The Role Of Abnormal Vagus Nerve Function In The Pathogenesis Of Inflammatory Bowel Disease

?Background and Aims?Inflammatory bowel disease(IBD)is a chronic recurrent nonspecific intestinal inflammation that seriously impairs the health-related quality of life of patients.IBD patients are often accompanied by significant psychological disorders.The incidence of anxiety and depression in IBD patients is significantly higher than that in common population.Anxiety and depression can further reduce the health-related quality of life of patients.Other studies had shown that that IBD patients had abnormal vagal nerve function,and vagus nerve could inhibit inflammation by regulating the production of pro-inflammatory factor TNF-alpha.Stimulation of vagus nerve could alleviate intestinal inflammation in mice with depression.The aim of this study was to assess the quality of life and the probability of anxiety and depression of patients with IBD by questionnaire,to examine the vagus nerve function by heart rate variability analysis and blood acetylcholine,and to analyze the relationship between vagus nerve function and psychologic disorders of patients with IBD.?Methods?A total of 159 IBD patients including 124 CD patients and 35 UC patients were enrolled from May 2014 to June 2018 in the First Affiliated Hospital of Nanjing Medical University.The quality of life of IBD patients was assessed with the SF-36 and IBDQ.Anxiety and depression was assessed with GAD-7 and PHQ-9.The heart rate variability of IBD patients was detected,and HF/(HF+LF)was evaluated as the vagus function.The serum levels of pancreatic polypeptide,epinephrine and acetylcholine were examined by ELISA.?Results?1.Assessment of health life quality of IBD patients: The total score of SF-36 in IBD patients was 60.70±18.88,which was significantly lower than 76.65±15.26 in the control group,P<0.005.The total score of SF-36 in CD and UC patients was also lower than that in the control group,P<0.005.The IBDQ score of CD patients was 169.07±31.45,and 150.64±35.91 of UC patients.The total and each dimension scores of IBDQ of UC patients were significantly lower than those of CD patients.The scores of IBDQ in active patients were significantly lower than those in remission,P<0.05.2.Rate of anxiety and depression and their risk factors of IBD patients: The rate of anxiety was 57.8%(92/159)in IBD patients,54.8%(68/124)in CD patients,68.6%(24/35)in UC patients,and 34.6%(36/104)in the control group,P<0.05.The rate of depression was 59.1%(94/159)in IBD patients,56.5%(70/124)in CD patients,68.6%(24/35)in UC patients and 39.4%(41/104)in the control group,P<0.05.Univariate analysis showed that occupational stress,lesion location and history of perianal operation were the risk factors of anxiety in CD patients,and the duration,lesion location,perianal lesion and history of perianal operation were the risk factors of depression.Logistic regression analysis confirmed occupational stress was the risk factors of anxiety in CD patients.However,none risk factors was found of depression in CD patients.3.Assessment of vagus nerve function in IBD patients: The average value of HF/(HF+LF)of CD patients was 0.502±0.259,and 0.441±0.16 of UC patients,which was significantly lower than that of the control group(P<0.05).The average serum level of pancreatic polypeptide of CD patients was 162.1±42.7ng/L,which was significantly higer than 97.2±47.6ng/L in control.The average level of acetylcholine in CD patients were 497.7±172.8 nmol/ml which was significantly lower than 612.1±154.6nmol/ml in control.4.Correlation between vagus nerve function and anxiety and depression: HF /(HF + LF)was negatively correlated with anxiety and depression in CD patients(P< 0.05).?Conclusions?This study indicated that IBD patients showed vagus nerve dysfunction,lower quality of life and higher incidence of anxiety and depression.The function of vagus nerve was negatively correlated with anxiety and depression in CD patients.Regulating vagus nerve function of IBD patients may improve the psychological disorders and be a potent therapy for IBD.?Background and Aims?The autonomic nervous system(ANS)including the sympathetic and vagus nerve system is a key element in brain–gut interaction.Our previous study showed that HF /(HF + LF)and serum acetylcholine levels in patients with inflammatory bowel diseases(IBD)were significantly lower than those in normal controls,suggesting vagus nerve dysfunction in IBD patients.Vagal anti-inflammatory pathway plays a protective role in experimental colitis.Some studies suggested that transcutaneous electrical acupoint stimulation(TEAS)stimulating the vagus nerve can improve the sympatho-vagal balance in different clinical conditions.The aim of this study was to investigate the effects of acute and chronic TEAS on vagus nerve function and intestinal inflammation in patients with IBD.?Methods?Eighty IBD patients including 54 CD patients and 26 UC patients were recruited from May 2014 to June 2018 in the First Affiliated Hospital of Nanjing Medical University.Informed consent was signed by all patients.Zusanli point(ST36)was electroacupuncted,and the stimulation parameters were as follows: 10 seconds on,90 seconds off,pulse width 0.5 ms,frequency 5 Hz,current intensity 2.0 m A to 2.5 m A(or maximum endurable intensity)for 30 minutes,twice a day(2 hours after breakfast and supper).54 CD patients and 26 UC patients completed acute electrical acupoint stimulation for 3 consecutive days,and 9 CD patients completed chronic acupoint electrical stimulation for 30 consecutive