| BackgroundIrritable bowel syndrome(IBS)is one of the most common functional gastrointestinal disorders(FGIDs)with a global incidence of 9.8%～2.8%.Unfortunately,making the accurate diagnosis of IBS still remains difficult because it is clinically heterogeneous,pathogenesis hypothesis remains unproved,various diseases share the same clinical manifestations and it is a multi-factor process.Reasons of patients’ visiting hospitals include abdominal discomfort,change in bowel habit and fecal Characters.However,the persistence of IBS remedy is poor during the long-term medication,so patients with persistent symptom should accept the repeated medication,which worse the quality of patients’ physical and psychological well-being.According to Rome II criteria,patients diagnosed with IBS can be classified into four subtypes:IBS-constipation(IBS-C),IBS-diarrhea(IBS-D),IBS-mixed type(IBS-M)and IBS-unclassified(IBS-U).In china,the major IBS subtype is IBS-D.Chinese medicine has certain advantages in the treatment of IBS-D.According to the theory of traditional Chinese clinic,the causes of IBS mainly include sentimental injury,contaminated diat,and bodily weakness,etc.Indeed,the long process,repeated syndromes and lasting diarrhea impair Kidney which may lead to Spleen and Kidney Yang deficiency,make physicians adopt the therapy of warming the Kidney and Strengthening the Spleen.And the results of meta analysis of this methodology in overall efficacy have been proved positive,with higher safety and lower side effect.Prescription for Warming the Kidney and Strengthening the Spleen,which is derived from Sishen decoction,and believe that the prescription has a good effect in the treatment of Spleen and Kidney Yang deficiency syndrome IBS-D,and it can significantly relieve anxiety and depression,improve abdominal pain and diarrhea symptoms.The therapeutic mechanism of prescription for warming the Kidney and Strengthening the Spleen may be related to brain gut interaction.Proteomics is a technology from systematic approach to understanding diseases,which helps to exploit the characteristics of disease and the law of treatment according to the expression of protein.At the same time,the research on the proteomic mechanism of IBS-D in the Spleen and Kidney Yang deficiency syndrome is still blank.ObjectiveBased on brain-gut interaction,to evaluate the effect of prescription for Warming the Kidney and Strengthening the Spleen in IBS-D rats with Spleen and Kidney Yang deficiency syndrome through the TMT proteomics experiments.Method1.By applying the literature analysis,we summarize the view of IBS therapy,included pathogenesis hypothesis and diagnosis theory been developed by both western and traditional chinse clinical scientists,as well as the progress of proteomics in this very field.2.Evaluate the clinical efficacy and safety of prescription for Warming the Kidney and Strengthening the Spleen on IBS-D through Meta-Analysis.3.Multidimensional evaluation of syndromes,behavior,diarrhea symptoms,visceral sensitivity and intestinal motility in IBS-D rats with spleen and kidney yang deficiency syndrome.4.Analyze the change of key protein in colon and hippocampus of IBS-D rat model with spleen and kidney yang deficiency syndrome after treated by prescription for Warming the Kidney and Strengthening spleen,as well as the mechanism of brain-gut interaction through the TMT proteomics experiments.Results1.Summarization of western and traditional Chinese medical researchThe development and progress of IBS can be regarded as a multi-factor process,during which brain-gut interaction may play a key role.The Modern Approach to the treatment of IBS includes drug therapy,healthy diet,and psychotherapy.However,all these methods fail to alleviate clinical symptom and recurrence.Furthermore,the research on the proteomics of IBS-D,the most common subtype,is still a blank.According to the overall and dynamic concept of Traditional Chinese Medicine Treatments,Spleen and Kidney Yang deficiency syndrome can be described as the main syndrome and it is usually treated with Warming Kidney and Strengthening Spleen.The curative effect is satisfactory,but the mechanism of traditional Chinese medicine is not clears and worth further study.2.The Meta-analysis of therapy of warming kidney and spleen of IBS-DUp to January 20th,2017,we selected 10 Randomized Controlled Trials(RCTs)about therapies of Warming Kidney and Strengthening Spleen of IBS-D,which have been published on the papers downloaded from various Science and Technology Journal Database,such as Cochrane Library,Pub Med,Embase,CNKI,CBM,Wanfang and VIP database.According to analysis of main outcome measures,we find out therapy with Warming Kidney and Strengthening Spleen show some certain advantages comparing with