The Role Of The Vagal Dysfunction In The Pathogenesis And Therapy Of Crohn’s Diseases

[Background]Inflammatory bowel disease(IBD)includes Crohn’s disease(CD)and ulcerative colitis(UC)and is characterized by repeated chronic inflammation of the digestive tract.There is increasing evidence that autonomic nervous system(ANS)dysfunction may play a role in the pathogenesis of CD,but the association between the degree of ANS dysfunction and disease severity is ambiguous.As an important component of ANS,vagus nerve has dual anti-inflammatory properties.It may be an effective and safe non-drug treatment for IBD,which is worth further exploration.[objective]To investigate the changes of autonomic nerve function in patients with CD,and to explore the relationship between vagal nerve dysfunction and inflammatory activity.To evaluate the therapeutic effect of transcutaneous auricular vagus nerve electrical stimulation(ta-VNS)on experimental enteritis induced by TNBS,and to explore its mechanism.[methods]Autonomic nervous function of CD was evaluated by heart rate variability(HRV),and the association and strength between HRV parameters and CD inflammatory activity index(CDAI)were analyzed by generalized linear model and generalized additive model(GAM).ta-VNS stimulated TNBS-induced experimental enteritis model in rats,and selective α 7nAChR agonist GTS-21 interfered with Lipopolysaccharide(LPS)-induced RAW264.7 cells model to investigate the anti-inflammatory effect and molecular mechanism of ta-VNS.[Results]Compared with the control group,ANS activity decreased in CD patients(P<0.001),decreased balance(P=0.005),increased psychological stress(P=0.005).The total HRV parameter power(TP),high frequency power(HF),low frequency power(LF)and standard deviation of cardiac interval(SDNN)in CD group were significantly lower than those in control group(P=0.001,P=0.001,P<0.001,P=0.002).Subgroup analysis showed that TP,HF,LF and SDNN in CD activity group were significantly lower than those in remission group(P=0.002,P=0.007,P=0.008,P=0.005),ANS activity was significantly lower than those in remission group(P=0.004).Correlation analysis showed that TP,HF,LF and SDNN was negatively correlated with inflammatory activity(r=-0.520,r=-0.489,r=-0.459,r=-0.484;P<0.001).After adjusting for potential confounding factors,The relationship between high frequency power HF of vagus nerve mediated HRV parameters and CD inflammatory activity index CDAI was always stable linear negative(β=-0.01).Other HRV parameters,TP,LF and SDNN,showed a curve relationship with CDAI,and there was a clear inflection point.There was a negative relationship on the left side of the inflection point,but no significant effect on the right side of the inflection point(P>0.05).In vivo,ta-VNS significantly reduced DAI,CMDI scores and histological scores in TNBS-induced rats(P<0.05);TNBS increased the expression of tissue inflammatory cytokines IL-1β,IL-6 and TNFa,while ta-VNS decreased the expression of tissue inflammatory cytokines(P<0.05),up-regulated α7nAChR expression in tissues(P<0.05).In addition,TNBS increased JAK2 and STAT3 phosphorylation and ta-VNS inhibited JAK2 and STAT3 phosphorylation(P<0.05).Methylcholine(MLA),a α7nAChR antagonist,can reverse the anti-inflammatory effect of ta-VNS in vivo(P<0.05).In vitro,the expression of inflammatory cytokines IL-lβ,IL-6 and TNFa decreased after GTS-21 treated LPS-stimulated RAW264.7 cells(P<0.05).GTS-21 inhibits LPS-induced phosphorylation of JAK2 and STAT3(P<0.05).MLA could reverse the effect of GTS-21(P<0.05).In addition,α7 nAChR was widely expressed on RAW264.7 cells surface.[Conclusion]Patients with CD have autonomic nerve dysfunction,mainly the decline of vagus nerve function,which is negatively correlated with the degree of inflammatory activity.ta-VNS plays an anti-inflammatory role by inhibiting the expression of pro-inflammatory cytokines through α 7nAChR mediated JAK2/STAT3 signaling pathway.