Circulatory context determines the anti-inflammatory efficacy of post-sepsis vagus nerve stimulation

Activation of the cholinergic anti-inflammatory pathway (CAP), including vagus nerve stimulation (VNS), suppresses inflammatory cytokine production and has shown efficacy in experimental sepsis when applied prior to sepsis induction. However, VNS before sepsis onset is rarely feasible in clinical practice, and whether VNS remains effective after sepsis onset is unclear. Using a lipopolysaccharide-induced mouse sepsis model, we evaluated VNS applied before and after sepsis onset. VNS applied before sepsis onset significantly reduced plasma TNF-α levels, whereas VNS applied after sepsis onset failed to suppress inflammation. Although post-sepsis VNS did not worsen hypotension or organ dysfunction, it was associated with increased lactate accumulation. Notably, fluid resuscitation restored the anti-inflammatory effect of VNS and reduced lactate levels. These findings suggest that CAP responsiveness depends on the host's physiological state. Impaired circulation and metabolic stress may limit CAP activation during sepsis, while circulatory stabilization appears necessary for effective inflammatory control.