammation was transient, with restoration occurring upon complete recovery. These findings demonstrate that VNS efficacy in colonic inflammation depends on circuitry distinct from canonical systemic anti-inflammatory pathways, and that tissue responsiveness is shaped by anatomical site and inflammatory history. Key PointsO_LIElectrical stimulation of the left cervical vagus nerve reduces LPS-induced inflammation in the mouse colon. C_LIO_LIThis colonic anti-inflammatory effect requires vagal efferents but not afferent signaling. C_LIO_LIUnlike canonical splenic anti-inflammatory pathways, the colonic response does not require ChAT+ T cells, IL-10, {beta}-adrenergic signaling, or local sympathetic innervation. C_LIO_LIRecent DSS colitis abolishes colonic responsiveness to VNS despite preserved splenic and systemic anti-inflammatory effects. C_LIO_LIRecovery of VNS anti-inflammatory efficacy after colitis shows that neuroimmune responsiveness in the colon is dynamically shaped by inflammatory history. C_LI