Abstract
BackgroundAutonomic nervous system dysfunction is implicated in the etiopathogenesis of inflammatory bowel diseases (IBD). Therapies that increase cardiovagal activity, such as Mind-Body interventions, are currently confirmed to be effective in clinical trials in IBD. However, a poor understanding of pathophysiological mechanisms limits the popularization of therapies in clinical practice. The aim of the present study was to explore the mechanisms of these therapies against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats using a chronic vagus nerve stimulation model in vivo, as well as the lipopolysaccharide (LPS)-induced inflammatory response in human epithelial colorectal adenocarcinoma cells (Caco-2) by acetylcholine in vitro.Methods and ResultsColitis was induced in rats with rectal instillation of TNBS, and the effect of chronic VNS (0.25 mA, 20 Hz, 500 ms) on colonic inflammation was evaluated. Inflammatory responses were assessed by disease activity index (DAI), histological scores, myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS), TNF-α and IL-6 production. The expression of Mitogen-activated protein kinases (MAPK) family members, IκB-α, and nuclear NF-κB p65 were studied by immunoblotting. Heart rate variability (HRV) analysis was also applied to assess the sympathetic-vagal balance. DAI, histological scores, MPO activity, iNOS, TNF-α and IL-6 levels were significantly decreased by chronic VNS. Moreover, both VNS and acetylcholine reduced the phosphorylation of MAPKs and prevented the nuclear translocation of NF-κB p65. Methyllycaconitine (MLA) only reversed the inhibitory effect on p-ERK and intranuclear NF-κB p65 expression by ACh in vitro, no significant change was observed in the expression of p-p38 MAPK or p-JNK by MLA.ConclusionVagal activity modification contributes to the beneficial effects of the cholinergic anti-inflammatory pathway in IBD-related inflamed colonic mucosa based on the activation of MAPKs and nuclear translocation of NF-κB. Our work may provide key pathophysiological mechanistic evidence for novel therapeutic strategies that increase the cardiovagal activity in IBD patients.
Highlights
Inflammatory Bowel Diseases (IBD) are a group of chronic inflammatory disorders of the gastrointestinal (GI) tract that are subdivided into ulcerative colitis (UC) and Crohn’s disease (CD)
We established a chronic VNS model to demonstrate the possible anti-inflammatory molecular mechanisms of these interventions in relation to modified sympathetic-vagal balance on experimental colitis induced by trinitrobenzenesulfonic acid (TNBS)
The potential mechanism of Complementary and alternative medicine (CAM) therapies such as biofeedback and relaxation training is thought to be central nervous system (CNS)-based, so a higher stimulus frequency(20Hz) used in the present study which involved the activation of both vagal afferents and efferents may preferably imitate CAM therapeutic effect on experimental colitis, and the significant amelioration of TNBS-induced colitis may be reflected by a combined activation of CNS(i.e. nucleus tractus solitarius (NTS)-PVN-HPA axis) and cholinergic anti-inflammatory pathway (CAP)
Summary
Inflammatory Bowel Diseases (IBD) are a group of chronic inflammatory disorders of the gastrointestinal (GI) tract that are subdivided into ulcerative colitis (UC) and Crohn’s disease (CD). Tracey and colleagues reported the antiinflammatory effect of vagus nerve stimulation on the systemic inflammatory response to endotoxin They identified the neural mechanisms of the cholinergic anti-inflammatory pathway (CAP): vagal efferents innervate many of the organs associated with the immune system, including the heart, liver, and gastrointestinal system. Α7nAchRs are thought to play an important role in gastrointestinal inflammation through an IκBα-dependent inhibition of NF-κB Given this evidence, we suspected that MAPK/NF-κB signaling was involved in activation of the cholinergic anti-inflammatory pathway in IBD. We studied the involvement of MAPKs and nuclear translocation of NF-κB signaling pathways in mounting the protective effect of chronic VNS or acetylcholine in vivo and in vitro, with the aim of providing pathophysiological mechanistic evidence for the therapeutic effectiveness of Mind-Body interventions
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