Discussion On The Effect Mechanism Of Banxia Xiexin Decoction On Functional Dyspepsia Based On "Brain-gut Axis"

BackgroundFunctional dyspepsia(FD)is one of the common clinical functional gastrointestinal disorders(FGIDs),divided into two subtypes:postprandial discomfort syndrome and epigastric pain syndrome.There are many causes of this disease,the mechanism is complicated,western medicine lacks specific drugs,and the curative effect is not good.It leads to recurrent symptoms,prolonged and difficult to heal,and brings heavy psychological pressure and financial burden to patients.Therefore,relevant research is of great significance to improve the clinical efficacy of this disease.The concept of brain-gut axis has led to more and more studies discovering that mental and psychological factors are closely related to the onset of FD.The survey shows that the incidence of FD with bad mental state is as high as 42-61%.A large number of FD patients have depression,tension,anxiety,insomnia and other mood disorders.Bad mood is positively correlated with the severity of FD symptoms;depression and anxiety can lead to reduced vagus nerve activity,Delayed gastric emptying,high gastrointestinal sensitivity,causing indigestion and other symptoms to occur repeatedly;therefore,the patient is overly worried that the condition will continue to aggravate depression and anxiety.Rome Ⅳ defines FGIDs as brain-gut interaction(brain-gut axis)disorders,in which visceral hypersensitivity is one of the recognized pathogenesis of FD,stress is an important inducing factor for the onset of FD,and corticotropin-releasing factor corticotropin-releasing factor(CRF)signaling pathway is one of the main response points of the body’s stress,which can coordinate the body’s feedback to stress stimuli through its specific receptors CRF-R1 and CRF-R2.CRF-R1 has a high affinity with CRF,and it is able to pass the G-protein duodenal barrier function damage and is closely related to the abnormal content of tight junction protein(tight junction protein)in the mucosal epithelium;the duodenal intestinal mucosal barrier is connected with inflammation The key point of the interaction between the intestinal flora and the body is also one of the focus points in the current FD pathogenesis research.FD patients have impaired duodenal mucosal integrity,and the intestinal mucosal epithelial cells include tight junctions(such as occludin).,ZO-1),adhesion junctions(such as β-catenin,E-cadherin),desmosomes(such as DSG2)and other connexins are abnormally expressed,and the expression of intercellular connexins,increased mucosal permeability and low-grade inflammation The severity of the three is closely related,and the impaired duodenal and gastrointestinal feedback mechanism may cause abnormal gastric function by changing local signals or systemic immune activation.Brain-gut peptides are small molecular peptides distributed in the central nervous system,enteric nerves and gastrointestinal tract.They are the molecular basis between the central nervous system,enteric nervous system,neuroendocrine and immune systems,and have dual functions of neurotransmitters and hormones.The adjustment of the anatomical connection between the central nervous system and gastrointestinal motility is accomplished by a variety of brain-gut peptides such as motilin,gastrin and cholecystokinin.Therefore,in-depth study of the mechanism of brain-gut peptides in the neuro-endocrine-immune network will reveal the relevant regulatory sites of functional gastrointestinal diseases.At present,brain-gut peptides related to FD are mainly distributed in the hypothalamus and gastrointestinal tract.FD is the dominant disease in TCM treatment.TCM has the characteristics of syndrome differentiation,individualized treatment and multi-target intervention.Traditional Chinese medicine believes that spleen deficiency and qi stagnation,gastric failure and depression are the basic pathogenesis of FD,and the mixed cold and heat,the mixture of deficiency and excess,and emotional dissatisfaction are the key links that lead to the lingering course of the disease.Banxia Xiexin Decoction is a classic recipe that has been passed down for thousands of years and is still widely used.It has definite curative effects and good prospects in the treatment of FD,and many clinical and basic researches have been carried out.Previous studies have shown that Banxia Xiexin Decoction can improve symptoms such as indigestion,abdominal