| Symptoms of functional dyspepsia(FD)include bothersome postprandial fullness,bothersome early satiety,bothersome epigastric pain and bothersome epigastric burning.Functional dyspepsia is diagnosed if a patient reports having≥1 of these symptoms,there is no evidence of structural disease that can account for the symptoms.Based on the specific anatomical part of the auricular region,our group has been conducting research on transcutaneous auricular vagus nerve stimulation(taVNS)for many years.The research is conducted to illustrate the effect of FD treatment by taVNS in the clinical observation and animal experiments so as to further interpret its treatment mechanism.MethodResearch 1:Observation on the efficacy of taVNS for functional dyspepsia90 cases with symptoms of functional dyspepsia(FD)were selected during the period from June 2018 to May 2019 in Beijing Tongren Hospital,Capital Medical University Those cases divided into two groups with 45 each:taVNS and sham-taVNS.The stimulation area in the former is inside of Cavity of concha,while the latter is middle of Scapha,with HuaTuo electroacupuncture stimulation,type SDZ-IIB,with dilatational wave.And the dense wave 20 Hz,the sparse wave 4 Hz.The current intensity was 8-20 mA,30 minutes/time,5 times/week,for 4 weeks.All patients were evaluated for symptoms using the Major Symptoms Scale,Functional Dyspepsia Quality of Life Scale(FDDQL),Hamilton Anxiety Scale(HAMA),Hamilton Depression Scale(HAMD),and Self-Depression Rating Scale(SDS)before and after treatment.The severity of the disease,and the efficacy evaluation method developed by referring to the consensus opinion of functional dyspepsia in the diagnosis and treatment of traditional Chinese medicine(2017)and the consensus opinion of the diagnosis and treatment of functional dyspepsia in integrated traditional Chinese and western medicine(2017),a comparative analysis of the taVNS and sham-taVNS Group treatment of functional dyspepsia.Statistical analysis is obtained with application of Software SPSS 24.0.P<0.05 was considered statistically significant.Research 2:Effect of taVNS on behavior and morphological changes for functional dyspepsia model rats31 adult SPF Sprague-Dawley(SD)rats,were randomly divided into control group,model group,taVNS group,and sham-taVNS group.In this study,method of the Tail-Clamp stimulation are applied in the model group,taVNS group and sham-taVNS group,to produce the FD modelAfter the model,the rats in control group and model group are allowed to get food and water discretionally without any control;while rats in taVNS and sham-taVNS are applied with HuaTuo electroacupuncture stimulation,type SDZ-ⅡB,with dilatational wave.And the dense wave 20 Hz,the sparse wave 4 Hz.The current intensity was 4 mA,30 minutes treatment daily and 14 days treatment consecutivelyComparison score of the four groups is concluded after the model production and after the intervention with regard of scored for general condition,weight and food intake for 3 hours,as well as horizontal movement and vertical movement in the open-field,forced swimming immobility time and also with the evaluation of digest systems of these FD rats and their psychological conditionsAfter the intervention,the FD rats were fasting but not water deprivation for 24 hours,and taken the stomach and duodenum.The morphological changes of stomach and duodenum were observed by HE staining.Research 3:Effect of taVNS on serology changes for functional dyspepsia model ratsThe serums of acetylcholine(ACh),interleukin-2(IL-2),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),serotonin(5-HT)and vasoactive intestinal peptide(VIP)of all the four groups of functional dyspepsia model rats are analyzed with Enzyme Linked Immunosorbent Assay(Elisa)to evaluate the impact on level of inflammatory factors and Brain-Gut peptide in the functional dyspepsia model rats.Research 4:Effect of taVNS on p38 MAPK/NF-κB signal pathway for functional dyspepsia model ratsp38 MAPK、IκB-α、p65 NF-κB of stomach and duodenum expression are checked with Western Blot to seek out impact on p38 MAPK/NF-κB,communication channel of functional dyspepsia model rats and Mechanism of taVNS treatment on themResultResearch 1:Observation on the efficacy of taVNS for functional dyspepsiaBaseline taVNS group had no statistically significant difference in gender,age,education,and