| BackgroundIrritable bowel syndrome(IBS),the most common functional gastrointestinal disorder across the world,is characterized by recurrent abdominal pain associated with disturbances in defecation and could not be explained by any structural or anatomical abnormality.According to the different bowel behaviors,IBS could be divided into four subtypes,in which IBS with predominant diarrhea(IBS-D)is the major subtype.With the high prevalence,it has serious influences on the quality of life of patients.However,the underlying pathogenesis has not been fully elucidated.The change of visceral sensitivity is one of the recognized mechanisms of IBS.Most IBS patients show different degrees of visceral hypersensitivity,and are closely related to stress.Corticotropin-releasing factor(CRF)signaling pathway plays an important role in it.Based on the concept of holism,Traditional Chinese medicine(TCM)has a systematic and unique view of the etiology,pathogenesis and diagnosis and treatment of the disease.Through the syndrome differentiation and treatment,TCM can alleviate and eliminate the clinical symptoms of the patients,significantly improve the quality of life,reduce the recurrence,showing a good prospect.Both clinical researches and systematic reviews show that TCM is an effective method to treat IBS-D.Our previous researches showed that Wenshen Jianpi formula,which is derived from Sishen Pill,has a significant clinical efficacy.The total effective rate was 92.24%,the effective rate of TCM syndrome was 90.52%,the recurrence rate was 15.79%,which was obviously superior than that of placebo.However,it is still unknown whether the CRF signaling pathway is involved in the mechanisms of the action of the Wenshen Jianpi formula.In addition,for animal models,more and more scholars believe that the animal model of combination of disease and syndrome is more consistent with the characteristics of TCM.It is helpful to the studies of the mechanisms of the action of Chinese medicine and prescription,and it is of great significance to the deeper study of the internal relations between Chinese and Western medicine theories.Although many scholars have carried out a large number of correlational studies in recent years,there is no report on the study of the IBS-D model with spleen-kidney yang deficiency syndrome.Therefore,it is urgent to establish an IBS-D model with spleen-kidney yang deficiency syndrome.ObjectiveThe aim of this study was to examine a new method,which combined with chronic stress and senna leaf gavage,to create a rat model of IBS-D with spleen-kidney yang deficiency syndrome.On this basis,Wenshen Jianpi formula was used as an intervention,and the observation of its regulatory effects on CRF signaling pathway was carried out.Methods1.Literature review and systematic assessmentThrough literature analysis,the latest advances in understanding and treatment of this disease were summarized.Then,a meta-analysis was performed to evaluate the clinical efficacy and safety of TCM in treating IBS-D.Eight databases,including PubMed,Web of Science,Cochrane Library,Embase,Chinese Biomedicine(CBM),China National Knowledge Infrastructure(CNKI),Chinese Scientific Journals Database(VIP),and WanFang Database,were searched to included randomized,double-blind,placebo-controlled clinical studies.Review Manager 5.3 was the utilized software for meta-analyze.2.Experimental studiesA senna leaf(Folium sennae)decoction was made in 3 concentrations of 1.0,0.5,and 0.25 g/mL.Rats were randomly divided into 4 groups:the control(C)-,high(H)-,middle(M)-,and low(L)-dose groups.The groups received saline or 1.0,0.5,or 0.25 g/mL senna leaf decoction,respectively,for 4 weeks.Body weight monitoring,food consumption,water intake,defecation frequency,stool Bristol score,weight-loaded forced swimming test,forelimb grip strength test,D-xylose absorption test,serum cortisone,adrenocorticotropic hormone(ACTH),24 h urine 17-hydroxycorticosteroid(17-OHCS),and histopathological detection were conducted to assess the success of the senna leaf decoction-induced model.Maternal separation(MS),water avoidance stress(WAS),colorectal distension(CRD)were combined with senna leaf gavage respectively to explore the method of building the IBS-D model with spleen-kidney yang deficiency syndrome.A four-dimensional assessment system,including behavioral Observation,biomarkers,modeling factors reverse and drug counterevidence,was utilized to select the reliable model.Using the selected IBS-D rat model as the research object,3 different doses of Wenshen Jianpi formula as interventions,to evaluate the curative effect.Observing the expression of CRF and its receptors in the colon and hypothalamus,to evaluate the interventional effect of Wenshen Jianpi formula.Results1.Literature reviewIBS has become a worldwide disease,with the prevalence ranging from 5.8 to 17.5%.The pathogenesis is complex