pain,bloating,anxiety,depression,and insomnia in FD patients,but its mechanism of action is still unclear.This study intends to focus on the "brain-gut axis" to systematically explore the effects of Banxia Xiexin Decoction on visceral hypersensitivity,mental state,duodenal mucosal barrier and local inflammation through CRF pathway and brain-gut peptide in FD model rats.This side’s multi-target intervention FD provides a biological mechanism.ObjectiveAround the "brain-gut axis",by observing the effects of Banxia Xiexin Decoction on the behavior,brain function connection,visceral sensitivity,gastrointestinal motility,duodenal mucosal permeability and other changes in functional dyspepsia model rats In order to explore the role of brain-gut axis related factors in the pathogenesis of FD and the mechanism of Banxia Xiexin Decoction through the brain-gut axis related pathways multi-target intervention in FD model rats.MethodsFD rat models were established by intragastric administration of iodoacetamide,which were divided into normal group,model group,Banxia Xiexin Decoction group,and mosapride group.The open field experiment and forced swimming experiment were used to observe the behavioral changes of rats,and the brain resting state BOLD method(Reho and ALFF)was used to dynamically detect and analyze the abnormal activity of neurons in the whole brain of the rat;electronic recorder and abdominal wall withdrawal were used Reflex method was used to detect gastric sensitivity in rats,gastric emptying and small intestine propulsion rate were used to detect gastrointestinal motility in rats;Western Blot method was used to detect the expression of CRF,CRF-R1 and CRF-R2 in the hypothalamus and stomach of each group of rats,Elisa method Detect the brain-gut peptide 5-HT,PYY,CCK,GLP-1,GHRL content in the serum of each group of rats;use FITC-Dextran method to detect duodenal mucosal permeability,qPCR method to detect duodenal tight junction protein ZO-1,Occludin,DSG2 mRNA expression,Elisa method to detect duodenal inflammatory factors IL-6,TNF-α,IL-1β content.Results1.Compared with the normal control group,the rats in the model group have the following changes:reduced exercise distance in the open field experiment(P<0.05),decreased number of standing uprights(P<0.01);prolonged immobility time in the water in the forced swimming experiment(P<0.01);Functional MRI Reho showed signal enhancement in the superior temporal gyrus,dentate gyrus,posterior cingulate gyrus,middle frontal gyrus,and temporal pole middle temporal gyrus in some brain areas(P<0.01),and ALFF showed the anterior cingulate gyrus,prefrontal lobe,and The signal of hypothalamus and anterior insula increased(P<0.01).Compared with the model group,the Banxia Xiexin Decoction group significantly increased the distance of exercise in the open field experiment(P<0.01),and decreased the number of uprights(P<0.05);the immobility time in the water in the forced swimming experiment was significantly reduced(P<0.05);brain function NMR Reho It showed that the signals of the middle frontal gyrus,the middle temporal gyrus,and the dentate gyrus were weakened in some brain areas(P<0.01).ALFF showed that the signals of the basolateral nucleus,the anterior cingulate gyrus,and the prefrontal lobe were weakened in some brain areas(P<0.01).Compared with the model group,the mosapride group had no significant changes in the distance of the open field test,the number of uprights,and the immobility time in the water in the forced swimming test(P>0.05).Compared with the mosapride group,the Banxia Xiexin Decoction group increased the distance of exercise in the open field experiment(P<0.01),and the number of uprights decreased(P<0.01);the immobility time in the water of the forced swimming experiment decreased significantly(P<0.01).2.Compared with the normal control group,the rats in the model group have the following changes:(1)Increased gastric sensitivity(EMG:P<0.01 when the intragastric balloon pressure is 40mmHg,60mmHg,and 80mmHg;AWR:the intragastric balloon pressure is 40mmHg,P<0.01 at 60mmHg,P<0.05 at 80mmHg),delayed gastric emptying(P<0.01),and reduced small intestine advancement rate(P<0.05).Compared with the model group,the stomach sensitivity of the Banxia Xiexin Decoction group was significantly lower(EMG:intragastric balloon pressure at 40mmHg,80mmHg,P<0.05,60mmHg,P<0.01;AWR:intragastric balloon pressure at 40mmHg,60mmHg,P<0.01,P<0.05 at 80mmHg),gastric emptying tends to be