course of disease compared with the control stimulation group(P>0.05).After intervention,the taVNS group had statistically significant differences in the Main Symptoms Score Table,FDDQL,HAMA,HAMD,SDS,and TCM Symptom Scores(P<0.05).Efficiency rate is 91.11%in taVNS,68.89%higher than that of sham-taVNS with error rate of P<0.05 statistically,among which 4 patients are recovered,29 with evident effect,8 effective cases,totaling 91.11%.While in sham-taVNS clinical recovery is zero,2 evident effect,29 effective cases with totality of 68.89%Research 2:Effect of taVNS on behavior and morphological changes for functional dyspepsia model ratsAfter modeling,the rats developed the symptoms of shaggy hair withered and yellowish,loose stool,less food and water intake,reduction of motion and agility,behavior of huddling together or in the corners of the cage,depression and discomposure and vulnerable to be frightened.Compared with the control group,the general condition scores of the model group rats was significantly reduced(P<0.05);compared with the model group,the general condition scores of taVNS group and the sham-taVNS group were increased(P<0.05);The general condition score of the taVNS group was higher than that of sham-taVNS group(P<0.05)Compared with the control group,the weight of the rats in the model group was significantly reduced(P<0.05);compared with the model group,the weight of the rats in the taVNS group and the sham-taVNS group were increased(P<0.05);Weight of the taVNS group was higher than the sham-taVNS group(P<0.05).Compared with the control group,the food intake for 3 hours of the rats in the model group was significantly reduced(P<0.05);compared with the model group,the food intake for 3 hours of the rats in the taVNS group and the sham-taVNS group were increased(P<0.05);Food intake for 3 hours of the taVNS group was higher than the sham-taVNS group(P<0.05).Compared with the control group,the horizontal movement in the open-field of the rats in the model group was significantly reduced(P<0.05);compared with the model group,the horizontal movement of the rats in the taVNS group and the sham-taVNS group were increased(P<0.05);The horizontal movement of the taVNS group was higher than the sham-taVNS group(P<0.05).Compared with the control group,the vertical movement in the open-field of the rats in the model group was significantly reduced(P<0.05);compared with the model group,the vertical movement of the rats in the taVNS group and the sham-taVNS group were increased(P<0.05);The vertical movement of the taVNS group was higher than the sham-taVNS group(P<0.05).Compared with the control group,the forced swimming immobility timein the model group was significantly increased(P<0.05);compared with the model group,the forced swimming immobility timein the taVNS group and the control stimulation group were decreased(P<0.05);Forced swimming immobility time in taVNS group was lower than that in control stimulation group(P<0.05).Shown in HE-stained gastric pathological sections,the model group had obvious micro-damage and shedding of the epithelial cells of the gastric mucosa,disordered arrangement,obvious glandular edema,irregular arrangement,and infiltration ofinflammatory cells;taVNS group:gastric epithelial cells were not see obvious damage,glandular structure is intact,neatly arranged,inflammatory cell infiltration is significantly reduced.Shown in HE-stained duodenal pathological sections,model group,the structure of the duodenal mucosa was relatively complete,the arrangement of intestinal villi was disordered,the height was uneven,part of the lodging,fusion,and the mucosal layer was infiltrated by inflammatory cells;compared with the structure of taVNS,the duodenal mucosa was more complete,and the intestinal villi are arranged neatly,the tip of some villi is broken,and the infiltration of inflammatory cells in the mucosa is reduced.Research 3:Effect of taVNS on serology changes for functional dyspepsia model ratsCompared with the contorl group,the serum ACh content in the model group was significantly increased(P<0.05);compared with the model group,the serum ACh content in the taVNS group was decreased(P<0.05);The serum ACh content was lower than that in the control stimulation group(P<0.05).Compared with the control group,the serum IL-2 content in the model group increased