The immunomodulatory effect of vagus nerve stimulation in humans: a systematic review and meta-analysis

The vagus nerve plays a central role in the immune system, and vagus nerve stimulation (VNS) shows promising approaches for reducing inflammation, indicating potential therapeutic applications. VNS has continuously evolved and has received FDA approval for the treatment of epilepsy and depression. Although research on VNS covers various clinical fields, including inflammatory diseases, its effectiveness in humans remains uncertain and requires further in-depth investigation. In this dissertation, I investigated the hypothesis that VNS reduces pro-inflammatory cytokines via the cholinergic anti-inflammatory pathway (CAP). Extensive database searches, including Cochrane, Web of Science, and PubMed, were conducted without filters or year restrictions. Bias was assessed using evaluation tools from the National Heart, Lung, and Blood Institute (NHLBI). A meta-analysis was performed for cytokines reported in at least five studies. Of the 1,076 identified studies, 36 were suitable for systematic review, and 27 were included in the meta-analysis on VNS and inflammation. The results showed no significant differences in pro-inflammatory cytokines, including TNF-α and IL-6 levels, between the VNS and control groups. However, subgroup analysis demonstrated that VNS significantly reduced CRP levels in acute inflammatory responses. The subgroup analyses showed no significant differences regarding stimulation technique (invasive vs. transcutaneous), stimulation duration, or study quality. The systematic review revealed that most studies examined very small sample sizes and exhibited substantial differences in study populations (various diseases and healthy subjects), VNS methods, and cytokines investigated. In summary, the review found no consistent evidence for the anti-inflammatory efficacy of VNS in humans. Further research with more targeted stimulation methods and controlled studies is needed to explore the potential of VNS for anti-inflammatory treatment.