normal(P<0.05),and small bowel advancement rate is enhanced(P<0.05).Compared with the model group,the EMG and AWR of the mosapride group did not change significantly(P>0.05),the gastric emptying tended to be normal(P<0.01),and the small bowel advancement rate was enhanced(P<0.05).Compared with the mosapride group,the Banxia Xiexin Decoction group had significant differences in EMG and AWR(P<0.01),and there was no significant difference in the rate of gastric emptying and small intestine advancement(P>0.05).3.Compared with the normal control group,the rats in the model group had the following changes:the expression of CRF and CRF-R1 protein in the hypothalamus was up-regulated(P<0.01),and the expression of CRF-R2 protein was down-regulated(P<0.01);the expression of gastric CRF and CRF-R1 protein Up-regulation,CRF-R2 expression down-regulation(P<0.01);serum PYY and CCK levels increased(P<0.01),5-HT,GLP-1,and GHRL levels decreased(P<0.01).Banxia Xiexin Decoction group compared with model group:hypothalamic CRF,CRF-R1 protein expression was down-regulated(P<0.01),CRF-R2 protein expression was up-regulated(P<0.01);gastric CRF,CRF-R1 protein expression was down-regulated,CRF-R2 expression was up-regulated(P<0.01);the levels of PYY and CCK in serum decreased(P<0.01),and the levels of 5-HT,GLP-1,and GHRL increased(P<0.01).Compared with the model group,the mosapride group had no significant difference in CRF,CRF-R1,CRF-R2 protein expression in the hypothalamus(P>0.05),gastric CRF expression was up-regulated(P<0.05),and there was no significant difference in CRF-R1,CRF-R2(P>0.05),serum 5-HT,GLP-1,GHRL content increased(P<0.05),CCK content decreased(P<0.05),PYY had no significant difference(P>0.05).Compared with the mosapride group,the Banxia Xiexin Decoction group increased the expression of CRF and CRF-R1 protein in the hypothalamus(P<0.01),and down-regulated the expression of CRF-R2 protein(P<0.01);the expression of gastric CRF and CRF-R1 protein was up-regulated.The expression of CRF-R2 was down-regulated(P<0.01),PPY,GHRL,and GIL-1 were different(P<0.05),and 5-HT and CCK were not significantly different(P>0.05).4.Compared with the normal control group,the model group rats have the following changes:the permeability of the duodenal mucosa was significantly increased(P<0.01);the duodenal mucosa tight junctions occludin,ZO-1,and DSG2 mRNA content were significantly reduced(P<0.01)0.01);the levels of IL-6,TNF-α,and IL-1β in the duodenum increased(P<0.01).Compared with the model group,the Banxia Xiexin Decoction group:the duodenal permeability tends to be normal(P<0.01);the duodenal mucosa tight junctions occludin,ZO-1,DSG2 mRNA content increased(P<0.01);The levels of IL-6,TNF-α,and IL-1β in the duodenum decreased(P<0.01).Compared with the model group,the mosapride group had the same permeability of duodenal mucosa,the contents of occludin,ZO-1,DSG2,and the contents of IL-6,TNF-α and IL-1β in the duodenum.No significant change(P>0.05).Compared with the mosapride group,the Banxia Xiexin Decoction group has the permeability of the duodenal mucosa,the tight junctions of the duodenal mucosa,the contents of occludin,ZO-1,and DSG2,and the levels of IL-6,TNF-α,and IL in the duodenum.There were significant differences in-1β content(P<0.01).ConclusionsThe dysfunction of "brain-gut axis" is the main pathophysiological mechanism of FD.Among them,delayed gastric emptying,visceral hypersensitivity,bad mood tendency,duodenal mucosal barrier damage and microinflammation are its specific manifestations.Banxia Xiexin Decoction is safe and effective in improving physical symptoms,bad mood,and visceral sensitivity of FD,and can better control recurrence.This study shows that the FD rat model induced by iodoacetamide has increased visceral sensitivity,gastrointestinal motility disorder,increased duodenal mucosal permeability,and mucosal microinflammation compared with the normal control group.At the same time,the model also has depression-like properties.Behavioral changes,abnormal neuronal activity in brain areas related to mood,gastric motility and pain,CRF system imbalance,and changes in brain-gut peptides.After the intervention of Banxia Xiexin Decoction,visceral hypersensitivity,gastrointestinal motility disorder,behavioral abnormal changes,duodenal mucosal barrier damage and local inflammation were all alleviated.Its mechanism of action may be related to the regulation of CRF system and NF-κB pathway Related to inflammatory factors.