significantly(P<0.05);compared with the model group,the serum IL-2 content in the taVNS group and the control stimulation group decreased(P<0.05);Serum IL-2 content in taVNS group was lower than that in control stimulation group(P<0.05).Compared with the control group,the serum IL-6 content in the model group was significantly increased(P<0.05);compared with the model group,the serum IL-6 content in the taVNS group and the control stimulation group was decreased(P<0.05);IL-6 content in taVNS group was lower than that in control stimulation group(P<0.05).Compared with the control group,the serum TNF-α content in the model group increased significantly(P<0.05);compared with the model group,the serum TNF-a content in the taVNS group and the control stimulation group decreased(P<0.05);Serum TNF-α content in taVNS group was lower than that in control stimulation group(P<0.05).Compared with the control group,the serum 5-HT content in the model group was significantly reduced(P<0.05).Compared with the model group,the serum 5-HT content in the taVNS group and the control stimulation group were increased(P<0.05);the content of 5-HT in serum of taVNS group was higher than that of control stimulation group(P<0.05).Compared with the control group,the serum VIP content of the model group significantly increased(P<0.05);compared with the model group,the serum VIP content of the taVNS group and the control stimulation group decreased(P<0.05);The VIP content of serum in the taVNS group was lower than that in the control stimulation group(P<0.05).Research 4:Effect of taVNS on p38 MAPK/NF-κB signal pathway for functional dyspepsia model ratsCompared with the control group,the gastric p38 MAPK protein level of the model group was up-regulated(P<0.05);compared with the model group,the gastric p38 MAPK protein level of the taVNS group was down-regulated(P<0.05);compared with the taVNS group,the control The gastric p38 MAPK protein level was up-regulated in the stimulation group(P<0.05).Compared with the control group,the gastric IκB-α protein level was increased in the model group(P<0.05);compared with the model group,the gastric IκB-α protein level was decreased in the taVNS group(P<0.05);compared with the taVNS group,IκB-α protein levels were up-regulated in the control stimulation group(P<0.05).Compared with the control group,the gastric p65 NF-κB protein level was increased in the model group(P<0.05);compared with the model group,the gastric p65 NF-κB protein level was decreased in the taVNS group(P<0.05);Compared with the control group,the p65 NF-κB protein level was up-regulated in the control stimulation group(P<0.05).Compared with the control group,the duodenal p38 MAPK protein levels were up-regulated in the model group(P<0.05);compared with the model group,p3 8 MAPK protein levels in the stomach were down-regulated(P<0.05);compared with the taVNS group In comparison,the p38 MAPK protein level in the stomach of the control stimulation group was up-regulated(P<0.05).Compared with the control group,the duodenal IκB-α protein levels were up-regulated in the model group(P<0.05);compared with the model group,duodenal IκB-α protein levels were down-regulated in the taVNS group(P<0.05);and Comparing the taVNS group,the duodenal IκB-α protein level in the control stimulation group was up-regulated(P<0.05).Compared with the control group,the duodenal p65 NF-κB protein level was increased in the model group(P<0.05);compared with the model group,duodenal p65 NF-κB protein level was decreased in the taVNS group(P<0.05);Compared with the taVNS group,the duodenal p65 NF-κB rotein level in the control stimulation group was up-regulated(P<0.05).Conclusion1.taVNS has effect on gastrointestinal and psycho-psychological symptoms of patients with functional dyspepsia.2.taVNS has effect on gastrointestinal and psycho-psychological behavior of FD model rats with functional dyspepsia and its tissue morphology.3.taVNS has the effect of inhibiting inflammation and controlling Brain-Gut peptide 4.taVNS can down-regulate p65 NF-κB、IκB-α、p38 MAPK expression in functional dyspepsia model rats,that is,the mechanism of taVNS treatment of functional dyspepsia may be through regulation of p38 MAPK/NF-κB signaling pathway suppresses the inflammatory response,improving the symptoms of functional dyspepsia. |
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