No consistent evidence for the anti-inflammatory effect of vagus nerve stimulation in humans: A systematic review and meta-analysis

Vagus nerve stimulation (VNS) has been identified as an innovative immunosuppressive treatment strategy in rodent studies. However, its' clinical potential is still unclear. Therefore, we aimed to assess whether VNS can reduce inflammatory proteins and/or immune cells in humans, through a pre-registered systematic review and meta-analysis according to PRISMA guidelines. The databases Cochrane, Pubmed and World of Knowledge were searched in duplicate up to the 3rd of March 2022 and publications from identified clinical trial registrations were identified until 20th of August 2023. Studies were included if they provided peer-reviewed data for humans who received VNS as short-term (<=1 day) or long-term (>=2 days-365 days) stimulation and reported at least one cytokine or immune cell after treatment. Screening of title, abstract, full text, and data extraction was performed in duplicate by two independent reviewers. Data were pooled using a random-effects model and metaregression was performed for moderating factors. Reporting bias was assessed. The standardized mean difference (Hedge's g) was used to indicate overall differences of cytokine data (mean and standard deviation or median and interquartile range at the study level) to test our a-priori hypothesis. The systematic review of 36 studies with 1135 participants (355 receiving a control/sham condition and 780 receiving VNS) revealed antiinflammatory effects of VNS for cytokines in several reports, albeit often in subgroup analyses, but our metaanalyses of 26 studies did not confirm these findings. Although most cytokines were numerically reduced, the reduction did not reach statistical significance after VNS: not in the between-group comparisons (short-term: TNF-alpha: g = -0.21, p = 0.359; IL-6: g = -0.94, p = 0.112; long-term: TNF-alpha: g = -0.13, p = 0.196; IL-6: g = -0.67, p = 0.306); nor in the within-study designs (short-term: TNF-alpha: g = -0.45, p = 0.630; IL-6: g = 0.28, p = 0.840; TNF-alpha: g = -0.53, p = 0.297; IL-6:g = -0.02, p = 0.954). Only the subgroup analysis of 4 long-term studies with acute inflammation was significant: VNS decreased CRP significantly more than sham stimulation. Additional subgroup analyses including stimulation duration, stimulation method (invasive/non-invasive), immune stimulation, and study quality did not alter results. However, heterogeneity was high, and most studies had poor to fair quality. Given the low number of studies for each disease, a disease-specific analysis was not possible. In conclusion, while numeric effects were reported in individual studies, the current evidence does not substantiate the claim that VNS impacts inflammatory cytokines in humans. However, it may be beneficial during acute inflammatory events. To assess its full potential, high-quality studies and technological advances are required.