Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis

Abstract

The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1β, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues. The autonomic function was assessed by the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. It was found that ) the area under curve (AUC) of DAI was substantially decreased with VNS + EA and VNS, with VNS + EA being more effective than VNS ( < 0.001); ) the macroscopic score was 6.43 ± 0.61 in the sham ES group and reduced to 1.86 ± 0.26 with VNS ( < 0.001) and 1.29 ± 0.18 with VNS + EA ( < 0.001); ) the histological score was 4.05 ± 0.58 in the sham ES group and reduced to 1.93 ± 0.37 with VNS ( < 0.001) and 1.36 ± 0.20 with VNS + EA ( < 0.001); ) the plasma levels of TNFα, IL-1β, IL-6, and MPO were all significantly decreased with VNS and VNS + EA compared with the sham ES group; and) autonomically, both VNS + EA and VNS substantially increased vagal activity and decreased sympathetic activity compared with sham EA ( < 0.001, < 0.001, respectively). In conclusion, chronic VNS improves inflammation in TNBS-treated rats by inhibiting proinflammatory cytokines via the autonomic mechanism. Addition of noninvasive EA to VNS may enhance the anti-inflammatory effect of VNS. This is the first study to address and compare the effects of vagal nerve stimulation (VNS), electrical acupuncture (EA) and VNS + EA on TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis in rats. The proposed chronic VNS + EA, VNS, and EA were shown to decrease DAI and ameliorate macroscopic and microscopic damages in rats with TNBS-induced colitis via the autonomic pathway. The addition of EA to VNS provided a significant effect on the behavioral assessment of inflammation (DAI, CMDI, and histological score) but not on cytokines or mechanistic measurements, suggesting an overall systemic effect of EA.View this article's corresponding video summary at https://youtu.be/-rEz6HMkErM.

Sacral nerve stimulation improves colonic inflammation mediated by autonomic‐inflammatory cytokine mechanism in rats

“…The autonomic nervous system was reported to be altered both structurally and functionally in IBD and more than 35% of patients with UC showed impaired parasympathetic function and overexcited sympathetic activity . The autonomic imbalance was reported to contribute to the inflammatory drive in IBD: sympathectomy improved experimental colitis and VNS improved colitis in animal models of inflammation . In the present study, we found that vagal efferent activity was decreased by administration of TNBS and DSS and significantly increased by SNS and VNS.…”

“…Sixty‐four male SD rats were randomized into eight groups (8 rats in each): 7 treated with TNBS and one group with saline (Control group). The rats were deprived of food for at least 24 hours; then a 7.5‐cm long soft tube was inserted into the colon and 2, 4, 6‐Trinitrobenzenesulfonic acid (TNBS, Sigma‐Aldrich) was injected at a dose of 22.5 mg per rat in 40% ethanol (total volume, 0.75 mL) . To ensure the retention of TNBS within the colon, the rats were maintained in a slightly head‐down position for 10 minutes following the administration.…”

“…The experimental protocols are shown in Figure A (TNBS model) and Figure B (DSS model). The rats received electrical stimulation (ES) or Sham‐ES (stimulation at 0 mA) for 3 hours (9:00‐12:00) daily using the parameters optimized in our previous study: 5 Hz, 0.5 ms pulse width, 10 seconds on, 90 seconds off, and 2.0 mA …”

“…Vagal nerve stimulation (VNS) has recently been shown to be effective in inhibiting inflammatory responses, including attenuating the systemic inflammatory response to endotoxin 12 and functioning as a modulator of intestinal inflammation 13 through the α7 nicotinic ACh receptor (α7nAChR) expressed in macrophages by inhibiting releases of pro-inflammatory cytokines, a pathway similar to the cholinergic anti-inflammation pathway. 14,15 It is known that the overproduction of pro-inflammatory mediators such as cytokines and the sympathetic nervous system, and imbalance of micro flora play major roles in the pathogenesis of IBD. 16 These recent studies seem to suggest a therapeutic potential of VNS for inflammation, including IBD.…”

Is-there a place for vagus nerve stimulation in inflammatory bowel diseases?

“…They observed a significant improvement of colitis under VNS, a decrease of pro-inflammatory cytokines (TNFα and IL-6), and an improvement of HRV. More recently, Jin et al (Jin et al, 2016) showed that chronic VNS improves inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines via an autonomic mechanism; addition of noninvasive electro-acupuncture to VNS enhanced the anti-inflammatory effect of VNS.…”