days.HRV changes and serum levels of IL-1,IL-6,HMGB1,TNF-alpha,adrenaline and acetylcholine by enzyme-linked immunosorbent assay were measured before and after TEAS.CDAI scores of 9 CD patients completed chronic TEAS were assessed before and after TEAS.?Results?Fifty-four CD patients and 26 UC patients completed acute electrical acupoint stimulation for 3 consecutive days.HF/(HF+LF)was 0.508±0.171 before TEAS and 0.532±0.177 after TEAS in patients with CD(P=0.338),and HF/(HF+LF)was 0.442±0.146 before TEAS and 0.470±0.148 after TEAS in patients with UC(P=0.502).HF/(HF+LF)increased after acute TEAS both in CD and UC patients,but the difference was not statistically significant.The subgroup analysis according to different clinical features in acute TEAS of CD and UC patients showed that there were no significant differences of HF/(HF+LF)after 3 days of TEAS.The levels of IL-1,IL-6,HMGB1,TNF-?,Ach and epinephrine were not significantly changed after 3 days of acute TEAS in CD patients.The value of HMGB-1 after TEAS was 1.8±1.0ng/ml,which was higher than that before TEAS 1.1±0.6 ng/ml(P=0.087),but the difference was not statistically significant.9 CD patients completed 30 days of chronic TEAS.HF/(HF+LF)was 0.463 ±0.102 before TEAS and 0.478±0.103 after chronic TEAS,which was slightly higher than that before TEAS,but difference was not significant(P=0.785).The average CDAI score before TEAS was 175.9±38.9 and 150.0±58.8 after chronic TEAS,which was lower than that before TEAS,but there was no significant difference(P=0.127).During acute TEAS,2 patients(2.5%)manifested local skin hyperemia,which was improved by replacing Zusanli acupoint stimulation on the other side of the limb.No severe side effect occurred in patients.?Conclusions?After acute and chronic acupoint electrical stimulation,HF /(HF + LF)of IBD patients increased slightly,but the differences were not statistically significant.After treatment of chronic TEAS,the average CDAI score of CD patients decreased,but there was no statistical significance.Because of the limited cases in this study,it is need further studies whether percutaneous electrical stimulation at Zusanli can improve vagus nerve function and clinical manifestations in IBD patients.?Background and Aims? Previous studies showed that the proinflammatory factor TNF-? could be inhibited by the vagus nerve through ?7 nicotinic acetylcholine receptor(?7n ACh R)on immune cells.This anti-inflammatory effect by vagus nerve through ?7n ACh R is called cholinergic anti-inflammatory pathway.The aim of this study was to investigate the effects of GTS-21,a specific agonist of ?7n ACh R,on intestinal inflammation in DSS mice and its possible mechanism.?Methods?Male BALB/c mice(6-8 weeks old)were randomly divided into four groups,including the control group,DSS group,GTS-21(?7n ACh R agonist)group and ?BGT(?7n ACh R blocker)group.The DSS group,GTS-21 group and ?-BGT group were performed with 3.5% DSS free drink and the control group drunk water.The GTS-21 group were performed with GTS-21(10mg/kg/d,ip.)for 7 days.The ?-BGT group was pre-treated with ?-BGT(0.1mg/kg/d,ip.)30 min prior to GTS-21 injection,and the control group was given saline 10 ml ip.for 7 days.Body weight,blood stool and fecal traits were observed daily in each group,and DAI scores were evaluated.On the 8th day,the mice were sacrificed.The gross changes and wet weight of colon in each group were observed.The colon histological inflammation score(HI)was determined.The levels of cytokines were detected by ELISA.The expression of CXCL9 in mice colon tissue and IBD patients was detected by immunohistochemistry.The chemotactic ability of CXCL9 in peripheral blood of patients with IBD was investigated by lymphocyte chemotactic assay.?Results?Compared with DSS group,the general condition in GTS-21 group was significantly improved.Weight loss was slowed down,stool blood and diarrhea were improved,and DAI score was significantly decreased(P < 0.05).In GTS-21 group,the colonic shortening was ameliorated and the wet weight of colon increased(P<0.05).Histological inflammation score in GTS-21 group was significantly decreased than that in DSS group(P < 0.05),while the colon inflammation in ?BGT group was significantly more severe than that in GTS-21 group.The serum levels of CXCL9,IL-12,TNF-a,IL-1? and IFN-? in DSS group were significantly higher than those in the control group,and the level of leptin were significantly lower.Compared with DSS group,the levels of CXCL9,IL-12,TNF-? and IL-1? in GTS-21 group decreased,and level of CXCL9 decreased significantly.The expression of CXCL9 in colon tissue in DSS group was significantly higher than that in the control group.The expression of CXCL9 was significantly decreased after given GTS-21,but the elevated CXCL9 expression by GTS-21 could be inhibited by ?BGT.The expression of CXCL9 in colon tissue of patients with CD or UC was significantly higher than that in control(P < 0.05).CXCL9 with a concentration of 100ng/ml can chemotactic more peripheral mononuclears in IBD patients than control.?Conclusions?In conclusion,?7n ACh R agonist GTS-21 could attenuate the colonic inflammation in DSS mice.GTS-21 could also reduce the expression of CXCL9 in serum and colonic tissue.These results suggested that GTS-21 might reduce the production of CXCL9 by activating ?7n ACh R.CXCL9 is one of chemokines,When the production of CXCL9 was reduced in tissues,the recruitment of immune cells such as lymphocytes in colon tissues was reduced,thereby improving intestinal inflammation and exerting anti-inflammatory effects.