Abstract
Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved.Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied.Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnfα and Cxcl1) in immature macrophages compared to sham stimulation.Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.
Highlights
More than 2 decades ago, the vagus nerve was proposed as an important regulator of the immune system
We observed that a single application of vagus nerve stimulation (VNS) 1 day prior to the induction of dextran sulfate sodium (DSS)-induced colitis caused a significant drop in the percentage of body weight in VNS-treated animals compared to the shamoperated animals, an effect most likely caused by a combination of surgical pain and a decreased appetite [29] following the VNS procedure
As the effect of VNS only lasts 48 h [30] and intestinal inflammation is triggered from day 3 following DSS exposure [19], we hypothesized that the beneficial effect of VNS was mediated by improved resistance of the epithelium toward the cytotoxic effect of DSS
Summary
More than 2 decades ago, the vagus nerve was proposed as an important regulator of the immune system. Electrical and pharmacological activation of the vagus nerve improved survival in a model of sepsis by reducing TNFα production of splenic macrophages (Mφ) [1]. Bonaz and colleagues demonstrated that 5 days of VNS successfully prevented body weight loss and improved colonic mucosal damage in a rat model of 2,4,6trinitrobenzenesulfonic acid (TNBS) colitis [14]. This effect was associated with a decrease in TNFα, IL-1β, and IL-6 levels through inhibition of the JAK2/STAT3 signaling pathway [2]. We evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved
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