western medicine:the improvement of abdominal pain and diarrhoea in IBS Patients treated with western medicince shows no significant difference with patients with chinisese medicine;when it comes to the evaluation of traditional Chinese medicine syndrome,only 4 trials has this kind of report,so the results can not lead to a statistical difference(P=0.05);though Chinese medicine may have lower side effect and recurrence rate by comparing with western modern therapy,we still hesitate to say that because of the small sample sizes.However,though the pre-experimental results of our lab,we still choose to make a point that therapy with Warming Kidney and Strengthening Spleen may act as a positive medication during the therapy of IBS.3.Therapeutic Evaluation of IBS-D rats with syndrome of Spleen and Kidney Yang deficiencyBased on the basis of the preliminary study to evaluate the curative effect of therapy with Warming Kidney and Strengthening Spleen in the treatment of Spleen and Kidney Yang deficiency IBS-D rats and found the moderate(1.55g/kg/d)and high(3.10g/kg/d)dose showed a positive effect on diarrhea,visceral sensitivity and intestinal motility,which can achieve a similar effect with Pinaverium bromide.Meanwhile,the moderate dose has a particular advantage on the improvement of the animals’ behavior.4.Proteomics Analysis of brain-gut interaction in IBS animal models with syndrome of Spleen Yang and Kidney deficiency and treated by warming the Kidney and Strengthening the SpleenWe filter the differentially expressed proteins in the colon tissue of IBS-D rats with Spleen and Kidney Yang deficiency syndrome and normal group.The changes of protein expression in different treatment groups were also be analyzed,and 3 major proteins(Wbp11,Gsk3b and Tgm2)and 3 minor proteins(Cox6b1,acss2 and mrp112)were determined.Furthermore,changes in multiple signaling pathways involved in Metabolic pathways、Oxidative phosphorylation、Ribosome、Alzheimer’s disease、Huntington’s disease and Spliceosome,Which implied that The pathogenesis of IBS is related to the intestinal environment,dynamic change,inflammation,immune and neural regulation,and the Warming Kidney and Strengthening Spleen prescription may play an important role in maintaining the stability of the nervous system after regress the protein expression.By analyzing the differentially expressed proteins in tissues of hippocampus in IBS-D rats with Spleen and Kidney Yang deficiency and normal rats,and the protein expression changes of different treatment groups,we identified 1 main proteins(Slc4a7)and 3 minor proteins(Cacnb2,Rbp4 and Rgs14).We found that Slc4a7 in the hippocampus and Tgm2 in colon tissue were related in the pathogenesis of IBS-D,which was also involved in neurotransmitter glutamate and glutamine.These two factors both increased after the treatment,so we speculated that the two proteins may induced visceral hypersensitivity,intestinal immunity and nerve stability changes in the pathogenesis of IBS-D,and an indirect correlation may exist between them.Cacnb2,Rbp4 and Rgs14 may play a dual role in the central nervous system and intestine,and may be related to the mechanism of IBS-D brain gut interaction.The the Warming Kidney and Strengthening Spleen prescription may regulate the expression of these 3 proteins through the intervening hippocampal protein expression in these proteins,and thus play a role in the treatment of stress change and visceral sensitivity,nerve homeostasis regulation,intestinal motility and immunity.Conclusion1.Literature review and Meta analysis showed that there were similarities and differences between Chinese and Western medicine in understanding of IBS-D and the effect of warming kidney and strengthening spleen on IBS-D is well.2.The moderate(1.55g/kg/d)and high(3.10g/kg/d)dose of therapy with Warming Kidney and Strengthening Spleen showed a positive effect on diarrhea,visceral sensitivity and intestinal motility.Meanwhile,the moderate dose has a particular advantage on the improvement of the animals’ behavior.3.Proteomic research shows that protein expression in both colon and hippocampus IBS-D rats with Spleen and Kidney Yang deficiency may have related with intestinal mucosal flora,dynamic,inflammation,immune and nervous regulation;the expression of Slc4a7in the hippocampus and Tgm2 in the colon may lead to an abnormal brain gut interaction in IBS-D rats with Spleen and Kidney Yang deficiency;the therapy with Warming Kidney and Strengthening Spleen influenced the regulation of expression of proteins in hippocampus and colon,and may play a therapeutic effect by reducing the stress changes and visceral sensitivity,maintaining neural homeostasis,and regulation of intestinal immune power,etc. |
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