and various,and the definition of "functional gastrointestinal disease" will be challenged as the research goes deep.The treatments are mainly symptomatic,including antidiarrheals,antispasmodics,antidepressants,probiotics and psychological treatments and so on.TCM through the overall concept,divide IBS-D into different syndromes,such as stagnation of liver qi and spleen deficiency,spleen-kidney yang deficiency.Using syndrome differentiation and treatment combining with the special external therapies,like acupuncture,acupoint application,TCM achieved a satisfactory efficacy.2.Efficacy of TCM for IBS-D:a meta-analysisA total of 17 trials involving 1667 patients were included.Meta-analysis demonstrated superior global symptom improvement(RR=1.62;95%CI 1.31,2.00;P<0.00001),abdominal pain improvement(RRF=1.95;95%CI 1.61,2.35;P<0.00001),diarrhea improvement(RR=1.87;95%CI 1.60,2.20;P<0.00001),pain threshold assessment(MD=;54.53;95%CI 38.76,70.30;P<0.00001)and lower IBS Symptom Severity Score(SMD=-1.05;95%CI-1.65,-0.45;P=0.0006),when compared with placebo.While for defecation threshold assessment,quality of life and adverse events,no differences were found between treatment groups and controlled groups.3.Establishment of a diarrhea model with spleen-kidney yang deficiency syndromeAfter 4-week's gavage:? All the senna leaf decoctions could induce diarrhea and dose-dependently slow body weight growth,reduce food consumption,and increase water intake,stool Bristol score,and defecation frequency.? The middle and high dose senna leaf could reduce rectal temperature,weight-loaded forced swimming time,forelimb grip strength,serum ACTH and D-xylose contents.? The serum cortisone and 24 h urine 17-OHCS were significantly reduced in high dose group only.4.Establishment of an IBS-D model with spleen-kidney yang deficiency syndromeSenna leaf gavage combined with chronic stress,MS,WAS or CRD respectively,could increase the frequency of diarrhea,Bristol score,water intake,slow weight gain,reduced food consumption,rectal temperature,weight-loaded forced swimming time,forelimb grip strength,and the contents of 17-OHCS in urine.However,only Senna leaf gavage combined with MS or WAS could induce visceral hypersensitivity and up regulate CRF expression in colon tissue.5.Mechanism study of Wenshen Jianpi fomula on CRF signal pathway of IBS-D rats with yang deficiency of spleen and kidneyAll the 3 doses could dose-dependently increase the weight of rats.The high and middle dose of Wenshen Jianpi fomula could reduce the number of fecal defecation and water intake,increase the food consumption of the rats.Only the high dose could improve the visceral sensitivity.So the high dose of Wenshen Jianpi fomula had the best efficacy.After the model building,the IBS-D rats showed:?The expressions of CRF and CRF receptor-1 were up-regulated,while the CRF receptor-2 was down-regulated in the colon tissues.?The expressions of CRF mRNA and CRF receptor-1 mRNA were up-regulated,while the CRF receptor-2 mRNA was down-regulated in the colon tissues.?The expressions of CRF and CRF receptor-1 were up-regulated,while the CRF receptor-2 was down-regulated in the hypothalamus tissues.After the intervention by Wenshen Jianpi fomula:?All the 3 doses could down-regulate expressions of CRF and CRF receptor-1,and up-regulate the expression of CRF receptor-2 in the colon tissues.?All the 3 doses could down-regulate expressions of CRF mRNA in the colon tissues.Both high and middle dose could dose dependently down-regulate CRF receptor-1 and up-regulate CRF receptor-2 in the colon.?Only the high dose could down-regulate the repressions of CRF and CRF receptor-1 in hypothalamus.Both high and middle dose could up-regulate the expression of CRF receptor-2 in hypothalamus.Conclusion1.Literature review and meta-analysis showed that TCM had a special view on IBS-D.It is an effective and safe treatment to improve the global symptoms,abdominal pain,diarrhea and visceral hypersensitivity for IBS-D patient.2.This study was guided by the TCM theory of "the bitter can chronic diarrhea could injury the yang",using senna leaf gavage to build the rat model of diarrhea with spleen-kidney yang deficiency syndrome.On this basis,MS and WAS were combined with senna leaf gavage respectively to establish the IBS-D model with spleen-kidney yang deficiency syndrome.In addition,the four-dimensional evaluation system of the model was established preliminarily.3.The expressions of CRF and CRF receptor-1 were up-regulated and the expressions of CRF receptor-2 were down-regulated in both colon and hypothalamus.The unbalance status of CRF receptor-1 and receptor-2 was the cause of visceral hypersensitivity and intestinal dysfunction.The underlying mechanism of Wenshen Jianpi fomula in treating IBS-D may through the adjustment on this unbalanced status. |
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